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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation V600E

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 266 clinical trials

Clinical Trials


1 A Phase I, Open Label, Multi-center Study to Assess the Efficacy and Safety of JMT101 in Patients With Advanced Solid Tumor.

This study is a Phase I, open label, multi-center study of to evaluate the safety and efficacy of JMT101 in patients with advanced solid tumor.

NCT04689100
Conditions
  1. Advanced Solid Tumor
Interventions
  1. Drug: JMT101
  2. Drug: JMT101
MeSH:Neoplasms
HPO:Neoplasm

The content of RAS(reticular activating system), EGFR(epidermal growth factor receptor), BRAF(B-Raf proto-oncogene) gene will be detected.. Inclusion Criteria: - Monotherapy: Pathologically or cytologically confirmed, advanced solid tumor, harboring RAS wild type; Combined with chemotherapy: Pathologically or cytologically confirmed, locally advanced /metastatic colorectal cancer, harboring RAS and BRAF V600E wild type. --- V600E ---

- Receiving an investigational product in another clinical study within 4 weeks; - History of serious systemic diseases; - Pregnancy or lactating wo Inclusion Criteria: - Monotherapy: Pathologically or cytologically confirmed, advanced solid tumor, harboring RAS wild type; Combined with chemotherapy: Pathologically or cytologically confirmed, locally advanced /metastatic colorectal cancer, harboring RAS and BRAF V600E wild type. --- V600E ---

Primary Outcomes

Measure: Incidence of adverse events (defined by the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE V4.03)).

Time: From enrollment until 30 days after the last dose

Measure: Number of Subjects Experiencing DLTs (Dose Limiting Toxicity).

Time: Time from the first dose of study drug up to 4 weeks

Measure: Maximum Tolerated Dose (MTD)

Time: 28 days

Secondary Outcomes

Measure: Objective Response Rate (ORR)

Time: From first dose to disease progression or end of study, an average of 1 year

Measure: Disease control rate (DCR).

Time: From first dose to disease progression or end of study, an average of 1 year

Measure: Progression free survival (PFS).

Time: From first dose to disease progression or end of study, an average of 1 year

Measure: Overall survival (OS).

Time: From first dose to death or end of study, an average of 1 year

Measure: Area under the concentration curve from time 0 to the concentration at last time point (AUC0-last) of JMT101.

Time: From enrollment until 30 days after the last dose

Measure: Maximum measured plasma concentration (Cmax) of JMT101.

Time: From enrollment until 30 days after the last dose

Measure: Time to maximum plasma concentration (Tmax) of JMT101.

Time: From enrollment until 30 days after the last dose

Measure: Half-life (T1/2) of JMT101.

Time: From enrollment until 30 days after the last dose

Description: Blood samples will be collected from subjects post treatment for assessment to detect the presence of anti-drug antibodies(ADA) and neutralizing antibodies by electrochemical luminescence(ECL).

Measure: Immunogenicity profile of JMT101.

Time: From enrollment until 30 days after the last dose

Description: The content of RAS(reticular activating system), EGFR(epidermal growth factor receptor), BRAF(B-Raf proto-oncogene) gene will be detected.

Measure: Potential biomarkers detected in plasma or tumor issue DNA.

Time: From enrollment up to disease progression, an average of 1 year

2 A Phase 1a/1b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PY159 as a Single Agent and In Combination With Pembrolizumab in Subjects With Advanced Solid Tumors

A Phase 1a/1b Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PY159 as a Single Agent and In Combination with Pembrolizumab in Subjects with Advanced Solid Tumors

NCT04682431
Conditions
  1. Advanced Solid Tumor
Interventions
  1. Drug: PY159 Single agent dose level 1
  2. Drug: PY159 Single agent dose level 2
  3. Drug: PY159 Single agent dose level 3
  4. Drug: PY159 Single agent dose level 4
  5. Drug: PY159 Single agent dose level 5
  6. Drug: PY159 Single agent dose level 6
  7. Drug: PY159 Single agent dose level 7
  8. Drug: PY159/Pembrolizumab Combination dose level 1
  9. Drug: PY159/Pembrolizumab Combination dose level 2
  10. Drug: PY159/Pembrolizumab Combination dose level 3
  11. Drug: PY159/Pembrolizumab Combination dose level 4
  12. Drug: PY159 Single agent dose expansion cohort 1
  13. Drug: PY159 Single agent dose expansion cohort 2
  14. Drug: PY159/Pembrolizumab Combination dose expansion cohort 1
  15. Drug: PY159/Pembrolizumab Combination dose expansion cohort 2
  16. Drug: PY159/Pembrolizumab Combination dose expansion cohort 3
  17. Drug: PY159/Pembrolizumab Combination dose expansion cohort 4
MeSH:Neoplasms
HPO:Neoplasm

drugs targeting EGFR, EGFR, ALK, ROS-1, NTRK, MET, RET and BRAF V600E, Her2neu). --- V600E ---

Primary Outcomes

Description: Adverse Events will be summarized by MedDRA system organ class and preferred term. Separate tabulations will be produced for all treatment emergent AEs, treatment related AEs, Serious Adverse Events (SAEs), discontinuations due to AEs, and AEs of at least NCI CTCAE grade 3 severity.

Measure: Incidence of Adverse Events (AE)

Time: 12 months

Description: Measure PY159 concentration at the end of infusion (CEOI) after the first dose.

Measure: Measure PY159 concentration at the end of infusion (CEOI)

Time: 12 months

Description: Measure PY159 maximum concentration (Cmax) at various time points during Cycle 1. All subjects who received at least 1 dose of PY159 and have at least 1 measured concentration at a scheduled PK time point after start of dosing.

Measure: Measure PY159 maximum concentration (Cmax)

Time: 12 months

Description: Measure PY159 concentration at the trough level (Ctrough). All subjects who received at least 1 dose of PY159 and have at least 1 measured concentration at a scheduled PK time point after start of dosing.

Measure: Measure PY159 concentration at the trough level (Ctrough)

Time: 12 months

Description: Determining PY159 time to maximum concentration (Tmax) during Cycle 1.

Measure: Determining PY159 time to maximum concentration (Tmax)

Time: 12 months

Description: Measure PY159 Area under the curve (AUC)0-t. All subjects who received at least 1 dose of PY159 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY159 Area under the curve (AUC)0-t

Time: 12 months

Description: Measure PY159 half-life (T1/2). All subjects who received at least 1 dose of PY159 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY159 half-life (T1/2)

Time: 12 months

Description: Measure PY159 Clearance (CL). All subjects who received at least 1 dose of PY159 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY159 Clearance (CL)

Time: 12 months

Description: Measure PY159 Volume at Steady State (Vss). All subjects who received at least 1 dose of PY159 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY159 Volume at Steady State (Vss)

Time: 12 months

Description: To evaluate the incidence of anti-drug antibody (ADA) formation to PY159

Measure: Incidence of Anti-Drug Antibody (ADA) formation to PY159

Time: 12 months

Secondary Outcomes

Description: The incidents of ORR is defined as either a complete or partial response per RECIST. Subjects with no baseline data will be considered no responders. ORR will be summarized by dose, tumor type, and overall. ORR will be summarized descriptively.

Measure: Objective response rate (ORR)

Time: 36 months

Description: DCR will be measure per resists 1.1 criteria. DCR will be summarized descriptively.

Measure: Deceased control rate (DCR)

Time: 36 months

Description: DOR will be calculated to determine durability. DOR will be measured from the time by which the criteria for CR or PR-whichever is recorded first-are met until the first date by which recurrent or progressive disease is objectively documented. DOR will be assessed using KAPLAN-MEIER methods.

Measure: Duration of response (DOR)

Time: 36 months

Description: PFS will be measure from entry onto the study until disease progression or death from any cause. PFS will be assessed using KAPLAN-MEIER methods.

Measure: Progress free survival (PFS)

Time: 36 months

Description: The duration of overall survival (OS) will be measured from the time of first study drug administration until the date of death. OS will be assessed using KAPLAN-MEIER methods.

Measure: Overall survival (OS)

Time: 36 months

3 Managed Access Program (MAP) to Provide Access to Trametinib and Dabrafenib Combination Therapy in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection

The purpose of this Treatment Plan is to allow access to trametinib and dabrafenib for eligible high-risk BRAF mutation-positive patients in the adjuvant treatment of melanoma after surgical resection. The patient's Treating Physician should follow the suggested treatment guidelines and comply with all local health authority regulations.

NCT04544202
Conditions
  1. Melanoma
  2. Adjuvant
Interventions
  1. Drug: Dabrafenib and Trametinib
  2. Drug: Dabrafenib
  3. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

2. Has the following diagnosis: Completely resected (R0) histologically confirmed high-risk (stage III) cutaneous melanoma with confirmed BRAF V600E/K activating mutation. --- V600E ---


4 Phase II Study of PDR001 in Combination With MAPK Pathway Inhibitors in Patients With Radioiodine-Refractory Thyroid Cancer

The purpose of this study is to find out whether a drug called PDR001, combined with either trametinib or dabrafenib, is a safe and effective treatment for thyroid cancer.

NCT04544111
Conditions
  1. Thyroid Cancer
  2. Thyroid Cancer, Follicular
  3. Papillary Thyroid Cancer
  4. Follicular Thyroid Cancer
  5. Hurthle Cell Tumor
  6. Poorly Differentiated Thyroid Gland Carcinoma
  7. Hurthle Cell Thyroid Neoplasia
Interventions
  1. Drug: Trametinib
  2. Drug: Dabrafenib
  3. Drug: PDR001
MeSH:Thyroid Neoplasms Thyroid Cancer, Papillary Adenocarcinoma, Follicular Adenoma, Oxyphilic Thyroid Diseases
HPO:Abnormality of the thyroid gland Follicular thyroid carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

V600E, V600K, V600D). --- V600E ---

Primary Outcomes

Description: The primary endpoint is to determine the overall response rate (ORR=CR+PR) as documented by RECIST v1.1 criteria within each cohort.

Measure: Overall response rate

Time: 1 year

5 Impact of Melanoma Adjuvant Treatment With Tafinlar® + Mekinist® (Dabrafenib + Trametinib) on Patients Quality of Life (QoL) and Clinical Outcomes in Portuguese Real World Setting

The primary objective for this non-interventional study is to assess the quality of life of melanoma patients under adjuvant treatment with dabrafenib and trametinib in real world setting in Portugal through disease specific FACT-M questionnaire and generic EQ-5D-3L questionnaire.The secondary study objectives are to assess the usage of adjuvant dabrafenib and trametinib in clinical practice and to evaluate clinical outcomes in patients that start adjuvant treatment with dabrafenib and trametinib. In addition, this study aims to explore if treatment discontinuation affects clinical outcomes in real-world practice.

NCT04547946
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: dabrafenib + trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Inclusion Criteria: - Patients with complete surgical resection of histologically confirmed AJCC (8th edition) clinical stage III (IIIA, IIIB, IIIC, IIID) melanoma, in whom a decision for adjuvant treatment with dabrafenib and trametinib has been made before entering the study - V600E/K mutation-positive cutaneous melanoma - Adjuvant treatment with combination therapy of Dabrafenib (Tafinlar®) and Trametinib (Mekinist®) as indicated in the SmPC and by prescription, that has been started before inclusion of the patient into the study; - ≥ 18 years of age - Written informed consent signed. --- V600E ---

Primary Outcomes

Description: Health-related quality of life in melanoma patients defined as the mean difference in FACT-M (Functional Assessment of Cancer Therapy - Melanoma ) score. FACT-M is a specific version of FACT questionnaire validated for patients with any stage of melanoma and includes items related to physical, functional, social and emotional well-being, and specific concerns of melanoma patients and melanoma patients undergoing surgery. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172. Higher scores represent a better quality of life.

Measure: Change from baseline in FACT-M score

Time: Baseline, months 3-4, months 6-8, months 9-12, months 12, months 15-16

Description: Health-related quality of life in melanoma patients defined as the mean difference in EQ-5D-3L score. EQ-5D-3L is a descriptive questionnaire comprising five dimensions regarding mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has three response levels of severity: no problems, some problems, extreme problems. The respondent is asked to indicate his/her health state by checking the box next to the most appropriate response level of each of the five dimensions.

Measure: Change from baseline in EQ-5D-3L score

Time: Baseline, months 3-4, months 6-8, months 9-12, months 12, months 15-16

Secondary Outcomes

Description: Total duration of treatment defined as median time on adjuvant treatment (from start to end of treatment/permanent treatment discontinuation).

Measure: Total duration of treatment

Time: months 12

Description: Proportion of patients on treatment in each visit

Measure: Proportion of patients on treatment in each visit

Time: Baseline, months 3-4, months 6-8, months 9-12, month 12

Description: Rate of permanent study drug discontinuation due to any reason.

Measure: Rate of permanent study drug discontinuation due to any reason

Time: month 12

Description: Rate of permanent drug discontinuation due to pirexia over the course of adjuvant treatment.

Measure: Rate of permanent drug discontinuation due to pirexia

Time: month 12

Description: Rate of permanent drug discontinuation due to AEs over the course of adjuvant treatment

Measure: Rate of permanent drug discontinuation due to AEs

Time: month 12

Description: Reason of treatment discontinuation (death, relapse, AEs, significant change in FACT-M, significant change in EQ-5D-3L , withdrawal of consent, other).

Measure: Reason of treatment discontinuation

Time: month 12

Description: Average dose of dabrafenib and trametinib used during the treatment, including dose reductions.

Measure: Average dose of dabrafenib and trametinib used during the treatment

Time: month 12

Description: Percentage of patients with dose reduction during treatment, and in this case, reason for dose reduction

Measure: Proportion of patients who had dose reduction

Time: month 12

Description: RFS (Relapse Free Survival)

Measure: Relapse Free Survival rate

Time: month 12

Description: DMFS (distant-metastasis-free survival) rate

Measure: distant-metastasis-free survival rate

Time: month 12

Description: OS (Overall Survival) rate

Measure: Overall Survival rate

Time: month 12

6 Evaluating BRAF Mutations as Predictors of Efficacy in Cetuximab-Treated Colorectal Cancer Patients: A Retrospective Study of Tissues From CALGB / SWOG

RATIONALE: Studying samples of tissue in the laboratory from patients who received cetuximab may help doctors understand and predict how well patients will respond to treatment. PURPOSE: This research study is studying biomarkers in predicting response to cetuximab in patients with advanced colorectal cancer.

NCT01243372
Conditions
  1. Colorectal Cancer
Interventions
  1. Genetic: mutation analysis
  2. Other: laboratory biomarker analysis
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

DISEASE CHARACTERISTICS: - Participation in CALGB-C80405 - Have KRAS WT or KRAS mut tumor - Randomized to treatment with either bevacizumab or cetuximab alone - Patients randomized to the combination therapy are not eligible - Available specimens at the PCO for BRAF mutation detection - Patient consent for use of samples DISEASE CHARACTERISTICS: - Participation in CALGB-C80405 - Have KRAS WT or KRAS mut tumor - Randomized to treatment with either bevacizumab or cetuximab alone - Patients randomized to the combination therapy are not eligible - Available specimens at the PCO for BRAF mutation detection - Patient consent for use of samples Colorectal Cancer Colorectal Neoplasms OBJECTIVES: Primary - To determine, among patients with advanced CRC, whether the effect of treatment (cetuximab vs bevacizumab) on progression-free survival (PFS) depends on tumor BRAF V600E mutational status. --- V600E ---

Secondary - To study the relationships between tumor BRAF V600E mutational status, OS, and tumor response. --- V600E ---

Previously collected formalin-fixed and paraffin-embedded baseline tumor samples are analyzed for BRAF V600E mutation. --- V600E ---

Primary Outcomes

Measure: Progression-free survival as measured by RECIST

Time: Up to 36 months

Secondary Outcomes

Measure: overall survival

Time: Up to 36 months

Measure: tumor response as measured by RECIST

Time: Up to 36 months

7 A Phase III Randomized, Open-label Study Comparing GSK1120212 to Chemotherapy in Subjects With Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma

This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.

NCT01245062
Conditions
  1. Melanoma
Interventions
  1. Drug: GSK1120212
  2. Drug: Chemotherapy
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Phase III Randomized, Open-label Study Comparing GSK1120212 to Chemotherapy in Subjects With Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma. --- V600E ---

GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. --- V600E ---

Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review. --- V600E ---

Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.. Progression-free Survival in All Participants. --- V600E ---

Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered.. PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator. --- V600E ---

PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.. PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator. --- V600E ---

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.. Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases. --- V600E ---

NA indicates data was not available.. Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review. --- V600E ---

Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.. Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator. --- V600E ---

Only participants who received at least one dose of Trametinib were included in this population.. Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review. --- V600E ---

NA indicates data was not available.. DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review. --- V600E ---

PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.. Inclusion Criteria: - ≥18 years of age - Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory - Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. --- V600E ---

- Intraocular pressure > 21 mm Hg as measured by tonography Inclusion Criteria: - ≥18 years of age - Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory - Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. --- V600E ---

Primary Outcomes

Description: Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.

Measure: Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Secondary Outcomes

Description: PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered.

Measure: Progression-free Survival in All Participants

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Measure: PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Measure: PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Measure: Overall Survival in All Participants

Time: Day 1 until death due to any cause (average of 20.3 months)

Description: Overall survival was defined as the time from the date of randomization to the date of death due to any cause. NA indicates data was not available.

Measure: Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases

Time: Day 1 until death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

Measure: Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

Measure: Number of Participants With OR as Assessed by the Investigator and Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

Measure: Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

Measure: Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1. Cross-over Population included the subset of participants who were randomized to CT and who elected to cross-over to Trametinib following disease progression on CT. Only participants who received at least one dose of Trametinib were included in this population.

Measure: Number of Participants With OR Following Cross-over to Trametinib

Time: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the investigator-assessed (INVA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the independently-assessed (INDA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INVA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INDA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all extra nodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR data were summarized per RECIST, Version 1.1Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator

Time: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)

Description: PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Measure: PFS Following Cross-over to Trametinib as Assessed by the Investigator

Time: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)

8 A Phase 1 Study of a RAF Inhibitor (BMS-908662) Administered in Combination With Immunotherapy (Ipilimumab) in Subjects With Unresectable Stage III or Stage IV Melanoma

The purpose of the study is to identify a safe and tolerable dose of BMS-908662 in combination with ipilimumab; and then to evaluate the anti-tumor response to BMS-908662 when administered in combination with ipilimumab.

NCT01245556
Conditions
  1. Melanoma
Interventions
  1. Drug: BMS-908662
  2. Drug: BMS-908662
  3. Drug: Ipilimumab
  4. Drug: Ipilimumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Melanoma Melanoma null --- V600E ---

Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Measure: Toxicity will be evaluated according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 3

Time: Assessments approximately every 3 weeks throughout the duration of the trial

Secondary Outcomes

Measure: Efficacy as determined by estimates of objective response rates and response duration

Time: Efficacy measured every 6 weeks until week 48, then every 12 weeks

Measure: PK for BMS-908662 as determined by minimum and maximum observed concentrations, time of maximum observed concentration, area under the concentration curve for one dosing interval and the accumulation index

Time: PK measured during first 4 weeks on study

Measure: PD will be assessed by evaluating markers of RAS/RAF pathway activity

Time: PD assessed during the first 4 weeks on study

9 A SINGLE ARM, OPEN LABEL, EXPANDED ACCESS STUDY OF RG7204 IN PREVIOUSLY TREATED PATIENTS WITH METASTATIC MELANOMA

This is an open-label, non-comparative, multicenter, expanded access study of RO5185426 in patients who have received prior systemic therapy for metastatic melanoma and who have no other satisfactory treatment options.

NCT01248936
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: RO5185426
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Participants were assessed for best overall response by investigator as per RECIST v1.1.. Inclusion Criteria: - Histologically confirmed metastatic melanoma with documented BRAF V600E mutation, determined by the cobas BRAF V600 mutation test - Patients with either measurable or non-measurable disease - Adequate recovery from most recent systemic or local treatment for metastatic melanoma - Adequate organ function - For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of RO5185426 - For men with female partners of childbearing potential, agreement to use a latex condom, and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of RO5185426 - Negative serum or urine pregnancy test within 7 days of commencement of treatment in premenopausal women. --- V600E ---

Women who are either surgically sterile or have been post-menopausal for at least 1 year are eligible to participate in this study - Agreement not to donate blood or blood products during the study and for at least 6 months after discontinuation of RO5185426; for male patients, agreement not to donate sperm during the study and for at least 6 months after discontinuation of RO5185426 Exclusion Criteria: - Pregnant or breast-feeding - Concurrent anti-tumor therapy - Uncontrolled medical illness - History of congenital prolonged QT syndrome or patients with a mean QTc interval greater than 470 milliseconds at baseline, or ongoing grade 2 or greater cardiac arrhythmia Inclusion Criteria: - Histologically confirmed metastatic melanoma with documented BRAF V600E mutation, determined by the cobas BRAF V600 mutation test - Patients with either measurable or non-measurable disease - Adequate recovery from most recent systemic or local treatment for metastatic melanoma - Adequate organ function - For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of RO5185426 - For men with female partners of childbearing potential, agreement to use a latex condom, and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of RO5185426 - Negative serum or urine pregnancy test within 7 days of commencement of treatment in premenopausal women. --- V600E ---

Primary Outcomes

Description: An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs will be graded according to the 'National Cancer Institute Common Terminology Criteria for Adverse Events' (NCI CTCAE, v4.0). However Laboratory data will be summarized by grade using the NCI CTCAE, v4.0 toxicity grade.

Measure: Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation

Time: Up to 1 year

Description: Serious Adverse Event (SAEs) is defined as those events that were fatal or immediately life-threatening, and those events that resulted in hospitalization; prolonged an existing hospitalization; resulted in disability; or was a congenital anomaly. Number of participants who died and the cause of death are also recorded.

Measure: Number of Participants With Any Serious Adverse Event, Death and Cause of Death

Time: Up to 1 year

Secondary Outcomes

Description: The best overall response (unconfirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed. Participants were assessed for best overall response by investigator as per 'Response Evaluation Criteria in Solid Tumors' (RECIST v1.1).

Measure: Number of Participants With Best Overall Response (Unconfirmed)

Time: Up to 1 year

Description: The best overall response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair >50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. This endpoint was tumor response category according to investigator assessment per RECIST v1.1 for efficacy assessment. The 'n' is number of participants with ECOG performance status in each criteria.

Measure: Number of Participants With Best Overall Response (Unconfirmed) by ECOG Performance

Time: Up to 1 year

Description: The best overall response (confirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was confirmed. Participants were assessed for best overall response by investigator as per RECIST v1.1.

Measure: Number of Participants With Best Overall Response (Confirmed)

Time: Up to 1 year

Description: The best overall response recorded from the start of the treatment until disease progression/recurrence which was confirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair >50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. Participants were assessed for best overall response by investigator as per RECIST v1.1. The 'n' is number of participants with ECOG performance status in each criteria.

Measure: Number of Participants With Best Overall Response (Confirmed) by ECOG Performance

Time: Up to 1 year

Description: Mean time to Complete Response (CR)/Partial Response(PR) (confirmed or unconfirmed was assessed). Participants were assessed for best overall response by investigator as per RECIST v1.1.

Measure: Mean Time to Complete Response/Partial Response

Time: Up to 1 year

10 A Phase II, Randomised, Open Label Study of Neoadjuvant Dabrafenib, Trametinib and / or Pembrolizumab in BRAF V600 Mutant Resectable Stage IIIB/C Melanoma

This study aims to determine which of 3 drug combinations best reduces the size of tumour prior to surgery for advanced melanoma and prevents the recurrence of melanoma after surgery.

NCT02858921
Conditions
  1. Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
  3. Drug: Pembrolizumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A positive V600E immunohistochemistry stain at study entry should be formally quantified with a local molecular test following study entry (e.g. --- V600E ---

Allocation of treatment will be concealed prior to randomisation which will be performed via a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF V600E mutation (i.e. --- V600E ---

Allocation of treatment will be concealed prior to randomisation which will be performed via a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF V600E mutation (i.e. --- V600E --- --- V600E ---

Primary Outcomes

Description: Proportion of patients with complete absence of residual melanoma cells in the planned resected tumour site(s) at week 6 surgery.

Measure: Pathological response rate

Time: From baseline to 6 weeks

Secondary Outcomes

Description: Proportion of patients with complete and partial responses at 6 weeks compared to baseline per RECIST guidelines for each treatment arm.

Measure: Objective clinical (RECIST) response rate

Time: From baseline to 6 weeks

Description: The amount of time that patients are disease free from the time of surgery at 6 weeks from study entry

Measure: Relapse free survival

Time: 5 years

Description: The proportion of patients who are alive from the time of study entry

Measure: Overall survival

Time: 5 years

Description: The number of patients (and the number of episodes) who develop a post operative infection of the surgical wound requiring intravenous antibiotics and/or wound drainage

Measure: Incidence of post operative infection

Time: 6 weeks

Description: The number of patients (and the number of episodes) who develop a seroma at the surgical site that requires any intervention and the volume of seroma drainage

Measure: Incidence of post operative seroma formation

Time: 6 weeks

Description: The number of days that a wound drain remains in situ from the time of surgery

Measure: Duration of post operative wound drainage time

Time: 6 weeks

Description: The number of patients (and the number of episodes) who have a bleed from the post operative surgical wound that requires a blood transfusion or return to theatre to stop the bleeding

Measure: Incidence of post operative bleeding requiring return to theatre or transfusion

Time: 6 weeks

Description: The change, if any, in the surgeon's assessment of 'operability' from baseline opinion (based on clinical and imaging examination) to time of operation

Measure: Comparison of surgeon's opinion of operability evaluated at baseline to time of surgery

Time: Baseline and 6 weeks

Description: The number of study treatment related adverse events of all Common Terminology Criteria for Adverse Events (CTCAE) grades from the time of starting study treatment to the time of permanent discontinuation of study treatment

Measure: Incidence of any treatment-emergent adverse events

Time: 52 weeks

Description: The effects of study treatment on the body's immune cells within the tumour tissue prior to surgery

Measure: Characterisation of the immunophenotype of tumour infiltrating cells in melanoma tissue

Time: Baseline, Week 1, Week 2, Week 6

Description: The effects of study treatment on the degree of necrosis and genetic markers in tumour tissue prior to surgery

Measure: Description of the morphological assessment of melanoma tissue

Time: Baseline, Week 1, Week 2, Week 6

Description: The effects of study treatment on the baseline function of RNA expression in tumour tissue prior to surgery

Measure: Description of the RNA expression profile of melanoma tumour

Time: Baseline, Week 1, Week 2, Week 6

Description: The effects of study treatment on the number and type of white cells in the blood

Measure: Measurement of leucocyte subpopulations in peripheral blood

Time: Baseline, Week 1, Week 2, Week 6

Description: The levels of melanoma DNA that is circulating in the blood stream and the changes during study treatment

Measure: Measurement of circulating tumour DNA

Time: Baseline, Week 1, Week 2, Week 6

Other Outcomes

Description: The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the findings from the pathological examination of completely excised tumour tissue

Measure: Concordance of metabolic response measured by pathological response

Time: 6 weeks

Description: The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

Measure: Concordance of metabolic response measured by RECIST response

Time: 52 weeks

Description: he findings from the pathological examination of completely excised tumour tissue and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

Measure: Concordance of pathological response measured by RECIST response

Time: 6 weeks

Description: The activity of recurrent melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

Measure: Concordance of metabolic response with RECIST response at relapse

Time: 52 weeks

Description: The application of two different criterion to establish the tumour burden as assessed with computed tomorgraphy and magnetic resonanse imaging

Measure: Concordance of immune related response criteria (irRC) with RECIST response

Time: Weeks 6 and 52

Description: Characterisation of the bacterial diversity and composition in stool samples at baseline, prior to surgery at week 6, week 24 and at relapse.

Measure: Correlation of the gut microbiome with RECIST response to immunotherapy.

Time: Baseline, Week 6, week 24, at relapse if this occurs within 5 years from study entry

Description: Diet plays a significant role in shaping the intestinal microbiome. Nutrition may influence the gut microbiome and response to immunotherapy.

Measure: Characterisation of self-reported dietary habits (including use of oral probiotics) and correlation with the gut microbiome.

Time: Baseline

11 A Phase 1 Study of an ERK1/2 Inhibitor (LY3214996) Administered Alone or in Combination With Other Agents in Advanced Cancer

The purpose of this study is to determine the safety of an extracellular signal regulated kinase (ERK1/2) inhibitor LY3214996 administered alone or in combination with other agents in participants with advanced cancer.

NCT02857270
Conditions
  1. Advanced Cancer
  2. Metastatic Melanoma
  3. Metastatic Non-small Cell Lung Cancer
  4. Colorectal Cancer
Interventions
  1. Drug: LY3214996
  2. Drug: Midazolam
  3. Drug: Abemaciclib
  4. Drug: Nab-paclitaxel
  5. Drug: Gemcitabine
  6. Drug: Encorafenib
  7. Drug: Cetuximab
MeSH:Carcinoma, Non-Small-Cell Lung Colorectal Neoplasms
HPO:Neoplasm of the large intestine Non-small cell lung carcinoma

- Part E: Metastatic BRAF V600E colorectal cancer. --- V600E ---

Primary Outcomes

Measure: Number of Participants with LY3214996 Dose Limiting Toxicities (DLTs)

Time: Cycle 1 (21 Days)

Secondary Outcomes

Measure: Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC) of LY3214996 Administered as Monotherapy and when Administered in Combination with Nab-Paclitaxel Plus Gemcitabine, Abemaciclib and Encorafenib Plus Cetuximab

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 28 Day Cycles)

Measure: PK: AUC of Gemcitabine when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 1 Day 15 (28 Day Cycles)

Measure: PK: AUC of Nab-Paclitaxel when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 1 Day 15 (28 Day Cycles)

Measure: PK: AUC of Abemaciclib and its Metabolites when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles)

Measure: PK: AUC of Encorafenib when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles)

Measure: PK: AUC of Cetuximab when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles)

Measure: PK: AUC of Midazolam and its 1'-Hydroxymidazolam Metabolite when Administered Alone and in Combination with LY3214996

Time: Cycle 1 Day 1 through Cycle 1 Day 16 (21 Day Cycles)

Measure: Objective Response Rate (ORR): Percentage of Participants With a Complete (CR) or Partial Response (PR)

Time: Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Estimated up to 6 Months)

Measure: Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 12 Months)

Measure: Time to First Response (TTR)

Time: Baseline to Date of CR or PR (Estimated up to 6 Months)

Measure: Progression Free Survival (PFS)

Time: Baseline to Progressive Disease or Death of Any Cause (Estimated up to 12 Months)

Measure: Disease Control Rate (DCR): Percentage of Participants who Exhibit Stable Disease (SD), CR or PR

Time: Baseline through Measured Progressive Disease (Estimated up to 6 Months)

Measure: Overall Survival (OS) (Dose Expansion Arms Only)

Time: Baseline to Date of Death from Any Cause (Estimated up to 2 Years)

12 A Randomized, Phase III Study of Fotemustine Versus the Combination of Fotemustine and Ipilimumab or the Combination of Ipilimumab and Nivolumab in Patients With Metastatic Melanoma With Brain Metastasis

This Phase 3, open-label, triple arm study aims to evaluate the overall survival (OS) of fotemustine versus the combination of ipilimumab and fotemustine or the combination of Ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis.

NCT02460068
Conditions
  1. Brain Metastases
Interventions
  1. Drug: Fotemustine
  2. Drug: Fotemustine and Ipilimumab
  3. Drug: Ipilimumab and nivolumab
MeSH:Melanoma Neoplasm Metastasis Neoplasms, Second Primary Brain Neoplasms
HPO:Brain neoplasm Cutaneous melanoma Melanoma

- Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard. --- V600E ---

- Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard. --- V600E --- --- V600E ---

Primary Outcomes

Description: To compare the efficacy of the combination of ipilimumab and fotemustine or the Combination of ipilimumab and nivolumab versus fotemustine in terms of overall survival (OS) in patients with metastatic melanoma with brain metastasis.Overall Survival (OS) is defined as the time from randomization until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.

Measure: Overall Survival (OS)

Time: 2 years

Secondary Outcomes

Description: Reporting of safety, extent of exposure, concomitant medications and discontinuation of study therapy will be based on all treated subjects; for on-study laboratory test results, all treated subjects with at least one on-study laboratory measurement available will be included in the analysis. The reporting period for safety data will be from the date of first dose received on this study to 70 days (5 half-lives) after the last dose is received. Serious adverse events are reported from the time of consent forward for all subjects.All subjects who receive at least 1 dose of study treatment will be evaluated for safety parameters

Measure: safety (adverse events)

Time: 2 years

Description: m-WHO and immune-related is the proportion of treated subjects with a ir-BOR of confirmed irCR, confirmed irPR or irSD in and outside the brain.

Measure: m-WHO and immune-related Disease Control Rate (DCR) in and outside the brain

Time: Weeks 24

Description: Immune-related progression free survival (irPFS) per irRC will be defined as the time between the date of randomization and the date of progression per irRC or death, whichever occurs first. A subject who dies without reported progression per irRC will be considered to have progressed on the date of death.

Measure: Immune-related Progression-free Survival (irPFS)

Time: 2 years

Description: Progression-free survival (PFS) per mWHO criteria will be defined as the time between the date of randomization and the date of progression per mWHO criteria or death, whichever occurs first. A subject who dies without reported progression per mWHO criteria will be considered to have progressed on the date of death.

Measure: m-WHO Progression-free Survival (irPFS)

Time: 2 years

Description: is the proportion of treated subjects with a BOR of confirmed CR or confirmed PR.

Measure: Objective Response Rate (ORR)

Time: Weeks 24

Description: is the proportion of treated subjects with a irBOR of confirmed irCR or confirmed irPR.

Measure: Immune-related Objective Response Rate (irORR)

Time: Weeks 24

Description: Time to Response (TTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of PR or CR (whichever status comes first, and provided it is subsequently confirmed).

Measure: Time to Response (TTR)

Time: Weeks 24

Description: Immune-related Time to Response (irTTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).

Measure: Immune-related Time to Response (irTTR)

Time: Weeks 24

Description: Duration of Response (DoR) is defined as the time between the date the measurement criteria are first met for an CR or PR (whichever status comes first and provided it is subsequently confirmed) and the date of PD or death (whichever comes first). For a subject who undergoes tumor resection following response but prior to disease progression, DOR will be censored at the date of the last evaluable TA on or prior to the date of resection. For subjects who remain alive and have no progressive disease as assessed by the investigator using RC, DOR will be censored on the date of last evaluable tumor assessment.

Measure: Duration of Response (DoR)

Time: 2 years

Description: Immune-related Duration of Response (irDoR) for the subjects whose irBOR is irCR or irPR will be defined as the time between the date of response of confirmed irCR or confirmed irPR (whichever occurs first) and the date of irPD or death (whichever occurs first). The onset of a confirmed irCR or irPR is determined by the initial assessment of response, not by the confirmatory assessment. Note that if an assessment of irPR occurs before confirmation of irCR, the duration of immune-related response endpoint will not begin at the time that the irBOR of irCR is shown but rather at the earlier time-point showing irPR. For subjects who remain alive and have not progressed following response, irDoR will be censored on the date of last evaluable TA.

Measure: Immune-related Duration of Response (irDoR)

Time: 2 years

Description: Brain progression-free survival (Brain-PFS) (3 and 6 months rates) is defined as the time from randomization date to the date of progression as per MRI of existing brain lesions, or of occurrence as per MRI of a new lesion located in the brain, or of death, whichever occurs first. For subjects who remain alive and have not progressed as per definition above, Brain-PFS will be censored at the day of last evaluable brain imaging assessment.

Measure: Brain progression-free survival (Brain-PFS)

Time: 6 months

13 A Phase I/II Study of Gleevec® Combined With Panitumumab (Vectibix®) in Patients Prescreened for C-kit/PDGFr Activated Pathways Using a Proteomic Based Assay

The purpose of this study is to evaluate the safety and tolerability of imatinib mesylate in combination with panitumumab for the treatment of stage IV colorectal cancer that has spread to the liver. It will also assess the whether imatinib mesylate, either alone or in combination with panitumumab, is effective in treating this type of cancer. In addition, the study will evaluate the feasibility of a predefined lab score and whether it can predict which patients will respond to treatment with imatinib mesylate.

NCT00867334
Conditions
  1. Colorectal Neoplasm
  2. Colorectal Cancer
Interventions
  1. Drug: Imatinib mesylate and panitumumab
  2. Drug: Standard-of-care treatment with panitumumab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Colorectal Neoplasm Colorectal Cancer Colorectal Neoplasms Recently, a series of clinical trial outcome reports have shown that KRAS mutations (and to a lesser extent KRAS mutations with BRAF V600E mutation) significantly negatively correlate with response to anti-epidermal growth factor (EGFR) mAbs, such as panitumumab, in metastatic colorectal cancer (mCRC) patients. --- V600E ---

Primary Outcomes

Description: Information about all adverse events, whether volunteered by the subject, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, will be collected and recorded.

Measure: Number of Patients With Adverse Events

Time: From consent up until 4 weeks after patient has stopped study participation

Secondary Outcomes

Description: Results reported as number of patients with stabilization or reduction in tumor size. Tumor response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) solid tumor response criteria, evaluated by CT.

Measure: Number of Participants With Stabilization or Reduction in Tumor Size

Time: 8 weeks after baseline

14 Phase II Trial of Hyd-sulfate AZD6244 [NSC 748727] in Patients With BRAF or NRAS Mutated Melanomas

This phase II trial is studying how well MEK inhibitor AZD6244 works in treating patients with stage III or stage IV melanoma. MEK inhibitor AZD6244 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT00866177
Conditions
  1. Recurrent Melanoma
  2. Stage III Skin Melanoma
  3. Stage IV Skin Melanoma
Interventions
  1. Other: Laboratory Biomarker Analysis
  2. Drug: Selumetinib
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Determine the response in patients with V600E or V600K BRAF-mutated or NRAS-mutated stage III or stage IV melanoma with low or high phospho-pAKT expression treated with MEK inhibitor AZD6244. --- V600E ---

Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Determine the response in patients with V600E or V600K BRAF-mutated or NRAS-mutated stage III or stage IV melanoma with low or high phospho-pAKT expression treated with MEK inhibitor AZD6244. --- V600E --- --- V600K --- --- V600E ---

Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Determine the response in patients with V600E or V600K BRAF-mutated or NRAS-mutated stage III or stage IV melanoma with low or high phospho-pAKT expression treated with MEK inhibitor AZD6244. --- V600E --- --- V600K --- --- V600E --- --- V600K --- --- V600E ---

Primary Outcomes

Description: Anti-tumor response defined as either a Complete Response, Partial Response, or Stable Disease as defined by RECIST

Measure: Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST

Time: Up to 4 weeks

15 Continuous ReAssessment With Flexible ExTension in Rare Malignancies - CRAFT: The NCT-PMO-1602 Phase II Trial

Whole-genome and transcriptome sequencing of patients with advanced solid tumors enrolled in the NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program revealed genetic alterations in a substantial proportion of patients including (i) alterations that lead to aberrant activation of BRAF, ERBB2, ALK, and the PI3K-AKT and MAPK pathways and (ii) changes that predict sensitivity to immune checkpoint inhibition, such as high tumor mutational burden and specific alterations of the PD-L1 locus. Within this seven-arm basket phase II clinical trial, we aim to investigate the efficacy of targeted-therapy plus immune checkpoint inhibition in patients with advanced tumors exhibiting one of the following genetic alterations detected within the NCT/DKTK MASTER study: (i) BRAF V600E/K, (ii)ERBB2 amplification and/or overexpression or activating ERBB2 mutation, (iii) ALK rearrangement or activating ALK mutation, (iv) activating PIK3CA or AKT mutations or other aberration predicting increased PI3K-AKT pathway activity, (v) abberations predicting increased RAF-MEK-ERK pathway activity; (vi) patients with high tumor mutational burden and/or specific alteration predicting sensitivity to PD-1/PD-L1 inhibition are eligible within this study for immune checkpoint inhibition. Recruitment of adequate patient numbers into these well-defined molecular subgroup is achieved in a multicenter approach including NCT Heidelberg and NCT Dresden as well as DKTK partner sites. Eligible patients will be identified by in-depth molecular characterization of tumors within the NCT/DKTK MASTER program. All study arms are based on similar biometrical assumptions, and sample size as well as power calculations are based on Simon's optimal two-stage design for each study arm separately. The overall aim is to reduce the cumulative hazard of progression-free survival observed within the study (PFS2) compared to the cumulative hazard of the progression-free time before inclusion into the study (PFS1) using a paired log-rank test. The sample size of the entire trial varies according to the performance of the individual study arms, ranging between 98 and 175 patients.

NCT04551521
Conditions
  1. Metastatic or Locally Advanced Malignancies
Interventions
  1. Drug: Vemurafenib
  2. Drug: Cobimetinib
  3. Drug: Atezolizumab
  4. Drug: Trastuzumab
  5. Drug: Pertuzumab
  6. Drug: Alectinib
  7. Drug: Ipatasertib
  8. Drug: Cobimetinib
  9. Drug: Atezolizumab
  10. Drug: Atezolizumab
  11. Drug: Atezolizumab
  12. Drug: Ipatasertib
  13. Drug: Atezolizumab
  14. Drug: Atezolizumab
MeSH:Neoplasms
HPO:Neoplasm

Within this seven-arm basket phase II clinical trial, we aim to investigate the efficacy of targeted-therapy plus immune checkpoint inhibition in patients with advanced tumors exhibiting one of the following genetic alterations detected within the NCT/DKTK MASTER study: (i) BRAF V600E/K, (ii)ERBB2 amplification and/or overexpression or activating ERBB2 mutation, (iii) ALK rearrangement or activating ALK mutation, (iv) activating PIK3CA or AKT mutations or other aberration predicting increased PI3K-AKT pathway activity, (v) abberations predicting increased RAF-MEK-ERK pathway activity; (vi) patients with high tumor mutational burden and/or specific alteration predicting sensitivity to PD-1/PD-L1 inhibition are eligible within this study for immune checkpoint inhibition. --- V600E ---

- Arm 1 (BRAF V600E/K): BRAF V600E/K mutation - Arm 2 (ERBB2): ERBB2 amplification/overexpression, activating ERBB2 mutation - Arm 3 (ALK): ALK rearrangement or activating ALK mutations including alternative transcription initiation (ALK-ATI) or RET-fusions - Arm 4 (PI3K-AKT): Activating PIK3CA or AKT mutations; other aberrations predicting increased PI3K-AKT pathway activity, e.g. --- V600E ---

- Arm 1 (BRAF V600E/K): BRAF V600E/K mutation - Arm 2 (ERBB2): ERBB2 amplification/overexpression, activating ERBB2 mutation - Arm 3 (ALK): ALK rearrangement or activating ALK mutations including alternative transcription initiation (ALK-ATI) or RET-fusions - Arm 4 (PI3K-AKT): Activating PIK3CA or AKT mutations; other aberrations predicting increased PI3K-AKT pathway activity, e.g. --- V600E --- --- V600E ---

PTEN lossa - Arm 6 (MAPK): Aberrations other than BRAF V600E/K predicting increased RAF-MEK- ERK pathway activity - Arm 7 (Immune evasion): High tumor mutational burden and/or specific alterations predicting sensitivity to PD1/PDL1 inhibition (e.g. --- V600E ---

Primary Outcomes

Description: Primary endpoint of the study is to DCR according to RECIST v1.1 including complete response (CR), partial response (PR) and stable disease (SD).

Measure: Disease Control Rate

Time: Day 110 (+/- 5 days)

Secondary Outcomes

Description: Paired Progression-free Survival 2 (PFS2) and Progression-free Survival 1 (PFS1)

Measure: Progression-free survival

Time: 24 months (median)

16 Abemaciclib in Metastatic or Locally Advanced Anaplastic/Undifferentiated Thyroid Cancer

The purpose of the study is to evaluate the efficacy of treatment with abemaciclib in patients with anaplastic thyroid/undifferentiated thyroid

NCT04552769
Conditions
  1. Thyroid Cancer
  2. Anaplastic Thyroid Cancer
  3. Undifferentiated Thyroid Cancer
Interventions
  1. Drug: Abemaciclib
MeSH:Thyroid Neoplasms Thyroid Carcinoma, Anaplastic Thyroid Diseases
HPO:Abnormality of the thyroid gland Anaplastic thyroid carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

This will be reported as median time with interquartile range.. Inclusion Criteria: 1. Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or undifferentiated thyroid cancer that does not have a known BRAF V600E positive on tissue/blood testing. --- V600E ---

BRAF V600E positive patients are eligible if they have previously received FDA approved therapy for this genetic abnormality and progressed or become intolerant. --- V600E ---

Inclusion Criteria: 1. Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or undifferentiated thyroid cancer that does not have a known BRAF V600E positive on tissue/blood testing. --- V600E ---

Primary Outcomes

Description: Overall response defined as either complete response or partial response assessed using RECIST v1.1 criteria. This measure will be reported as a number without dispersion. RECIST v1.1 criteria: Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, no appearance of new lesions. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) Progressive Disease (PD): Appearance of one or more new lesions

Measure: Overall response (OR)

Time: 8 (+/-4) weeks from start of treatment

Secondary Outcomes

Description: Overall survival defined as duration of time from start of treatment to death from any cause. This will be reported as median survival time with interquartile range

Measure: Overall survival (OS)

Time: 3 years

Description: Progression-free survival (PFS) defined as the duration of time from start of treatment to time of progression or death from any cause. This will be reported as median time with interquartile range.

Measure: Progression-free survival (PFS)

Time: 3 years

17 Phase I Study of INCB039110 in Combination With Dabrafenib and Trametinib in Patients With BRAF-mutant Melanoma and Other Solid Tumors.

This research study is studying a combination of drugs as a possible treatment for BRAF-mutant melanoma. The drugs involved in this study are: - Itacitinib (INCB039110) - Dabrafenib - Trametinib

NCT03272464
Conditions
  1. Melanoma
Interventions
  1. Drug: Trametinib
  2. Drug: Dabrafenib
  3. Drug: INCB039110
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Inclusion Criteria: - For Dose-Escalation Phase: Patients must have histologically confirmed, BRAF-mutant (V600E/K) malignancy (molecularly confirmed using Cobas assay or a comparable FDA-approved assay (for exceptions, see below*) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy or not previously received BRAF targeted therapy, and for which standard curative or palliative measures do not exist or are no longer effective. --- V600E ---

- For Dose-Expansion Phase: Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using Cobas assay or a comparable FDA-approved assay (for exceptions, see below*) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF targeted therapy. --- V600E ---

Current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded Inclusion Criteria: - For Dose-Escalation Phase: Patients must have histologically confirmed, BRAF-mutant (V600E/K) malignancy (molecularly confirmed using Cobas assay or a comparable FDA-approved assay (for exceptions, see below*) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy or not previously received BRAF targeted therapy, and for which standard curative or palliative measures do not exist or are no longer effective. --- V600E ---

Primary Outcomes

Description: Doses at which fewer than one third of patients have severe toxicity

Measure: Maximum Tolerated Dose

Time: 2 years

Secondary Outcomes

Description: Proportion of patients with tumor shrinkage that meets standard criteria for response

Measure: Objective Response Rate

Time: 2 years

Description: Time until worsening of cancer

Measure: Progression Free Survival

Time: 6 Months

Description: Time until death from cancer

Measure: Overall Survival

Time: 1 year

Description: Proportion of patients with complete tumor shrinkage

Measure: Complete response rate

Time: 2 years

Description: Proportion of patients with less than complete tumor shrinkage

Measure: Partial Response Rate

Time: 2 years

Description: Proportion of patients with no change in tumor size

Measure: Stable Disease

Time: 2 years

Description: Proportion of patients with worsening of cancer at or before first response assessment

Measure: Progressive Disease

Time: 2 years

18 A Phase 1 Study of ERK1/2 Inhibitor JSI-1187 Administered as Monotherapy and in Combination With Dabrafenib for the Treatment of Advanced Solid Tumors With MAPK Pathway Mutations

This is a Phase 1 study of JSI-1187 as monotherapy and in combination with dabrafenib for the treatment of advanced solid tumors with MAPK pathway mutations, including mutations that cause MAPK pathway hyperactivation.

NCT04418167
Conditions
  1. Solid Tumors
Interventions
  1. Drug: JSI-1187
  2. Drug: Dabrafenib
MeSH:Neoplasms
HPO:Neoplasm

In consenting subjects and when clinically available, tumor biopsies will be taken pre-study and on study to assess change in tumor pRSK.. Inclusion Criteria: - Males and females ≥ 18 years of age - Have locally advanced or metastatic solid tumor malignancy with measurable disease and be an appropriate candidate for experimental therapy - Part A (JSI-1187 Monotherapy Dose Escalation): Histologically or cytologically confirmed MAPK pathway mutation, including hyperactivating pathway mutations or gene fusions, e.g., BRAF (Class I, II or III), RAS (H/K/N), MEK (MAP2K1), RAS-GAP (NF1 loss, RASA1), RAS-GEF, refractory to or relapsed on prior therapy, and have received all available therapy known to confer clinical benefit - Part B (JSI-1187 Plus Dabrafenib Combination Dose Escalation): Histologically or cytologically confirmed BRAF V600-mutated locally advanced or metastatic solid tumor, refractory to, or relapsed on, prior therapy, and have received all available therapy known to confer clinical benefit - Part C (JSI-1187 Plus Dabrafenib Expansion Cohorts): Histologically or cytologically confirmed: - Cohort 1: BRAF V600-mutated metastatic melanoma after two prior therapies for metastatic disease, including anti-PD1 therapy, with or without ipilimumab, and BRAF/MEK inhibitor treatment - Cohort 2: BRAF V600-mutated metastatic melanoma after adjuvant therapy for Stage 3 disease followed by one prior therapy for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab or BRAF/MEK inhibitor treatment - Cohort 3: Either BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC), or BRAF V600-mutated metastatic solid tumor, after 1 or 2 prior therapies - MAPK mutation tumor status will be established prior to entry based on previous MAPK pathway mutation reports from a CLIA qualified laboratory, or, if a report is not available, the mutation analysis will be performed at Screening on archival tissue or newly biopsied tumor tissue. --- V600E ---

- If female, pregnant, breast-feeding, or planning to become pregnant Inclusion Criteria: - Males and females ≥ 18 years of age - Have locally advanced or metastatic solid tumor malignancy with measurable disease and be an appropriate candidate for experimental therapy - Part A (JSI-1187 Monotherapy Dose Escalation): Histologically or cytologically confirmed MAPK pathway mutation, including hyperactivating pathway mutations or gene fusions, e.g., BRAF (Class I, II or III), RAS (H/K/N), MEK (MAP2K1), RAS-GAP (NF1 loss, RASA1), RAS-GEF, refractory to or relapsed on prior therapy, and have received all available therapy known to confer clinical benefit - Part B (JSI-1187 Plus Dabrafenib Combination Dose Escalation): Histologically or cytologically confirmed BRAF V600-mutated locally advanced or metastatic solid tumor, refractory to, or relapsed on, prior therapy, and have received all available therapy known to confer clinical benefit - Part C (JSI-1187 Plus Dabrafenib Expansion Cohorts): Histologically or cytologically confirmed: - Cohort 1: BRAF V600-mutated metastatic melanoma after two prior therapies for metastatic disease, including anti-PD1 therapy, with or without ipilimumab, and BRAF/MEK inhibitor treatment - Cohort 2: BRAF V600-mutated metastatic melanoma after adjuvant therapy for Stage 3 disease followed by one prior therapy for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab or BRAF/MEK inhibitor treatment - Cohort 3: Either BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC), or BRAF V600-mutated metastatic solid tumor, after 1 or 2 prior therapies - MAPK mutation tumor status will be established prior to entry based on previous MAPK pathway mutation reports from a CLIA qualified laboratory, or, if a report is not available, the mutation analysis will be performed at Screening on archival tissue or newly biopsied tumor tissue. --- V600E ---

Cohort 3: JSI-1187 plus dabrafenib in either BRAF V600E-mutated non-small cell lung cancer (NSCLC) or BRAF V600-mutated solid tumors after 1 or 2 prior therapies. --- V600E ---

Primary Outcomes

Description: Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs)

Measure: Incidence of treatment emergent adverse events (safety and tolerability)

Time: 35 months

Secondary Outcomes

Description: Proportion of subjects with objective responses (complete response [CR] + partial response [PR]) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.

Measure: Objective Response Rate

Time: Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following last dose of study drug (each cycle is 28 days)

Description: Length of time from first evidence of objective response (CR, PR) to the first objective evidence of disease progression

Measure: Duration of Response

Time: Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following the last dose of study drug (each cycle is 28 days)

Description: Length of time from the date of first dose of study drug to the first evidence of objective response (CR, PR)

Measure: Time to Response

Time: Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following the last dose of study drug (each cycle is 28 days)

Description: Proportion of subjects with best response of CR, PR or stable disease (SD)

Measure: Disease Control Rate

Time: Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following the last dose of study drug (each cycle is 28 days)

Description: Length of time from the date of first dose of study drug to the first evidence of disease progression or death, whichever is earlier

Measure: Progression-Free Survival

Time: Assessed from the date of the first dose of study drug to the first evidence of disease progression or death, whichever is earlier, assessed up to 35 months

Description: Length of time from the date of first dose of study drug to date of death from any cause

Measure: Overall Survival

Time: Assessed from the date of the first dose of study drug to date of death from any cause, assessed up to 35 months

Other Outcomes

Description: Mean plasma concentrations of JSI-1187 and dabrafenib will be determined and summarized by dose group

Measure: Mean plasma concentrations of JSI-1187 alone and in combination with dabrafenib

Time: Cycle 1, Day 1; Cycle 1, Day 15; Cycle 2 Day 1; Cycle 4 Day 1; Cycle 6 Day 1 (each cycle is 28 days)

Description: Change from baseline in whole blood (PBMC) pRSK/RSK ratio will be determined and summarized by dose group

Measure: pRSK/RSK ratio in whole blood (PBMCs) (pharmacodynamic endpoint)

Time: Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)

Description: In consenting subjects and when clinically available, tumor biopsies will be taken pre-study and on study to assess change in tumor pRSK.

Measure: Change in pRSK levels in tumor (pharmacodynamic endpoint)

Time: At Screening and Week 2 or 3 on study

19 A Phase 1a/1b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PY314 as a Single Agent and In Combination With Pembrolizumab in Subjects With Advanced Solid Tumors

A Phase 1a/1b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PY314 as a Single Agent and In Combination with Pembrolizumab in Subjects with Advanced Solid Tumors

NCT04691375
Conditions
  1. Advanced Solid Tumor
Interventions
  1. Drug: Dose of PY314
MeSH:Neoplasms
HPO:Neoplasm

drugs targeting EGFR, EGFR, ALK, ROS-1, NTRK, MET, RET and BRAF V600E, Her2neu)). --- V600E ---

Primary Outcomes

Description: Adverse Events will be summarized by MedDRA system organ class and preferred term. Separate tabulations will be produced for all treatment emergent AEs, treatment related AEs, Serious Adverse Events (SAEs), discontinuations due to AEs, and AEs of at least NCI CTCAE grade 3 severity.

Measure: Incidence of Adverse Events (AE)

Time: 12 months

Description: Measure PY314 concentration at the end of infusion (CEOI) after the first dose.

Measure: Measure PY314 concentration at the end of infusion (CEOI)

Time: 12 months

Description: Measure PY314 maximum concentration (Cmax) at various time points during Cycle 1. All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing.

Measure: Measure PY314 maximum concentration (Cmax)

Time: 12 months

Description: Measure PY314 concentration at the trough level (Ctrough). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing.

Measure: Measure PY314 concentration at the trough level (Ctrough)

Time: 12 months

Description: Determining PY314 time to maximum concentration (Tmax) during Cycle 1.

Measure: Determining PY314 time to maximum concentration (Tmax)

Time: 12 months

Description: Measure PY314 Area under the curve (AUC)0-t. All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY314 Area under the curve (AUC)0-t

Time: 12 months

Description: Measure PY314 half-life (T1/2). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY314 half-life (T1/2)

Time: 12 months

Description: Measure PY314 Clearance (CL). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY314 Clearance (CL)

Time: 12 months

Description: Measure PY314 Volume at Steady State (Vss). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte.

Measure: Measure PY314 Volume at Steady State (Vss)

Time: 12 months

Description: To evaluate the incidence of anti-drug antibody (ADA) formation to PY314

Measure: Incidence of Anti-Drug Antibody (ADA) formation to PY314

Time: 12 months

Secondary Outcomes

Description: The incidents of ORR is defined as either a complete or partial response per RECIST. Subjects with no baseline data will be considered no responders. ORR will be summarized by dose, tumor type, and overall. ORR will be summarized descriptively.

Measure: Objective response rate (ORR)

Time: 36 months

Description: DCR will be measure per resists 1.1 criteria. DCR will be summarized descriptively.

Measure: Deceased control rate (DCR)

Time: 36 months

Description: DOR will be calculated to determine durability. DOR will be measured from the time by which the criteria for CR or PR-whichever is recorded first-are met until the first date by which recurrent or progressive disease is objectively documented. DOR will be assessed using KAPLAN-MEIER methods.

Measure: Duration of response (DOR)

Time: 36 months

Description: PFS will be measure from entry onto the study until disease progression or death from any cause. PFS will be assessed using KAPLAN-MEIER methods.

Measure: Progress free survival (PFS)

Time: 36 months

Description: The duration of overall survival (OS) will be measured from the time of first study drug administration until the date of death. OS will be assessed using KAPLAN-MEIER methods.

Measure: Overall survival (OS)

Time: 36 months

20 MATCH Treatment Subprotocol H: Phase II Study of Dabrafenib and Trametinib in Patients With Tumors With BRAF V600E or V600K Mutations (Excluding Melanoma, Thyroid Cancer, Colorectal Adenocarcinoma, and Non-Small Cell Lung Cancer)

This phase II MATCH treatment trial identifies the effects of trametinib and dabrafenib in patients whose cancer has genetic changes called BRAF V600 mutations. Dabrafenib may stop the growth of cancer by blocking BRAF proteins which may be needed for cell growth. Trametinib may stop the growth of cancer cells by blocking MEK proteins which, in addition to BRAF proteins, may also be needed for cell growth. Researchers hope to learn if giving trametinib with dabrafenib will shrink this type of cancer or stop its growth.

NCT04439292
Conditions
  1. Advanced Lymphoma
  2. Advanced Malignant Solid Neoplasm
  3. Hematopoietic and Lymphoid Cell Neoplasm
  4. Refractory Lymphoma
  5. Refractory Malignant Solid Neoplasm
  6. Refractory Plasma Cell Myeloma
Interventions
  1. Drug: Dabrafenib Mesylate
  2. Drug: Trametinib Dimethyl Sulfoxide
MeSH:Lymphoma Neoplasms Multiple Myel Multiple Myeloma Neoplasms, Plasma Cell
HPO:Lymphoma Multiple myeloma Neoplasm

MATCH Treatment Subprotocol H: Phase II Study of Dabrafenib and Trametinib in Patients With Tumors With BRAF V600E or V600K Mutations (Excluding Melanoma, Thyroid Cancer, Colorectal Adenocarcinoma, and Non-Small Cell Lung Cancer). --- V600E ---

PFS will be estimated using the Kaplan-Meier method.. Inclusion Criteria: - Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol - Patients must have a BRAF V600E or, V600K, V600R or V600D mutation, or another aberration, as identified via the MATCH Master Protocol - Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to registration to treatment - Patients must have an ECHO or a nuclear study (multigated aquisition scan [MUGA] or First Pass) within 4 weeks prior to registration to treatment and must not have a left ventricular ejection fraction (LVEF) < the institutional lower limit of normal (LLN). --- V600E ---

However, if the results of previous RAS testing are known, they must be used in assessing eligibility Inclusion Criteria: - Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol - Patients must have a BRAF V600E or, V600K, V600R or V600D mutation, or another aberration, as identified via the MATCH Master Protocol - Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to registration to treatment - Patients must have an ECHO or a nuclear study (multigated aquisition scan [MUGA] or First Pass) within 4 weeks prior to registration to treatment and must not have a left ventricular ejection fraction (LVEF) < the institutional lower limit of normal (LLN). --- V600E ---

Primary Outcomes

Description: ORR is defined as the percentage of patients whose tumors have a complete or partial response to treatment among eligible and treated patients. Objective response rate is defined consistent with Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. For each treatment arm, 90% two-sided binomial exact confidence interval will be calculated for ORR.

Measure: Objective response rate (ORR)

Time: Tumor assessments occurred at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration

Secondary Outcomes

Description: OS is defined as time from treatment start date to date of death from any cause. Patients alive at the time of analysis are censored at last contact date. OS will be evaluated specifically for each drug (or step) using the Kaplan-Meier method.

Measure: Overall survival (OS)

Time: Assessed every 3 months for =< 2 years and every 6 months for year 3

Description: PFS is defined as time from treatment start date to date of progression or death from any cause, whichever occurs first. PFS will be estimated using the Kaplan-Meier method.

Measure: Progression free survival (PFS)

Time: Assessed at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration

21 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03255083
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: DS-1205c
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, rearranged during transfection (RET) rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation. --- V600E ---

Primary Outcomes

Measure: Number of participants with dose-limiting toxicities (DLTs) when taking DS-1205c in combination with osimertinib during dose escalation

Time: within 28 days

Description: Categories: during dose escalation, during dose expansion

Measure: Number of participants with clinically significant safety measures when taking DS-1205c in combination with osimertinib

Time: within 36 months

Secondary Outcomes

Description: DS-1205a is the free form of DS-1205c when DS-1205c is administered alone

Measure: Area under the plasma concentration time curve (AUC) for DS-1205a

Time: during Cycle 0 of the dose escalation period (within 28 days)

Measure: Maximum observed analyte concentration (Cmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Actual sampling time to reach Cmax (Tmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: first dose to 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: baseline to objective disease progression or death from any cause (within 36 months)

Measure: Overall survival (OS)

Time: baseline to death from any cause (within 36 months)

22 A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer

Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib administered as a single agent and in combination with trametinib in stage IV disease to subjects with BRAF mutant advanced non-small cell lung cancer. Subjects will receive dabrafenib 150 mg twice daily (BID) in monotherapy treatment and dabrafenib 150 mg bid and trametinib 2 mg once daily in combination therapy and continue on treatment until disease progression, death, or unacceptable adverse event.

NCT01336634
Conditions
  1. Cancer
Interventions
  1. Drug: Dabrafenib
  2. Device: Trametinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. --- V600E ---

Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. --- V600E ---

Subjects in Cohort C will be required to have not received prior systemic anti-cancer therapies for metastatic disease (i.e., dabrafenib/trametinib will be 1st line treatment for metastatic disease); - Measurable disease according to Response Evaluation Criteria in Solid Tumors [RECIST 1.1]; - At least 18 years of age; - Anticipated life expectancy of at least three months; - Presence of a BRAF V600E mutation in lung cancer tissue. --- V600E ---

Primary Outcomes

Description: ORR is defined as the percentage of par. with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per Response Evaluation Criteria In Solid Tumors evaluates the response on the basis of target and non-target lesions, and best over all response. The response rate was analyzed every 6 weeks (wks) after initiation of study treatment until Week 36 and then every 12 wks until discharge or crossover. Percentage of par. analyzed as number of par. having overall response on the date of analysis from Baseline multiply by 100. The Second Line Plus All Treated Population used for cohort A and B consisted of all par. in the All Treated Population who had received at least one line of prior anti-cancer therapy for advanced/metastatic disease. The First-Line All Treated Population used for cohort C consisted of all par. in the All Treated Population who had not received any prior anti-cancer therapy for advanced/metastatic disease.

Measure: Percentage of Participants With Overall Response Rate (ORR) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Secondary Outcomes

Description: DoR is defined for the subset of participants with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression or death due to any cause. The response was analyzed every 6 weeks after initiation of study treatment until Week 36 and then every 12 wks. Disease progression will be based on radiological assessments [magnetic resonance imaging (MRI) or computed tomography (CT)]. Confidence Intervals (CIs) estimated using the Brookmeyer Crowley method. Upper limit of confidence interval was not reached as data were not yet mature. A value of NA indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in that population (27 percent).

Measure: Duration of Response (DoR) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. The target and non-target lesions were identified at time of screening and the same lesions were re-assessed by a contrast-enhanced brain magnetic resonance imaging (MRI) or Computed tomography (CT) every 6 wks after initiation of study treatment until Week 36 and then every 12 wks. CI estimated using the Brookmeyer Crowley method. A value of NA indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in the population (36 percent).

Measure: Progression Free Survival (PFS) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: OS defined as the time from first dose until death due to any cause. CI estimated using the Brookmeyer Crowley method. A value of NA indicates where no data is available or not able to determine the value. The upper bound of the 95 percent CI for the median was not reached due to insufficient event rates for Arm 2 (58 percent) and Arm 3 (28 percent).

Measure: Overall Survival (OS) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: Number of participants with abnormal values of vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and temperature were evaluated. Participants with worst case post-Baseline vital sign values were presented at the given timepoints. Only those participants with data available at the specified data points were analyzed. All treated population was used for monotherapy cohort which comprised of all participants in the monotherapy cohort who receive at least one dose of study treatment. HR: <60 bpm clinical concern-low; >100 bpm Clinical concern-high Temperature: <=35 °C clinical concern - low; >=38 °C clinical concern - high For SBP change from baseline, the following categories will be used: Grade 0: <120 mm Hg; Grade 1: >=120-<140 mmHg; Grade 2: >=140-<160 mmHg; Grade 3: >=160 mmHg; For DBP change from baseline, the following categories will be used: Grade 0: <80 mm Hg; Grade 1: >=80-<90 mmHg; Grade 2: 90-<100 mmHg; Grade 3: >=100mmHg

Measure: Number of Participants With Abnormal Vital Signs Values

Time: Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months

Description: Single measurements of 12-lead ECGs were obtained at given time points using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) interval. ECG values at worst case post-Baseline were categorized as 'clinically significant change from Baseline' and 'not a clinically significant change'.

Measure: Number of Participants With Abnormal Electrocardiogram (ECG) Values

Time: Week 3, Week 6, Week 15 and then every 9 weeks until discharge, for an average of 13.8 months

Description: Echocardiography scans were obtained at given time points using an echocardiogram and the findings for left ventricular ejection fraction (LVEF) were obtained. LVEF values at worst case post-Baseline were recorded as any increase and any decrease values.

Measure: Number of Participants With Abnormal Echocardiogram Findings

Time: Week 6, Week 15 and then every 9 weeks until discharge, for an average of 13.8 months

Description: Blood samples were collected from participants for evaluation of clinical chemistry parameters by worst case post-Baseline increase. The clinical chemistry parameters included creatinine, phosphate and high and low calcium, glucose, magnesium, potassium and sodium. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Measure: Number of Participants With Abnormal Clinical Chemistry Values

Time: Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months

Description: Blood samples were collected from participants for evaluation of hematology parameters by worst case post-Baseline increase. The hematology parameters included leukocytes, neutrophils, platelets and high and low hemoglobin and lymphocytes. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Measure: Number of Participants With Abnormal Hematology Values

Time: Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months

Description: An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function.

Measure: Number of Participants With AEs and Serious AEs (SAEs)

Time: Up to Week 12 and then every 3 weeks up to follow up, for an average of 13.8 months

Description: Blood samples from participants were collected for population pharmacokinetic analysis including CL/F following oral dosing of dabrafenib and trametinib.

Measure: Apparent Clearance (CL/F) of Dabrafenib and Trametinib

Time: Week 3, Week 6, Week 12 and Week 18

Description: Blood samples from participants were collected for population pharmacokinetic analysis including V/F following oral dosing of dabrafenib and trametinib.

Measure: Volume of Distribution (V/F) of Dabrafenib and Trametinib

Time: Week 3, Week 6, Week 12 and Week 18

23 A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5- Fluorouracil (5-FU)/Folinic Acid (FA) /Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.

NCT02928224
Conditions
  1. BRAF V600E-mutant Metastatic Colorectal Cancer
Interventions
  1. Drug: Encorafenib
  2. Drug: Binimetinib
  3. Drug: Cetuximab
  4. Drug: Irinotecan
  5. Drug: Folinic Acid
  6. Drug: 5-Fluorouracil
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5- Fluorouracil (5-FU)/Folinic Acid (FA) /Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer. --- V600E ---

Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. --- V600E ---

An additional study ARRAY-162-105 is not required to register.. Key Inclusion Criteria: - Age ≥ 18 years at time of informed consent - Histologically- or cytologically-confirmed CRC that is metastatic - Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory - Progression of disease after 1 or 2 prior regimens in the metastatic setting - Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1 - Adequate bone marrow, cardiac, kidney and liver function - Able to take oral medications - Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential - Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up Key Exclusion Criteria: - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other epidermal growth factor receptor (EGFR) inhibitors - Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks - Symptomatic brain metastasis or leptomeningeal disease - History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) - Known history of acute or chronic pancreatitis - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization - Uncontrolled blood pressure despite medical treatment - Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) - Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli - Concurrent neuromuscular disorder that is associated with the potential of elevated creatine (phosphor)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) - Residual common terminology criteria for adverse events (CTCAE) ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy - Known history of HIV infection - Active hepatitis B or hepatitis C infection - Known history of Gilbert's syndrome - Known contraindication to receive cetuximab or irinotecan at the planned doses Key Inclusion Criteria: - Age ≥ 18 years at time of informed consent - Histologically- or cytologically-confirmed CRC that is metastatic - Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory - Progression of disease after 1 or 2 prior regimens in the metastatic setting - Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1 - Adequate bone marrow, cardiac, kidney and liver function - Able to take oral medications - Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential - Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up Key Exclusion Criteria: - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other epidermal growth factor receptor (EGFR) inhibitors - Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks - Symptomatic brain metastasis or leptomeningeal disease - History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) - Known history of acute or chronic pancreatitis - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization - Uncontrolled blood pressure despite medical treatment - Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) - Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli - Concurrent neuromuscular disorder that is associated with the potential of elevated creatine (phosphor)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) - Residual common terminology criteria for adverse events (CTCAE) ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy - Known history of HIV infection - Active hepatitis B or hepatitis C infection - Known history of Gilbert's syndrome - Known contraindication to receive cetuximab or irinotecan at the planned doses BRAF V600E-mutant Metastatic Colorectal Cancer Colorectal Neoplasms null --- V600E ---

Primary Outcomes

Measure: (Safety Lead-in) Number of Participants With Dose-limiting Toxicities (DLTs)

Time: Cycle 1 (up to 28 days)

Description: Refer to AE/SAE section for additional data that were measured and analyzed.

Measure: (Safety Lead-in) Number of Participants With Adverse Events (AEs)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Response Rate (ORR) by Blinded Independent Central Review (BICR) Per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Secondary Outcomes

Measure: (Safety Lead-in) Response Rate (ORR) by Investigator

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Description: ORR per RECIST, v1.1, defined as the number of patients achieving an overall best response of CR or partial response (PR) divided by the total number of patients

Measure: (Safety Lead-in) Response Rate (ORR) by BICR

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Duration of Response (DOR) by Investigator

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Description: DOR defined as the time from first radiographic evidence of response to the earliest documented disease progression or death due to underlying disease

Measure: (Safety Lead-in) Duration of Response (DOR) by BICR

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Description: Time to response defined as the time from first dose to first radiographic evidence of response

Measure: (Safety Lead-in) Time to Response by Investigator

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Description: Time to response defined as the time from first dose to first radiographic evidence of response

Measure: (Safety Lead-in) Time to Response by BICR

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Progression-free Survival (PFS) by Investigator

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Description: PFS defined as the time from first dose to the earliest documented disease progression or death due to any cause

Measure: (Safety Lead-in) Progression-free Survival (PFS) by BICR

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in Doublet Arm vs Control Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in Doublet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Description: The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: (Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Description: FACT-C is a well-characterized and commonly used questionnaire that belongs to the Functional Assessment of Chronic Illness Therapy Measurement System (FACIT). The FACT-G (G for general) questionnaire (27 questions) constitutes the core of all subscales and is applicable to all tumor types. The FACT-C questionnaire contains 9 additional questions on symptoms specific to CRC, 2 of which are only answered by patients with ostomy appliances. These 9 CRC-specific questions are categorized as "additional concerns" on the questionnaire and constitute the "colorectal cancer subscale" score. The patient self-reports his/her QoL for the previous 7 days. The overall score is calculated across all items and a higher score reflects better quality of life (QoL). The table summarizes the functional well-being subscale, the individual questions are linearly scaled and combined to form the functional well-being subscale score, which ranges from 0-28 (higher is better QoL).

Measure: (Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Description: The EQ-5D-5L contains 1 item for each of 5 dimensions of health-related QoL (i.e., mobility, self-care, usual activities, pain or discomfort and anxiety or depression). Response options for each item varied from having no problems to moderate problems or extreme problems. The EQ-5D-5L (v4.0) is a standardized measure of health utility that provides a single index value for one's health status. The EQ-5D-5L is frequently used for economic evaluations of health care and has been recognized as a valid and reliable instrument for this purpose. The EQ visual analog scale (VAS) is a score that is directly reported by the patient and ranges from 0 to 100 (higher is better quality health).

Measure: (Phase 3) Change From Baseline in the EuroQol-5D-5L (EQ-5D-5L) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Description: The PGIC is a measure of patients' perceptions of change in their symptoms over time that can be used as an anchoring method to determine the minimal clinically important difference for other patient reported outcome (PROs). For this assessment, patients answered the following question: "Since starting treatment, my colorectal cancer symptoms are: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse or (7) very much worse."

Measure: (Phase 3) Change From Baseline in the Patient Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Cetuximab

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Encorafenib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Metabolite of Binimetinib (AR00426032)

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032)

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032)

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Description: The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

Measure: (Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib

Time: 2 and 6 hours post-dose on Day 1 of Cycle 1. Predose and 2 hours post-dose on Day 1 of Cycle 2.

Description: The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

Measure: (Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib

Time: 2 and 6 hours post-dose on Day 1 of Cycle 1. Predose and 2 hours post-dose on Day 1 of Cycle 2.

Description: The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

Measure: (Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab

Time: 2 and 6 hours post-dose on Day 1 of Cycle 1. Predose and 2 hours post-dose on Day 1 of Cycle 2.

24 Molecular Disease Profile of Haematological Malignancies. A Prospective Registry Study by the Rete Ematologica Lombarda (REL) Clinical Network

In this prospective multicentric study, the University of Pavia together with the Fondazione IRCCS Policlinico San Matteo, Pavia and the IRCCS Fondazione Maugeri, Pavia, Italy will provide a systematic analysis of gene mutations in hematological malignancies by using NGS techniques. Patients with a conclusive diagnosis of haematological malignancies according to WHO criteria referred to the Rete Ematologica Lombarda clinical network (REL, www.rel-lombardia.net) will be enrolled. The investigators will analyse genomic DNA extracted from hematopoietic cells at different time points of patient disease. The study contemplates the use of molecular platforms (Next Generation Sequencing, NGS) aimed at the identification of recurrent mutations in myeloid and lymphoid neoplasms, respectively. Screening of gene mutations by NGS will be prospectively implemented in the context of REL clinical network. Patient samples will be analyzed at diagnosis and sequentially during the course of the disease at specific timepoints. The researchers will analyze the correlations between somatic mutations, specific clinical phenotypes (according to the WHO classification) and disease evolution. This will allow to: 1) identify new recurrent genetic mutations involved in the molecular pathogenesis of hematological malignancies; 2) define the role of mutated genes, distinguishing between genes which induce a clonal proliferation of hematopoietic stem cells, and genes which determine the clinical phenotype of the disease; 3) identify mutations which are responsible for disease evolution; 4) define the diagnostic/prognostic role of the identified mutations, and update the current disease classifications and prognostic scores by including molecular parameters. A systematic biobanking of biological material will be provided.

NCT02459743
Conditions
  1. Hematological Malignancies
MeSH:Neoplasms Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia Neoplasm

Moreover in last years, researchers from the University of Pavia gave a significant contribution in the definition of the molecular basis of lymphoid neoplasms (i.e., BRAF V600E mutation in Hairy cell Leukemia, MYD88 L265P mutation in Waldenstrom disease, and SF3B1 mutations in Chronic Lymphocytic Leukemia). --- V600E ---

Primary Outcomes

Measure: Cumulative incidence of gene mutations in principal clone and subclones in each hematological malignancy

Time: 3 years

Secondary Outcomes

Measure: Genotype-phenotype correlations between clinical characteristics and mutational status

Time: 3 years

Measure: Overall survival and disease-free survival according to clinical and biological risk factors at diagnosis and during disease evolution

Time: 3 years

25 A Phase I Study to Evaluate the Pharmacokinetics and Safety of Repeat Oral Doses of Dabrafenib and the Combination of Dabrafenib With Trametinib in Chinese Subjects With Melanoma

Present clinical study will be conducted in China to evaluate the pharmacokinetics (PK) of single and repeat oral doses of dabrafenib alone and dabrafenib and trametinib in combination, the safety profile and the clinical activity of dabrafenib in combination with trametinib in Chinese melanoma subjects with BRAF V600E/K mutation. Approximately 20 evaluable subjects will be enrolled in the study, out of which, the first 10 subjects will be enrolled into cohort A (Part I and II) and remaining 10 subjects will be enrolled in cohort B. Subjects in cohort A (Part I) will receive dabrafenib 150 mg twice daily (BID) and subjects in cohort A (Part II) and Cohort B will receive combination of dabrafenib 150 mg BID and trametinib 2 mg once daily (QD). Study treatment will continue until disease progression, death or unacceptable toxicity. After disease progression, all enrolled subjects will be followed up for overall survival. The study will be completed after all subjects have died or surviving subjects have had at least 5 years of follow-up, whichever occurs first.

NCT02447939
Conditions
  1. Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Pharmacokinetics of Repeat Oral Doses of Dabrafenib and the Combination of Dabrafenib and Trametinib in Chinese Subjects With Melanoma Present clinical study will be conducted in China to evaluate the pharmacokinetics (PK) of single and repeat oral doses of dabrafenib alone and dabrafenib and trametinib in combination, the safety profile and the clinical activity of dabrafenib in combination with trametinib in Chinese melanoma subjects with BRAF V600E/K mutation. --- V600E ---

- Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and BRAF V600E/K mutation-positive from the designated qualified laboratory for this study. --- V600E ---

Primary Outcomes

Description: Maximum observed plasma concentration (Cmax), time to Cmax (Tmax) and area under the concentration-time curve over the dosing interval [AUC(0-tau)] will be calculated for dabrafenib and its metabolites.

Measure: Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) dose: Cmax,Tmax and AUC(0-tau)

Time: At Day 1: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Description: Tmax, minimum concentration at steady state (Css_min), maximum concentration at steady state (Css_max), average concentration at steady state (Css_av), AUC(0-tau) will be calculated for dabrafenib and its metabolites.

Measure: A Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) dose : Tmax, Css_min, Css_max, Css_av and AUC(0-tau)

Time: At Day 21: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Accumulation ratio of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) dose

Time: At Day 21.

Measure: Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose: Cmax, Tmax, AUC(0-tau)

Time: At Day 1: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose : Tmax, Css_min, Css_max, Css_av, AUC(0-tau)

Time: At Day 21: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Accumulation ratio of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose

Time: At Day 21.

Measure: Composite of PK parameters of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose: Cmax, Tmax, AUC(0-tau)

Time: At Day 1: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Composite of PK parameters of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose : Tmax, Css_min, Css_max, Css_av, AUC(0-tau)

Time: At Day 21: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Accumulation ratio of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose

Time: At Day 21.

Measure: Effective half-life of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose

Time: At Day 21.

Secondary Outcomes

Description: Physical examination will include assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and skin, genitourinary (pelvic) and rectal exams.

Measure: Composite of Physical examination assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Description: Vital sign measurements will include systolic and diastolic blood pressure, body temperature and pulse rate.

Measure: Composite of Safety and tolerability as assessed by vital signs assessment: blood pressure, temperature and pulse rate

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Description: 12-lead ECGs will be obtained at each time point using an ECG machine that automatically to calculate the heart rate and measures PR, QRS, QT and corrected QT interval duration (QTc intervals).

Measure: Electrocardiogram (ECG) assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Description: ECHO assessment will include an evaluation for left ventricular ejection fraction.

Measure: Echocardiogram (ECHO) assessment

Time: At week 4, week 8, and then every 8 weeks until treatment discontinuation.

Description: Eye exam will include indirect fundoscopic examination,visual acuity, visual field examination, and tonometry, with special attention to retinal abnormalities.

Measure: Eye exams assessment

Time: At screening, and when clinical indicated until treatment discontinuation.

Measure: Chemistry laboratory values assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Measure: Number of subjects with Adverse events (AEs)

Time: Up to 5 years.

Measure: Number of subjects with Serious Adverse events (SAEs)

Time: Up to 5 years.

Description: ORR defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation

Measure: Objective response rate (ORR)

Time: Up to 5 years.

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: Progression free survival(PFS)

Time: Up to 5 years.

Description: OS defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact.

Measure: Overall survival(OS)

Time: Up to 5 years.

Measure: Hematology laboratory values assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Measure: Urinalysis laboratory values assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

26 Comparison of KRAS/BRAF Mutational Status Between Tumor Tissue Section Analysis With Conventional Techniques and Plasma Samples Analysis (KPLEX2)

The goal of this multicenter prospective study is to validate, and ultimately translate in routine clinical practice, the use of plasma analysis of ccfDNA for the determination of KRAS mutation status in mCRC patients.

NCT02784639
Conditions
  1. Colorectal Cancer
Interventions
  1. Other: Plasma Analysis of circulating cell free DNA
  2. Other: Tumor tissue analysis of circulating cell free DNA
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

As a consequence, the method was adapted to detect the six more frequent KRAS mutations in CRC (G12D, G12V, G13D, G12S, G12C, G12A) and the BRAF V600E. --- G12D --- --- G12V --- --- G13D --- --- G12S --- --- G12C --- --- G12A --- --- V600E ---

CcfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. --- V600E ---

Primary Outcomes

Description: Area under the ROC curve of the mutation percentage obtained from plasma ccfDNA analysis

Measure: Area under ROC curve

Time: 12 month

27 A Phase I, Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Subjects With Solid Tumors and Non-Hodgkin's Lymphoma

The study drug, GSK3326595, is an inhibitor of protein arginine methyltransferase 5 (PRMT5) that potently inhibits tumor growth in vitro and in vivo in animal models. This first time in human (FTIH), open-label, dose escalation study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in participants with advanced or recurrent solid tumors, as well as clinical activity in participants with a subset of solid tumors and NHL. This is an open-label, repeat-dose, multicenter, three-part study to establish the maximally tolerated dose (MTD)/ recommended phase 2 dose (RP2D) based on safety and tolerability and preliminary clinical efficacy of orally-administered GSK3326595. Part 1 is a dose-escalation phase to identify the MTD/RP2D based on the safety, PK, and PD profiles observed after oral administration of GSK3326595 and to preliminarily identify whether or not there is an effect of fed versus fasted state and of tablet versus capsule formulation on the PK of GSK3326595. This Part will be conducted in adult participants with relapsed and/or refractory solid tumors. It is estimated that up to 66 participants will be enrolled into the dose escalation cohort of the study, including up to 42 participants to identify the MTD and approximately 12 participants in the PK/PD/metabolite/biomarker expansion cohort(s) and approximately 12 participants in the food effect and relative bioavailability sub-study. Disease-specific expansion cohorts (Part 2) are planned to further explore clinical activity of GSK3326595 in participants with selected solid tumors and NHL. It is estimated that up to 316 participants will be enrolled in Part 2. Part 3 will be a dose determination study to evaluate the safety, PK/PD profile, and clinical activity of orally-administered GSK3326595 in combination with intravenous pembrolizumab. Overall, approximately 30 participants will be enrolled in Part 3. The duration of study will depend on recruitment rates and the timing of participant's duration on study (withdrawal rates due to toxicity or progression), with an approximate duration of 6 years.

NCT02783300
Conditions
  1. Neoplasms
Interventions
  1. Drug: GSK3326595
  2. Drug: Pembrolizumab
MeSH:Lymphoma Lymphoma, Non-Hodgkin
HPO:Lymphoma Non-Hodgkin lymphoma

Tumors with actionable mutations (e.g., BRAF V600E gene mutation in melanoma; Epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements in NSCLC) must have received prior therapy with targeted agents prior to enrollment. --- V600E ---

Primary Outcomes

Description: An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.

Measure: Part 1: Number of participants with any adverse events (AEs)

Time: Up to approximately 2 years

Description: An SAE is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement.

Measure: Part 1: Number of participants with serious adverse events (SAEs)

Time: Up to approximately 2 years

Description: Number of participants withdrawn due to AEs will be evaluated.

Measure: Part 1: Number of participants withdrawn due to AEs

Time: Up to approximately 2 years

Description: Number of participants with dose interruptions and with dose reductions will be analyzed.

Measure: Part 1: Number of participants with dose interruptions and with dose reductions

Time: Up to approximately 2 years

Description: Number of participants withdrawn due to AEs will be evaluated.

Measure: Part 3: Number of participants withdrawn due to AEs

Time: Up to approximately 2 years

Description: An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.

Measure: Part 3: Number of participants with any AEs

Time: Up to approximately 2 years

Description: An SAE is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement.

Measure: Part 3: Number of participants with SAEs

Time: Up to approximately 2 years

Description: Number of participants with dose interruptions and with dose reductions will be analyzed.

Measure: Part 3: Number of participants with dose interruptions and with dose reductions

Time: Up to approximately 2 years

Description: An event is considered to be a DLT if the event is attributed (definitely, probably or possibly) to the study treatment during the first 21 days of treatment.

Measure: Part 1: Number of participants with dose limiting toxicity (DLT)

Time: Up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 1: Change from Baseline in Hemoglobin (Hb) (Grams per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 3: Change from Baseline in Hb (Grams per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 1: Change from Baseline in Hematocrit (Proportion of red blood cells in blood)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 3: Change from Baseline in Hematocrit (Proportion of red blood cells in blood)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 1: Change from Baseline in Mean Corpuscle Hemoglobin (MCH) (Picograms)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 3: Change from Baseline in MCH (Picograms)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 1: Change from Baseline in Mean Corpuscle Volume (MCV) (Femtoliters)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 3: Change from Baseline in MCV (Femtoliters)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameters.

Measure: Part 1: Change from Baseline in hematology parameter: red blood cells (RBC) Count and Reticulocytes (Trillion cells per liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameters.

Measure: Part 3: Change from Baseline in hematology parameter: RBC Count and Reticulocytes (Trillion cells per liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameters.

Measure: Part 1: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameters.

Measure: Part 3: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 1: Change from Baseline in Blood urea nitrogen (BUN), Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 3: Change from Baseline in BUN, Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 1: Change from Baseline in Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT), Alkaline phosphatase (International units per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 3: Change from Baseline in AST, ALT, Alkaline phosphatase (International units per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 1: Change from Baseline in total protein and albumin (grams per day)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 3: Change from Baseline in total protein and albumin (grams per day)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 1: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 3: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter)

Time: Baseline and up to approximately 2 years

Description: Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.

Measure: Part 1: Change from Baseline in temperature (Degrees Celsius)

Time: Baseline and up to approximately 2 years

Description: Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.

Measure: Part 3: Change from Baseline in temperature (Degrees Celsius)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of specific gravity.

Measure: Part 1: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of specific gravity.

Measure: Part 3: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).

Measure: Part 1: Change from Baseline in Urinalysis Parameters- Urine potential of hydrogen (pH)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).

Measure: Part 3: Change from Baseline in Urinalysis Parameters- Urine pH

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary glucose.

Measure: Part 1: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary glucose.

Measure: Part 3: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary ketones.

Measure: Part 1: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary ketones.

Measure: Part 3: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary occult blood.

Measure: Part 1: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary occult blood.

Measure: Part 3: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary protein.

Measure: Part 1: Change from Baseline in urinalysis parameter: Protein

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary protein.

Measure: Part 3: Change from Baseline in urinalysis parameter: Protein

Time: Baseline and up to approximately 2 years

Description: Change from Baseline pulse rate will be assessed in a seated or semi-supine position.

Measure: Part 1: Change from Baseline in Pulse rate (Beats per minute)

Time: Baseline and up to approximately 2 years

Description: Change from Baseline pulse rate will be assessed in a seated or semi-supine position.

Measure: Part 3: Change from Baseline in Pulse rate (Beats per minute)

Time: Baseline and up to approximately 2 years

Description: 12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR, QRS, QT, and QTcF intervals. Twelve lead ECG will be measured in a supine or semi supine position after 10 minutes rest.

Measure: Part 1: Change from Baseline in Electrocardiogram (ECG) Parameters: PR Interval, QRS Interval, QT Interval, Corrected QT interval using the Fridericia formula (QTcF) (Milliseconds)

Time: Baseline and up to approximately 2 years

Description: 12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR, QRS, QT, and QTcF intervals. Twelve lead ECG will be measured in a supine or semi supine position after 10 minutes rest.

Measure: Part 3: Change from Baseline in ECG Parameters: PR Interval, QRS Interval, QT Interval, QTcF (Milliseconds)

Time: Baseline and up to approximately 2 years

Description: Change from Baseline in SBP and DBP will be assessed in a seated or semi-supine position with a completely automated device.

Measure: Part 1: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Millimeter of mercury)

Time: Baseline and up to approximately 2 years

Description: Change from Baseline in SBP and DBP will be assessed in a seated or semi-supine position with a completely automated device.

Measure: Part 3: Change from Baseline in SBP and DBP (Millimeter of mercury)

Time: Baseline and up to approximately 2 years

Description: Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.

Measure: Part 1: Number of participants with clinically significant change in respiratory rate

Time: Up to approximately 2 years

Description: Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.

Measure: Part 3: Number of participants with clinically significant change in respiratory rate

Time: Up to approximately 2 years

Description: Organ-specific evaluations will be done for abnormal values.

Measure: Part 1: Number of participants with clinically significant change in organ-specific parameters

Time: Up to approximately 2 years

Description: ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1

Measure: Part 2: Solid tumor cohorts (non-GBM): Overall response rate (ORR) of participants

Time: Up to approximately 2 years

Description: ORR is defined as the percentage of participants achieving CR or PR based on Lugano criteria.

Measure: Part 2: NHL cohort(s): ORR of participants

Time: Up to approximately 2 years

Description: PFS is defined as the percentage of participants free from radiographic progression per Response Assessment in Neuro-Oncology (RANO) criteria, or death due to any cause, for six months after starting GSK3326595.

Measure: Part 2: GMB cohort: Progression free survival (PFS) rate of participants

Time: Up to approximately 2 years

Description: Organ-specific evaluations will be done for abnormal values.

Measure: Part 3: Number of participants with clinically significant change in organ-specific parameters

Time: Up to approximately 2 years

Description: A complete physical examination will include, assessments of the head, eyes, ears, nose, throat, Skin, thyroid, Cardiovascular, Respiratory, Gastrointestinal, Neurological systems, lymph nodes and extremities. Brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen.

Measure: Part 1: Number of participants with abnormality in physical examinations

Time: Up to approximately 2 years

Description: A complete physical examination will include, assessments of the head, eyes, ears, nose, throat, Skin, thyroid, Cardiovascular, Respiratory, Gastrointestinal, Neurological systems, lymph nodes and extremities. Brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen.

Measure: Part 3: Number of participants with abnormality in physical examinations

Time: Up to approximately 2 years

Secondary Outcomes

Description: Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.

Measure: Part 1:Change from Baseline in symmetrical arginine dimethylation (SDMA) as a PD measure

Time: Baseline and up to approximately 2 years

Description: Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.

Measure: Part 2:Change from Baseline in SDMA as a PD measure

Time: Baseline and up to approximately 2 years

Description: Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.

Measure: Part 3:Change from Baseline in SDMA as a PD measure

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.

Measure: Part 1: Maximum observed plasma concentration (Cmax) in plasma following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: Cmax in plasma following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 1: Area under the plasma concentration-time curve (AUC) extrapolated from time zero to infinity (AUC[0-inf]) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: AUC (0-inf) following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.

Measure: Part 1: AUC from time zero to the last quantifiable concentration after dosing (AUC[0-t]) following single-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: AUC(0-t) following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 1: AUC over the dosing interval tau (AUC[0-tau]) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: AUC(0-tau) following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 1: Terminal phase half-life (t½) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: t½ following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 1: Oral clearance (CL/F) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: CL/F following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 1: Accumulation ratio (AR) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: AR following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 1: Time invariance (TI) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: TI following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 1: Time to Cmax (tmax) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 1: tmax following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria

Measure: Part 1: ORR of participants

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: AUC(0-inf) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: AUC(0-t) following single-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: AUC(0-t) following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: AUC(0-tau) following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: AUC(0-tau) following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: AUC[0-inf] following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: tmax following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: tmax following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: t½ following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: t½ following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: CL/F following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: CL/F following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: AR following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: AR following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: Cmax in plasma following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: Cmax in plasma following repeat-dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.

Measure: Part 3: TI following single dose administration of GSK3326595

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.

Measure: Part 3: TI following repeat dose administration of GSK3326595

Time: Up to approximately 2 years

Description: ORR is defined as the percentage of participants achieving a confirmed CR or PR based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and based on independent central review (ICR) in ACC cohort administered with tablet formulation.

Measure: Part 3: ORR of participants

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.

Measure: Part 1: Cmax following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: Tmax following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: t½ following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: CL/F following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: TI following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AR following single-dose administration of GSK3326595 tablets in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: Cmax following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: Tmax following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: t½ following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Tumor biopsies will be performed to obtain p53 gene data.

Measure: Part 2: Relationship between p53 mutational status and ORR in participants with NHL

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: CL/F following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AR following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: TI following single-dose administration of GSK3326595 tablets in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: Cmax following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: Tmax following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: CL/F following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: TI following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: AR following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.

Measure: Part 1: t½ following single-dose administration of GSK3326595 capsules in fasted condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: Cmax following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: Tmax following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: CL/F following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: TI following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: AR following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.

Measure: Part 1: t½ following single-dose administration of GSK3326595 capsules in fed condition

Time: Up to approximately 2 years

Description: An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Measure: Part 2: Number of participants with any AEs

Time: Up to approximately 2 years

Description: Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

Measure: Part 2: Number of participants with SAEs

Time: Up to approximately 2 years

Description: Number of participants withdrawn due to AEs will be evaluated.

Measure: Part 2: Number of participants withdrawn due to AEs

Time: Up to approximately 2 years

Description: Number of participants with dose interruptions and with dose reductions will be analyzed.

Measure: Part 2: Number of participants with dose interruptions and with dose reductions

Time: Up to approximately 2 years

Description: PFS defined as time from first dose until radiographic progression per standard criteria, or death due to any cause, whichever is earlier.

Measure: Part 2: PFS of participants

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595.

Measure: Part 2: AUC following administration of GSK3326595

Time: Up to approximately 2 years

Description: ORR is defined as CR + PR based on Response Assessment in Neuro-Oncology (RANO) Working Group criteria.

Measure: Part 2: ORR of participants present in GBM cohort

Time: Up to approximately 2 years

Description: Blood sample will be collected at given time points to study the PK profile of GSK3326595.

Measure: Part 2: Cmax, dose concentration following administration of GSK3326595

Time: Up to approximately 2 years

Description: DOR is defined as time from first evidence of response (CR or PR per Immune Response Evaluation Criteria in Solid Tumors [iRECIST 1.1]) to earlier date of disease progression or death due to any cause.

Measure: Part 2: Duration of Response (DOR) for ACC cohort

Time: Up to approximately 2 years

Description: ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria.

Measure: Part 2: ORR of participants for ACC cohort

Time: Up to approximately 2 years

Description: OS is defined as time from first dose until death from any cause in ACC participants who are systemic-treatment naïve.

Measure: Part 2: Overall survival (OS) of participants for ACC cohort

Time: Up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 2: Change from Baseline in Hb (Grams per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 2: Change from Baseline in Hematocrit (Proportion of red blood cells in blood)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 2: Change from Baseline in MCH (Picograms)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameter.

Measure: Part 2: Change from Baseline in MCV (Femtoliters)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameters.

Measure: Part 2: Change from Baseline in hematology parameter: RBC Count and Reticulocytes (Trillion cells per liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of hematology parameters.

Measure: Part 2: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 2: Change from Baseline in BUN, Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 2: Change from Baseline in AST, ALT, Alkaline phosphatase (International units per Liter)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 2: Change from Baseline in total protein and albumin (grams per day)

Time: Baseline and up to approximately 2 years

Description: Blood samples will be collected at indicated time points for analysis of chemistry parameters.

Measure: Part 2: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter)

Time: Baseline and up to approximately 2 years

Description: Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.

Measure: Part 2: Change from Baseline in temperature (Degrees Celsius)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of specific gravity.

Measure: Part 2: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).

Measure: Part 2: Change from Baseline in Urinalysis Parameters- Urine pH

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary glucose.

Measure: Part 2: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary ketones.

Measure: Part 2: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary occult blood.

Measure: Part 2: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter)

Time: Baseline and up to approximately 2 years

Description: Urine samples will be collected at indicated time points for the assessment of urinary protein.

Measure: Part 2: Change from Baseline in urinalysis parameter: Protein

Time: Baseline and up to approximately 2 years

Description: Change from Baseline pulse rate will be assessed in a semi-supine position.

Measure: Part 2: Change from Baseline in Pulse rate (Beats per minute)

Time: Baseline and up to approximately 2 years

Description: Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.

Measure: Part 2: Number of participants with clinically significant change in respiratory rate

Time: Up to approximately 2 years

Description: Temperature measurements will be performed in a seated or semi-supine position after 5 minutes of rest.

Measure: Part 2: Number of participants with clinically significant change in temperature

Time: Up to approximately 2 years

Description: 12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR, QRS, QT, and QTcF intervals. Twelve lead ECG will be measured in a supine or semi supine position after 10 minutes rest.

Measure: Part 2: Change from Baseline in ECG Parameters: PR Interval, QRS Interval, QT Interval, QTcF (Milliseconds)

Time: Baseline and up to approximately 2 years

Description: Change from Baseline in SBP and DBP will be assessed in a semi-supine position with a completely automated device.

Measure: Part 2: Change from Baseline in SBP and DBP (Millimeter of mercury)

Time: Baseline and up to approximately 2 years

Description: A complete physical examination will include, assessments of the head, eyes, ears, nose, throat, Skin, thyroid, Cardiovascular, Respiratory, Gastrointestinal, Neurological systems, lymph nodes and extremities. Brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen.

Measure: Part 2: Number of participants with abnormality in physical examinations

Time: Up to approximately 2 years

Description: Organ-specific evaluations will be done for abnormal values.

Measure: Part 2: Number of participants with clinically significant change in organ-specific parameters

Time: Up to approximately 2 years

28 Prognostic Impact of Immunohistochemical and Molecular Expression of the Endocytosis Receptor LRP1 in Colonic Adenocarcinomas

Colorectal cancer (CRC) is a major public health problem in France and worldwide. CRC is the third most common cancer in incidence and mortality in France. The vast majority of these cancers are adenocarcinomas that arise sporadically and develop from precursor lesions: adenoma. All CCR with the same disease stage do not have the same prognosis. Various parameters have been identified as factors influencing the prognosis and allows adjustment of the treatment. The poor histoprognostic factors are vessels and nerves invasion by the tumor or the mucinous adenocarcinoma subtype. At the molecular level, the presence of microsatellite instability (MSI) improves the prognosis, while the presence of a BRAF mutation is an independent poor prognostic factor. LRP-1 is a multifunctional endocytic receptor that belongs to the family of LDL receptors. It is involved in the clearance of matrix proteases. A loss of expression or a decrease of the LRP-1 activity is correlated with an increase of aggressiveness of cancer cells. This effect was demonstrated in vitro in vesicular thyroid carcinomas after LRP-1 blocking. The decrease in the immunohistochemical expression and LRP-1 genomic in hepatocellular carcinomas and lung adenocarcinomas was correlated with a decrease in the overall survival. In CRC, only one immunohistochemical expression study of LRP-1 in colonic adenocarcinoma has been published to date. This study shows that tumor cells express LRP-1, but in nearly half the cases, weaker than in normal colonic cells. The clinical and prognostic impact of LRP-1 expression in colon cancer and its association with a particular molecular or morphological profile has not been studied to date. In this work, the investigators will study the immunohistochemical and genic expression of LRP-1 in a series of colorectal cancers.

NCT02788669
Conditions
  1. Colon Cancer
  2. Adenocarcinoma
MeSH:Adenocarcinoma Colonic Neoplasms
HPO:Colon cancer Neoplasm of the colon

- Immunohistochemical analysis on formalin fixed and paraffin embedded tissue will be performed: - qualitative and semi-quantitative evaluation of LRP1 immunoexpression with anti-5A6 and 8G1 antibodies - RER phenotype research (MLH1, MSH2, MSH6 and PMS2 immunohistochemistry) and BRAF V600E immunohistochemistry - Molecular analyzes: - analysis of LRP-1 gene expression on frozen tissue - for selected cases: search for microsatellite instability, search for BRAF V600E, KRAS (exon 2, 3 and 4) and NRAS (exons 2, 3 and 4) mutation on formalin fixed and paraffin embedded tissue Statistical analysis: - Data description: mean and standard deviation for quantitative variables; number and percentage for categorical variables. --- V600E ---

- Immunohistochemical analysis on formalin fixed and paraffin embedded tissue will be performed: - qualitative and semi-quantitative evaluation of LRP1 immunoexpression with anti-5A6 and 8G1 antibodies - RER phenotype research (MLH1, MSH2, MSH6 and PMS2 immunohistochemistry) and BRAF V600E immunohistochemistry - Molecular analyzes: - analysis of LRP-1 gene expression on frozen tissue - for selected cases: search for microsatellite instability, search for BRAF V600E, KRAS (exon 2, 3 and 4) and NRAS (exons 2, 3 and 4) mutation on formalin fixed and paraffin embedded tissue Statistical analysis: - Data description: mean and standard deviation for quantitative variables; number and percentage for categorical variables. --- V600E --- --- V600E ---

Primary Outcomes

Measure: LRP1 molecular expression

Time: between 2006 and 2012

29 Adoptive T Cell Immunotherapy for Advanced Melanoma Using Engineered Lymphocytes: A Phase 1b Study

Phase I clinical trial to determine the Phase II dose of autologous TIL 1383I TCR gene modified T Cells using a retrovirus. This is a novel National Cancer Institute (NCI) funded investigator initiated therapy for patients with advanced melanoma.

NCT02870244
Conditions
  1. Melanoma
Interventions
  1. Biological: Escalating Doses
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- Patients with V600E mutations are eligible if they have failed an approved BRAF inhibitor or MEK inhibitor therapy or have refused treatment with an approved BRAF inhibitor or MEK inhibitor. --- V600E ---

Primary Outcomes

Description: Establish a recommended phase II dose of autologous T cell receptor transduced T cells by evaluating unexpected Grade 2 adverse events through Grade 5 regardless of attribution, all toxicities attributed to the cells, and all incidences of intubation including the duration and reason for intubation.

Measure: Approximately 18 patients with Grade 2 through Grade 5 Adverse Events that are related to study drug, graded according to NCI CTCAE Version 4.0

Time: 4 weeks

Secondary Outcomes

Description: Change in T cell count from baseline to 4 weeks.

Measure: Immunologic changes in T cell count

Time: Baseline and 4 weeks

Description: Potential auditory changes from baseline to 4 weeks.

Measure: Audiologic changes of Grade 2 or higher as related to study drug, graded according to NCI CTCAE Version 4.0

Time: Baseline and 4 weeks

Description: Potential visual changes from baseline to 4 weeks.

Measure: Ophthalmologic changes or development of Uveitis of Grade 2 or higher as related to study drug, graded according to NCI CTCAE Version 4.0

Time: Baseline and 4 weeks

Description: CT scan or physical examination will be used to evaluate for a clinical objective response in patients who have received transduced T Cells at scheduled time points.

Measure: CT scans or physical examination from approximately 18 patients will be used to evaluate for a clinical objective response using RECIST Guideline Version 1.1

Time: Baseline and 4 weeks

30 A Phase I, Randomized, Open-label, Multi-center, Two Period Crossover Study to Investigate the Effect of Food on the Pharmacokinetics of a Single Oral Dose of RO5185426, Followed by Administration of 960 mg RO5185426 Twice Daily to BRAF V600E Positive Metastatic Melanoma Patients

This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. Patients will be randomized to receive in a crossover design single oral doses of RO5185426 with or without food, with a 10-day washout period between doses. Following the crossover periods, patients will receive RO5185426 orally twice daily on a continuous basis until disease progression or unacceptable toxicity occurs.

NCT01264380
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: RO5185426
  2. Drug: RO5185426
  3. Drug: RO5185426
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Phase I, Randomized, Open-label, Multi-center, Two Period Crossover Study to Investigate the Effect of Food on the Pharmacokinetics of a Single Oral Dose of RO5185426, Followed by Administration of 960 mg RO5185426 Twice Daily to BRAF V600E Positive Metastatic Melanoma Patients. --- V600E ---

A Study of the Effect of Food on the Pharmacokinetics of Single Dose RO5185426 And the Safety And Efficacy of Continuous Administration in Patients With BRAF V600E Mutation-Positive Metastatic Melanoma This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. --- V600E ---

A Study of the Effect of Food on the Pharmacokinetics of Single Dose RO5185426 And the Safety And Efficacy of Continuous Administration in Patients With BRAF V600E Mutation-Positive Metastatic Melanoma This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. --- V600E --- --- V600E ---

OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Malignant Melanoma Melanoma null --- V600E ---

OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Malignant Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Description: Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 hours (h) post-dose (pd) on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Sample With Last Measurable Concentration (AUC[0-last]) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: Single dose Pre-dose concentration is referred as Cmin here. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States

Time: Pre-dose on Periods A and B

Description: PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: T1/2 is the time required for the concentration of the drug to reach half of its original value. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: Apparent first-order terminal elimination rate constant (kel), was calculated as the negative slope of the linear regression of the terminal phase in plasma vemurafenib concentration-time profile using specific appropriate time points. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Secondary Outcomes

Description: BOR was defined as the best objective response assessed by investigator during the treatment period according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. BOR was the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. It is defined as the number of participants whose best objective response was complete response (CR) or partial response (PR) divided by the total number of efficacy evaluable participants. CR: disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) were non-pathological in size (less than [<] 10 millimeter [mm] short axis). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR)

Time: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until disease progression or death (Up to Week 124)

Description: OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.

Measure: Overall Survival (OS)

Time: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until death (Up to Week 124)

31 BRF113929: An Open-Label, Two-Cohort, Multicentre Study of GSK2118436 as a Single Agent in Treatment Naïve and Previously Treated Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. Subjects in Cohort A will not have received any local brain therapy, and subjects in Cohort B will have received prior local therapy for brain metastases. Subjects will continue on treatment until disease progression, death, or unacceptable adverse event.

NCT01266967
Conditions
  1. Melanoma and Brain Metastases
Interventions
  1. Drug: GSK2118436
MeSH:Melanoma Neoplasm Metastasis
HPO:Cutaneous melanoma Melanoma

A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. --- V600E ---

Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator. --- V600E ---

Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.. Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator. --- V600E ---

Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.. Duration of Intracranial Response for the Subset of V600E Mutation-positive Participants. --- V600E ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Duration of Overall Response for the Subset of V600E Mutation-positive Participants. --- V600E ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Progression-free Survival in V600E Mutation-positive Participants. --- V600E ---

If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters [e.g., percent change from Baseline]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.. Overall Survival of V600E Mutation-positive Participants. --- V600E ---

- Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation. --- V600E ---

Primary Outcomes

Description: OIR is defined as the number of participants whose intracranial response was a confirmed complete response (CR) or partial response (PR) assessed by investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters (e.g., percent change from Baseline). For the primary analysis, OIR was measured when all participants in both treatment arms had two post-Baseline disease assessments. Participants who had an intracranial response of not evaluable or a missing response were treated as non-responders. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.

Measure: Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)

Secondary Outcomes

Description: OR is defined as the number of participants achieving either a CR (the disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) per modified RECIST, version 1.1. To determine the OR, the extracranial response was combined with the intracranial response. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol-scheduled assessment. Participants who had an overall response of not evaluable or a missing response were treated as non-responders.

Measure: Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 24 weeks)

Description: OR is defined as the number of participants achieving either a CR (the disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) per modified RECIST, version 1.1. To determine the OR, the extracranial response was combined with the intracranial response. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol-scheduled assessment. Participants who had an overall response of not evaluable or a missing response were treated as non-responders.

Measure: Number of Participants With V600K Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 17 weeks)

Description: OIR is defined as the number of participants whose intracranial response was a confirmed complete response (CR) or partial response (PF) assessed by investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters (e.g., percent change from Baseline). For the primary analysis, OIR was measured when all participants in both treatment arms had two post-Baseline disease assessments. Participants who had an intracranial response of not evaluable or a missing response were treated as non-responders. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.

Measure: Number of Participants With V600K Mutation-positive Melanoma With OIR, as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 16 weeks)

Description: Duration of Intracranial Response is defined as the time from the first documented evidence of intracranial CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented intracranial disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Intracranial Response for the Subset of V600E Mutation-positive Participants

Time: Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 27 weeks)

Description: Duration of Intracranial Response is defined as the time from the first documented evidence of intracranial CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented intracranial disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Intracranial Response for the Subset of V600K Mutation-positive Participants

Time: Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 31 weeks)

Description: Duration of Overall Response is defined as the time from the first documented evidence of overall CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Overall Response for the Subset of V600E Mutation-positive Participants

Time: Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 28 weeks)

Description: Duration of Overall Response is defined as the time from the first documented evidence of overall CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Overall Response for the Subset of V600K Mutation-positive Participants

Time: Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 31 weeks)

Description: PFS is defined as the time from the first dose of study medication to the earliest of death or progression (at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters [e.g., percent change from Baseline]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Measure: Progression-free Survival in V600E Mutation-positive Participants

Time: Time from the first dose of study medication to the earliest of death or progression (average of 23 weeks)

Description: PFS is defined as the time from the first dose of study medication to the earliest of death or progression (at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters [e.g., percent change from Baseline]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Measure: Progression-free Survival in V600K Mutation-positive Participants

Time: Time from the first dose of study medication to the earliest of death or progression (average of 17 weeks)

Description: Overall survival (OS) is defined as the time from the first dose of study medication until death due to any cause. OS was censored using the date of last known contact for those participants who were alive at the time of analysis.

Measure: Overall Survival of V600E Mutation-positive Participants

Time: Time from the first dose of study medication until death due to any cause (average of 35 weeks)

Description: Overall survival (OS) is defined as the time from the first dose of study medication until death due to any cause. OS was censored using the date of last known contact for those participants who were alive at the time of analysis.

Measure: Overall Survival in V600K Mutation-positive Participants

Time: Time from the first dose of study medication until death due to any cause (average of 26 weeks)

Description: An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

Measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Clinical chemistry data were summarized at each scheduled assessment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade (G) 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death related to toxicity. Blood sample was collected for the assessment of glucose, potassium, magnesium, sodium, phosphorus, potassium. aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, total bilirubin, albumin, amylase, cholesterol, creatine kinase, gamma glutamyl transferase (GGT), lipase, blood pH, and triglycerides.

Measure: Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Clinical Chemistry Parameters

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Blood samples were collected for the assessment of hepatobiliary parameters. ALT=alanine aminotranserase; AST=aspartate aminotransferase; ALP=alkaline phosphatase; BIL=total bilirubin; INR=international normalized ratio; ULN=upper limit of normal. Hepato-cellular injury is defined as (ALT/ULN)/(ALP/ULN) >=5.

Measure: Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Hematology data were summarized at each scheduled assessment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe, Grade 4, life threatening, Grade 5, death related to toxicity. Blood sample was collected for the assessment of hemoglobin, white blood cells, and platelet count.

Measure: Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Hematology Parameters

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Systolic and diastolic blood pressure were measured for all treated participants.

Measure: Mean Blood Pressure at Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36

Time: Baseline; Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36

Description: An increase in the QTc interval corrected using Bazett's formula (Bazett's QTc) was recorded for all treated participants. Grade 1 (450-480 milliseconds [msec]), Grade 2 (481-500 msec), Grade 3/4 (>=501 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade.

Measure: Number of Participants With a Worst-case On-therapy Increase From Baseline in Bazett's QTc Reading in the 12-lead Electrocardiogram (ECG)

Time: Baseline; Weeks 4, 12, 20, 28, 40, 52, and 64

Description: Echocardiograms (ECHO) were measured for all treated participants. An echocardiogram test gives information about the structure and function of the heart. LLN=lower limit of normal (determined by the institution).

Measure: Number of Participants With Abnormal Echocardiograms (ECHO) at Weeks 4 and 12

Time: Weeks (W) 4 and 12

Description: Summary statistics were calculated for each time point by cohort. The population pharmacokinetics were determined using a non-linear mixed effects modeling approach after pooling the data with other studies. These results are reported separately.

Measure: Median Concentrations of GSK2118436 and Its Metabolites Including GSK2285403, GSK2298683, and GSK2167542

Time: Week 4 (pre-dose and 1-3 hours post-dose) and Weeks 8, 16, 24, and 32 (either pre-dose in the morning or in the afternoon at 4-8 hours post-dose)

Description: This outcome measure could not be analyzed because too few participants participated in the dexamethasone study.

Measure: Composite of Pharmacokinetic Parameters of GSK2118436 in a Subset of Participants Receiving Dexamethasone

Time: Day 15

Description: The BRAF screening assay determines the specific BRAF mutational status (V600 E and K) in participants with metastatic melanoma who may benefit from treatment with GSK2118436. Per RECIST, version 1.1, CR is defined as the disappearance of all lesions. PR is defined as a >=30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline (BL) sum of the diameters (e.g., percent change from BL). Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as a >=20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir [smallest sum of diameters recorded since treatment start]). In addition, the sum must have an absolute increase from nadir of 5 millimeters. Not evaluable: cannot be classified by a preceding definition.

Measure: Number of Response Genetics Incorporated (RGI) Investigational Use Only (IUO) Assay Mutation Positive Participants and THxID BRAF Assay Mutation Positive Participants With the Indicated Best Intracranial Response

Time: Screening

32 A Phase 2 Trial of Oxaliplatin and Sorafenib Combination in Patients With Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma, Relapsed After a Cisplatin Based Treatment

In Spain, the gastric carcinoma is the 5th most frequent malignant tumor in women and the 6th in men, and represents the 3rd cause of cancer-related deaths amongst women and the 4th amongst men. The average of 5-year survival rate in Spain is under 30%. The main reason of it is that, despite carrying out an adjuvant treatment, more than the 50% will present relapsed disease. Sorafenib has been the first RAF inhibitor, both of RAF-1 and B-rRAF and its b-RAF variant V600E. Moreover, it has shown its ability to inhibit other tyrosin-quinase receptors as VEGFR 2 and 3, c-kit, Flt-3 or PDGFR. Its activity has been clearly proven in clear cell renal carcinoma. The mechanism by which Sorafenib seems to act is not because of the existence of a mutation of RAS or RAF, but because as there is a VHL shortage the HIP produces a VEGF, bFGF or TGF overexpression that produces in turn a hyper-stimulation on the RAF/ERK/MEK pathway. The RAF/MEK/ERK pathway and angiogenesis seem to be clearly involved in the gastric carcinoma tumorigenesis and progression. Because of that, it seems interesting to associate Sorafenib to an oxaliplatin-based chemotherapy, which has shown its effectiveness in relapsed patients after receiving cisplatin-based schemes. Moreover, there is a phase 1 trial confirming the tolerance of the oxaliplatin and Sorafenib association, describing partial responses amongst gastric cancer patients previously treated with cisplatin.

NCT01262482
Conditions
  1. Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (Relapsed After a Cisplatin Based Treatment)
Interventions
  1. Drug: Oxaliplatin
  2. Drug: Sorafenib
MeSH:Adenocarcinoma Esophageal Neoplasms
HPO:Esophageal neoplasm

Sorafenib has been the first RAF inhibitor, both of RAF-1 and B-rRAF and its b-RAF variant V600E. --- V600E ---

Primary Outcomes

Description: Measurements according to RECIST criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan and Magnetic Resonance Imaging (MRI)

Measure: Progression free survival

Time: anticipated 3 years

Secondary Outcomes

Description: Measurements according to RECIST criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan and Magnetic Resonance Imaging (MRI)

Measure: Tumoral response

Time: anticipated 3 years

Description: Duration of the partial or total response to the treatment. Evaluation and classification according to RECIST criteria (Response Evaluation Criteria in Solid Tumors)

Measure: Response duration

Time: anticipated 3 years

Measure: Overall survival

Time: anticipated 3 years

Measure: Toxicity

Time: anticipated 3 years

33 A Phase Ib/II Clinical Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies

This is an open label, single arm phase 1 dose escalation study and phase 2 study of BBI608 in combination with paclitaxel in patients with advanced malignancies. Currently the study is only enrolling patients with thymic carcinoma.

NCT01325441
Conditions
  1. Cancer
Interventions
  1. Drug: BBI608
  2. Drug: Paclitaxel
MeSH:Neoplasms
HPO:Neoplasm

If melanoma is positive for the V600E or V600K BRAF mutation, must have received at least one line of prior therapy with a BRAF-specific inhibitor; either alone or in combination. --- V600E ---

Primary Outcomes

Measure: Safety by reporting the adverse events and serious adverse events

Time: 6 months

Measure: Determination of the Recommended Phase 2 Dose by assessing dose-limiting toxicities (DLTs)

Time: 6 months

Secondary Outcomes

Measure: Preliminary anti-tumor activity of BBI608 when administered in combination with paclitaxel in patients with advanced malignancies by performing tumor assessments every 8 weeks

Time: 6 months

Measure: Pharmacokinetic profile of BBI608 and paclitaxel assessed by area under the plasma concentration versus time curve

Time: On Day 3 and Day 17 of the first cycle prior to dosing and 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 8.5, 9, 10, 11, 24 and 27 hours after first dose

34 A Phase 1 Safety and Tolerability Study of Personalized Live, Attenuated, Double-Deleted Listeria Monocytogenes (pLADD) Immunotherapy in Adults With Metastatic Colorectal Cancer

This study will evaluate the safety and tolerability of a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD) treatment in adults with metastatic colorectal cancer.

NCT03189030
Conditions
  1. Colorectal Neoplasms
Interventions
  1. Biological: pLADD
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Colorectal Neoplasms Colorectal Neoplasms This single arm study is designed to evaluate the safety and tolerability of a personalized treatment in adults with metastatic colorectal cancer by first analyzing the expression of tumor-associated antigens and then treating the patients with a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD)-based immunotherapy. --- V600E ---

Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Colorectal Neoplasms Colorectal Neoplasms This single arm study is designed to evaluate the safety and tolerability of a personalized treatment in adults with metastatic colorectal cancer by first analyzing the expression of tumor-associated antigens and then treating the patients with a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD)-based immunotherapy. --- V600E --- --- V600E ---

Primary Outcomes

Description: Number of patients with treatment-related adverse events as assessed by CTCAE v 4.0

Measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)

Time: Through study completion, an average of 12 months

35 The BAMM2 (BRAF, Autophagy, MEK Inhibition in Melanoma) Study: A Randomized Double Blind Phase II Study of Dabrafenib and Trametinib With or Without Hydroxychloroquine in Advanced BRAF V600E/K Melanoma

This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E/K melanoma. Hydroxychloroquine may cause cell death in tumor cells that rely on a process called "autophagy" for survival. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with dabrafenib and trametinib may work better than dabrafenib and trametinib alone to shrink and stabilize the cancer.

NCT04527549
Conditions
  1. Clinical Stage IV Cutaneous Melanoma AJCC v8
  2. Locally Advanced Melanoma
  3. Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  4. Pathologic Stage IV Cutaneous Melanoma AJCC v8
  5. Unresectable Melanoma
Interventions
  1. Drug: Dabrafenib Mesylate
  2. Drug: Hydroxychloroquine Sulfate
  3. Drug: Placebo Administration
  4. Drug: Trametinib Dimethyl Sulfoxide
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

The BAMM2 (BRAF, Autophagy, MEK Inhibition in Melanoma) Study: A Randomized Double Blind Phase II Study of Dabrafenib and Trametinib With or Without Hydroxychloroquine in Advanced BRAF V600E/K Melanoma. --- V600E ---

Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E/K melanoma. --- V600E ---

Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E/K melanoma. --- V600E --- --- V600E ---

Will be estimated by treatment arm.. Inclusion Criteria: - Patient must have locally advanced unresectable stage IIIC or stage IV melanoma - Patient must have BRAF V600E or BRAF V600K tumor genotype based on a Clinical Laboratory Improvement Act (CLIA) approved assay - Patient must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. --- V600E ---

phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine) within 4 weeks prior to randomization - Patient must not have a current use of a prohibited medication Inclusion Criteria: - Patient must have locally advanced unresectable stage IIIC or stage IV melanoma - Patient must have BRAF V600E or BRAF V600K tumor genotype based on a Clinical Laboratory Improvement Act (CLIA) approved assay - Patient must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. --- V600E ---

Primary Outcomes

Description: Estimated from the Kaplan-Meier curves and compared by treatment arm. A test statistic of the difference in one-year PFS rates divided by the square root or the sum of the variances will be used with a normal approximation. Progression will be evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).

Measure: Progression-free survival (PFS) rate

Time: From randomization to progression or death (whichever occurs first), assessed at 1 year after completion of treatment

Secondary Outcomes

Description: Will be estimated using the method of Kaplan-Meier by treatment arm and compared using the log-rank test. In this analysis, all cases with PFS assessed (including cases with censored < one-year) will be included. Progression will be evaluated based on international criteria proposed by the revised RECIST guideline (version 1.1).

Measure: PFS distribution

Time: From randomization to progression or death (whichever occurs first), assessed at 1 year after completion of treatment

Description: Will be estimated by treatment arm and 95% confidence intervals (CIs) will be provided. Response will be defined by the RECIST guidelines (version 1.1).

Measure: Overall response rate

Time: Up to 1 year after completion of treatment

Description: Will be estimated by treatment arm and 95% CIs will be provided. Response will be defined by the RECIST guidelines (version 1.1).

Measure: Complete response rate

Time: Up to 1 year after completion of treatment

Description: Overall survival will be described using the method of Kaplan-Meier by treatment arm.

Measure: Overall survival

Time: From randomization to death from any cause, assessed up to 1 year after completion of treatment

Description: Will be monitored carefully throughout the study and will be summarized by treatment arm. Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

Measure: Incidence of adverse events

Time: Up to 1 year after completion of treatment

Description: Will be estimated by treatment arm.

Measure: Treatment duration

Time: Up to 1 year after completion of treatment

36 A Phase II Study of the BRAF Inhibitor Encorafenib in Combination With the MEK Inhibitor Binimetinib in Patients With BRAFV600E-mutant Metastatic Non-small Cell Lung Cancer

A Phase II study of the BRAF inhibitor Encorafenib in combination with the MEK inhibitor Binimetinib in Patients with BRAFV600E-mutant metastatic Non-small Cell Lung Cancer

NCT04526782
Conditions
  1. Non Small Cell Lung Cancer
  2. BRAF V600E
Interventions
  1. Drug: Encorafenib 75 MG
  2. Drug: Binimetinib 15 MG
  3. Drug: Docetaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Non Small Cell Lung Cancer BRAF V600E Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- V600E ---

Primary Outcomes

Description: Objective Response Rate at 6 months using RECIST1.1 criteria

Measure: Objective response rate

Time: 8 weeks

Secondary Outcomes

Description: Time from the date of the first documented response (CR or PR) to the earliest date of disease progression (RECIST 1.1), or death due to any cause.

Measure: Duration Response Rate

Time: 8 weeks

Description: Time from enrollment to first observation of progression (RECIST1.1) or date of death (from any cause)

Measure: Progression-free Survival

Time: about 24 months

Description: Time from enrollment until death due to any cause

Measure: Overall Survival

Time: about 24 months

Description: Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0

Measure: Incidence, type and severity of adverse events

Time: From time of informed consent through treatment period and up to 30 days post last dose of study treatment (about 24 months)

37 ENABLE-NGS: Enhancing Diagnosis in Chronic B-cell Lymphoproliferative Disorders Using Next-Generation Sequencing

To enhance the diagnosis of unclassifiable, non-CLL B-LPDs using next-generation sequencing technology.

NCT03344809
Conditions
  1. Lymphoma
MeSH:Lymphoproliferative Disorders
HPO:Lymphoproliferative disorder

While some of these mutations, such as the BRAF V600E mutation in Hairy Cell Leukaemia (HCL)2, are now accepted as disease defining mutations, others such as MYD88 and NOTCH1/2 mutations are found in more than one subtype of B-LPD3. --- V600E ---

Primary Outcomes

Description: This will be reported as a percentage of the total number of cases sequenced

Measure: Proportion of cases where a definite category and/or detectable mutation can be identified.

Time: 2 years

Secondary Outcomes

Description: Age and sex distribution will be reported along with the proportion of cases in each immunomorphologic category

Measure: Demographics and distribution in each immunomorphological category

Time: 2 years

Description: The distribution of mutations within each immunomorphological category will be reported descriptively.

Measure: Correlation of each immunomorphological category with the mutation profile.

Time: 2 years

38 A Phase 2, Multi-center, Open Label Study of NIR178 in Combination With PDR001 in Patients With Selected Advanced Solid Tumors and Non-Hodgkin Lymphoma

The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

NCT03207867
Conditions
  1. NSCLC, Non Small Cell Lung Cancer
  2. RCC, Renal Cell Cancer
  3. Pancreatic Cancer
  4. Urothelial Cancer
  5. Head and Neck Cancer
  6. DLBCL, Diffused Large B Cell Lymphoma
  7. MSS, Microsatellite Stable Colon Cancer
  8. TNBC, Triple Negative Breast Cancer
  9. Melanoma
  10. mCRPC, Metastatic Castration Resistant Prostate Cancer
Interventions
  1. Drug: NIR178
  2. Drug: PDR001
MeSH:Lymphoma Lymphoma, Non-Hodgkin Triple Negative Breast Neoplasms Carcinoma, Renal Cell
HPO:Clear cell renal cell carcinoma Lymphoma Non-Hodgkin lymphoma Papillary renal cell carcinoma Renal cell carcinoma

Patients with melanoma: BRAF V600E wild type patients: must have received anti-PD-1/PD-L1 single agent, or in combination with anti-CTLA-4 therapy BRAF V600E mutant patients: must have received prior anti-PD-1/PD-L1 single-agent, or in combination with anti-CTLA-4 therapy. --- V600E ---

Patients with melanoma: BRAF V600E wild type patients: must have received anti-PD-1/PD-L1 single agent, or in combination with anti-CTLA-4 therapy BRAF V600E mutant patients: must have received prior anti-PD-1/PD-L1 single-agent, or in combination with anti-CTLA-4 therapy. --- V600E --- --- V600E ---

In addition, subjects must have received prior BRAF V600E inhibitor therapy, either single-agent or in combination with a MEK inhibitor Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC): - Of the 1-3 prior lines of therapy, patients must have received and failed at least one line of treatment after emergence of castration resistant disease - Patients must not have received prior immunotherapy (previous immune checkpoint inhibitors; single agent and/or combination therapy with anti-CTLA-4, anti-PD-1, anti-PD-L1), except for NSCLC patients enrolled in part 3 and Japanese safety run-in part. --- V600E ---

Primary Outcomes

Description: Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL) or PCWG3 criteria (for mCRPC)

Measure: Determine the overall response rate

Time: Every 8 weeks for first 40 weeks

Description: Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL) or PCWG3 criteria (for mCRPC)

Measure: Determine the overall response rate

Time: Every 12 weeks after the first 40 weeks until disease progression or study discontinuation (an average of 6 months)

Description: Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL), or PCWG3 criteria (for mCRPC)

Measure: Determine the overall response rate

Time: Baseline

Secondary Outcomes

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Baseline

Description: Time from first documented response to disease progression

Measure: Determine the duration of response (DoR)

Time: Baseline

Description: Time from start of treatment to date of death due to any reason

Measure: Determine the overall survival rate (OR)

Time: Every 12 weeks until end of study for at least 24 months from the start date of the study treatment

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Baseline

Description: Type, frequency, and severity of AEs and SAEs; Frequency of dose interruptions, reductions and discontinuation, Dose intensity

Measure: Safety and tolerability of the NIR178 and PDR001 combination

Time: Date of consent to end of study (An average of 24 months)

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Screening

Description: Presence and/or concentration of anti-PDR001 antibodies

Measure: Presence and/or concentration of anti-PDR001 antibodies

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of NIR178 and its metabolites

Measure: Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Pharmacokinetics: Area under the plasma concentration versus time curve (AUC) (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Plasma concentration Vs Time profiles (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of PDR001

Measure: Plasma concentration Vs Time profiles (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Peak plasma concentration- Cmax (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of PDR001

Measure: Peak plasma concentration- Cmax (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Time of maximum concentration observed- Tmax (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of PDR001

Measure: Time of maximum concentration observed- Tmax (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Every 8 weeks for first 40 weeks

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Every 12 weeks after the first 40 weeks until disease progression

Description: Time from first documented response to disease progression

Measure: Determine the duration of response (DoR)

Time: Until study discontinuation (an average of 6 months)

Description: Time from first documented response to disease progression

Measure: Determine the duration of response (DoR)

Time: Every 8 weeks for first 40 weeks

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Until study discontinuation (an average of 6 months)

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Every 8 weeks for first 40 weeks

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Cycle 6 Day 1

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Cycle 1 Day 8

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Cycle 3 Day 1

Description: Presence and/or concentration of anti-PDR001 antibodies

Measure: Presence and/or concentration of anti-PDR001 antibodies

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178 and its metabolites

Measure: Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Plasma concentration Vs Time profiles (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Plasma concentration Vs Time profiles (PDR001)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of NIR178

Measure: Peak plasma concentration- Cmax (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Peak plasma concentration- Cmax (PDR001)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of NIR178

Measure: Time of maximum concentration observed- Tmax (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Time of maximum concentration observed- Tmax (PDR001)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Until study discontinuation (an average of 6 months)

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the duration of response (DoR)

Time: Every 12 weeks after the first 40 weeks until disease progression

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Every 12 weeks after the first 40 weeks until disease progression

39 A Phase Ib Trial of Vemurafenib Plus Copanlisib to Enhance Radioiodine Avidity in Radioiodine-Refractory Thyroid Cancers

The purpose of this study is to develop a new drug treatment to reverse tumor resistance to radioiodine in BRAF mutant tumors so that radioiodine can be given to shrink tumors. This study is also being done to find out the highest doses of copanlisib and vemurafenib that, when given in combination, do not cause serious side effects, and whether the study treatment will make radioiodine therapy work better in patients with BRAF-mutant thyroid cancers.

NCT04462471
Conditions
  1. Thyroid Carcinoma
  2. Thyroid Cancer
  3. Thyroid Cancer, Follicular
  4. Thyroid Cancer (Follicular Cell)
  5. Thyroid Cancer, Papillary
  6. BRAF V600E Mutation Positive
Interventions
  1. Diagnostic Test: I-124 PET/CT lesion dosimetry
  2. Drug: Vemurafenib
  3. Drug: Copanlisib
MeSH:Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Thyroid Carcinoma Thyroid Cancer Thyroid Cancer, Follicular Thyroid Cancer (Follicular Cell) Thyroid Cancer, Papillary BRAF V600E Mutation Positive Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases null --- V600E ---

Primary Outcomes

Description: The primary objective of this study is to determine the MTD of vemurafenib plus copanlisib inpatients with advanced BRAF mutant RAIR thyroid cancer. The MTD is defined as the highest dose at which no more than 1 of 6 patients treated at that dose experience a DLT.

Measure: Maximum tolerated dose of vemurafenib plus copanlisib

Time: 6 months

40 A Phase 1b Trial of Talimogene Laherparepvec in Combination With Dabrafenib and Trametinib in Advanced Melanoma With an Activating BRAF Mutation

The purpose of the study is to determine safety and tolerability of the combination of talimogene laherparepvec in combination with dabrafenib and trametinib in BRAF mutated advanced melanoma.

NCT03088176
Conditions
  1. Melanoma
  2. BRAF Gene Mutation
Interventions
  1. Drug: Talimogene Laherparepvec 1 Million Pfu/Ml Inj,Susp,1Ml,Vil
  2. Drug: Talimogene Laherparep 100 Mil Pfu/Ml 1Ml
  3. Drug: Dabrafenib
  4. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Primary or recurrent Stage IIIB to IVM1c melanoma for whom surgery is not recommended 3. Activating BRAF mutation (limited to V600E or V600K mutations if being treated first-line, but can include any well-defined BRAF mutation after failure of prior immunotherapy) 4. Measurable disease defined as follows: At least one melanoma lesion that can be accurately and serially measured in one dimension and for which the longest diameter is ≥10 mm as measured by calipers, CT scan, or MRI. --- V600E ---

Primary Outcomes

Description: Number of DLT seen in the subject population

Measure: Rate of Dose Limiting Toxicities (DLT)

Time: 2 years

Secondary Outcomes

Description: per RECIST 1.1

Measure: Progression Free Survival

Time: 4 years

Description: per RECIST 1.1

Measure: Objective Response Rate

Time: 4 years

Description: Best change in tumor diameters

Measure: Change in tumor burden

Time: 4 years

Description: In responding patients, time from first dose to achieving objective response

Measure: Time to Response

Time: 4 years

Description: In responding patients, time from first evidence of objective response until progression or end of study

Measure: Duration of Response

Time: 4 years

Other Outcomes

Description: Change in diameters of individual lesions

Measure: Lesion-level objective response

Time: 4 years

Description: Exploratory analysis including number of participants with changes in CD8+ tumor infiltrating lymphocytes between pre-study and on-study biopsies

Measure: Biomarker analysis

Time: 4 years

41 A Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma

BRF113683 is a Phase III, randomized, open-label study comparing the efficacy, safety, and tolerability of GSK2118436 to dacarbazine (DTIC), in subjects with BRAF mutant advanced (Stage III) or metastatic (Stage IV) melanoma. Subjects will be randomized to receive 150 mg of GSK2118436 twice daily or 1000 mg/m2 DTIC every 3 weeks and continue on treatment until disease progression, death, or unacceptable adverse event. Subjects who progress on DTIC will be allowed to crossover to an optional extension arm of the study to receive GSK2118436.

NCT01227889
Conditions
  1. Cancer
Interventions
  1. Drug: GSK2118436
  2. Drug: Dacarbazine (DTIC)
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

The number of participants with non-melanoma skin lessions was assessed from the time of Screening until study completion or discontinuation from the study for any reason.. Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay. --- V600E ---

Multiple specimen per participant were analyzed.. Inclusion Criteria: - Adults at least 18 years of age - Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E) - Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed. --- V600E ---

- Certain cardiac abnormalities Inclusion Criteria: - Adults at least 18 years of age - Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E) - Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed. --- V600E ---

Primary Outcomes

Description: PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). For participants who did not progress or die, PFS was censored at the date of last contact. Data are presented as median and 96% confidence interval.

Measure: Progression-free Survival (PFS) as Assessed by the Investigator

Time: Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)

Description: PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by an independent radiologist according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.

Measure: Progression-free Survival (PFS) as Assessed by an Independent Radiologist: Randomized Phase

Time: Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)

Secondary Outcomes

Description: Overall survival is defined as the interval of time between the date of randomization and the date of death due to any cause. For participants who did not die, overall survival was censored at the date of last contact.

Measure: Overall Survival

Time: Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months)

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

Measure: Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Randomized Phase

Time: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks)

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an independent radiologist per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

Measure: Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase

Time: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks)

Description: Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

Measure: Duration of Response as Assessed by the Investigator: Randomized Phase

Time: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 65.6 weeks)

Description: Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. NA indicates that data is not available.

Measure: Duration of Response as Assessed by an Independent Radiologist: Randomized Phase

Time: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 7.4 months)

Description: PFS2 is defined as the time from the first dose of GSK2118436, in participants randomized to DTIC who crossed over to GSK2118436 after initial progression, to the earliest date of radiographic or photographic disease progression or death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.

Measure: Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase

Time: Time from first dose of GSK2118436 in participants who crossover after initial progression to the earliest date of radiographical or photographical PD or death due to any cause (up to 6.4 months)

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

Measure: Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Crossover Phase

Time: From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months)

Description: Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

Measure: Duration of Response as Assessed by the Investigator: Crossover Phase

Time: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 6.4 months)

Description: Dermatological examinations were performed by the investigator, or at the discretion of the investigator, referred to a dermatologist. The number of participants with non-melanoma skin lessions was assessed from the time of Screening until study completion or discontinuation from the study for any reason.

Measure: Number of Participants With Non-melanoma Skin Lesions: Randomized Phase

Time: From Screening until study completion or discontinuation from the study (up to 9.9 months)

Description: Analytical and clinical validation of the companion diagnostic (cDx) assay was performed to determine the extent of agreement between the bioMerieux cDx assay (THxID BRAF Assay) and the Clinical Trial Assay (CTA) to detect BRAF mutations to determine participant eligibility into the study. Skin tissue samples collected at the Screening visit were used for this analysis. Multiple specimen per participant were analyzed.

Measure: Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay

Time: Screening

42 Randomized Controlled Trial of Total Thyroidectomy With and Without Prophylactic Central Neck Lymph Node Dissection in Patients With Low-risk Papillary Thyroid Cancer

Background: - Papillary thyroid cancer (PTC) often spreads to lymph nodes in the neck. This can be hard to detect. People often have lymph nodes removed anyway, and researchers want to study if this is a good idea. Objective: - To compare the effectiveness of removing lymph nodes in the neck that show no evidence of cancer along with the thyroid, or removing only the thyroid. Eligibility: - Adults age 18 and older with PTC or thyroid nodules suspicious for PTC, with no evidence that the disease has spread in the body. Design: - Participants will be screened with medical history, physical exam, blood tests, scans, and x-rays. - Participants will: - Answer questions. They may have a tumor biopsy. - Have a flexible laryngoscopy. A small tube will pass through the nose to the vocal cords. - Group 1: have surgery to remove the thyroid gland only. Lymph nodes in the neck will be removed if the cancer has spread. - Group 2: have surgery to remove the thyroid and lymph nodes in the neck. - At all post-surgery visits, participants will answer questions and have blood drawn. In addition: - 1 day: laryngoscopy. - 2 weeks: possible laryngoscopy. - 3 months: ultrasound of the thyroid and neck. - Discuss whether to try hormone treatment and/or radioactive iodine. - Possible diagnostic whole body radioiodine scan (WBS). Participants will swallow a capsule or liquid and lie under a camera. - 6 months: ultrasound and maybe laryngoscopy. - 1 year: diagnostic WBS and ultrasound. Participants may get thyroid stimulating hormone. - Participants will have annual follow-up visits for 10 years. They will have a physical exam, blood drawn, scans, and may complete a questionnaire.

NCT02408887
Conditions
  1. Low-risk Papillary Thyroid Cancer
  2. Endocrine Malignancy
  3. Thyroid Cancer
Interventions
  1. Procedure: Total Thyroidectomy (TT)
  2. Procedure: Prophylactic central neck lymph nodedissection (pCND)
MeSH:Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

The impact of BRAF V600E mutation status on lymph node metastasis. --- V600E ---

Correlation between BRAF V600E of tumor and median amount of time before disease progression. --- V600E ---

but less than or equal to 4 cm measured in greatest dimension and confirmed by the Laboratory of Pathology, NCI or confirmed by the pathology laboratory of the enrolling institution: - Indeterminate thyroid biopsy per Bethesda System for reporting thyroid cytopathology with BRAF V600E mutation or RET/PTC rearrangement - Cytologically or histologically suspicious or confirmed PTC per Bethesda System for reporting thyroid cytopathology. --- V600E ---

but less than or equal to 4 cm. in size with either: - inconclusive thyroid cytology positive for BRAF V600E mutation or RET/PTC rearrangement or - cytologically suspicious for or consistent with PTC - Absence of extrathyroidal extension or lymphadenopathy suggesting metastatic PTC on physical examination and neck ultrasound. --- V600E ---

Primary Outcomes

Description: Proportion of patients that have biochemical cure after totalthyroidectomy (TT) with and without pCND

Measure: Biochemical cure rates undergoing total thyroidectomy (TT) with and without pCND as measured by postoperative TSH-stimulated serum thyroglobulin (stim-Tg) at 3 months (prior to RAI treatment)

Time: 3 months

Secondary Outcomes

Description: Proportion of patients that have biochemical cure after TT with andwithout pCND

Measure: Biochemical cure rates in patients undergoing total thyroidectomy with and without pCND by postoperative TSH-stimulated serum thyroglobulin (stim-Tg) at 1 year postoperatively in patients who will not receive RAI or 1 year post remnant ablation

Time: 1 year

Description: Proportion of patients that have improvement in quality of life afterTT with and without pCND

Measure: The QOL of patients

Time: 10 years

Description: Proportion of patients that have improvement in voice quality,swallowing impairment after TT with and without pCND

Measure: Subjective voice quality, swallowing impairment

Time: 6 month

Description: Rate and duration hypoparathyroidism

Measure: Rate and duration of both symptomatic and asymptomatic hypoparathyroidism

Time: 6 month

Description: Proportion of patients that have cervical wound complications

Measure: Rate of cervical wound complications

Time: 3 month

Description: Correlation between BRAF V600E of tumor and median amount of time before disease progression

Measure: The impact of BRAF V600E mutation status on lymph node metastasis

Time: at progression

Description: Proportion of patients that have less neck pain

Measure: Neck pain

Time: 6 month

43 Biopsy- and Biology-driven Optimization of Targeted Therapy of Metastatic Melanoma in BRAF Inhibitor Non-pretreated and Pretreated Subjects With Advanced, Non-resectable (STAGE IIIC) or Metastatic (StAGE IV) BRAF Mutation-positive Melanoma

This is an open-label, multi-center, clinical phase II study to explore the correlation of the genetic make-up of the treated tumor before start of therapy and to correlate clinical response at 8 weeks as well as metabolic response at 2 and 8 weeks with genetic features of the tumor. It will be conducted as a rationale optimization of targeted therapy in BRAF naïve and pretreated patients. Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B)

NCT02410863
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B) Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.. To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.. Correlation of the tumor´s molecular composition to metabolic responses. --- V600E ---

3. Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive by the central laboratory. --- V600E ---

Primary Outcomes

Description: To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.

Measure: Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.

Time: Week 8

Secondary Outcomes

Description: To correlate the tumor´s molecular composition to metabolic responses and biological effects on the downstream signaling cascade in order to get first insights into an adaptive mechanism in the downstream signaling of an oncogenic driver mutation upon its selective inhibition.

Measure: Correlation of the tumor´s molecular composition to metabolic responses

Time: Baseline, week 2 and 8

Description: Occurrence of adverse events and reactions

Measure: Safety / toxicity according to the Common Toxicity Criteria (CTC, Version 4.0)

Time: 1 year

Description: Proportion of patients with PFS after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs first.

Measure: Progression free survival rate

Time: 6 and 12 months

Description: Time after date of the first dose of study medication until documented date of death

Measure: Overall survival

Time: 6 and 12 months

Description: Time after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs

Measure: Progression free survival according to RECIST criteria

Time: 6 and 12 months

Description: Proportion of patients with PR and CR

Measure: Overall response rate according to RECIST criteria

Time: 6 and 12 months

Description: Proportion of patients with SD, PR and CR

Measure: Disease control rate according to RECIST criteria

Time: 6 and 12 months

44 An Open Label Non Randomized Access Study of Trametinib for Patients With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma

This is a single arm open label, multicenter, non randomized, access study of trametinib for subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV). Trametinib may be given as monotherapy or in combination since first line metastatic melanoma as per inclusion criteria. Subjects who received prior BRAF inhibitor may be included if they have not progressed under such treatment or if they have presented limited progression as per eligibility criteria. It is estimated that between 250 and 400 subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV) will be enrolled.

NCT02416232
Conditions
  1. Melanoma
Interventions
  1. Drug: Trametinib
  2. Drug: Dabrafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

An Open Label Non Randomized Access Study of Trametinib for Patients With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma. --- V600E ---

Access Study of Trametinib for Subjects With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma This is a single arm open label, multicenter, non randomized, access study of trametinib for subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV). --- V600E ---

Access Study of Trametinib for Subjects With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma This is a single arm open label, multicenter, non randomized, access study of trametinib for subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV). --- V600E --- --- V600E ---

It is estimated that between 250 and 400 subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV) will be enrolled. --- V600E ---

- Has histologically confirmed cutaneous melanoma BRAF V600E/K positive mutation either unresectable (stage IIIc) or distant metastatic (stage IV). - Is not eligible for enrolment in any other ongoing relevant hypothesis testing clinical study for metastatic melanoma or, if eligible, is so geographically distant from a participating site that attending frequent clinic visits is not feasible. --- V600E ---


45 Phase 2 Study With COmbination of Vemurafenib With Cobimetinib in B-RAF V600E/K Mutated Melanoma Patients to Normalize LDH and Optimize Nivolumab and Ipilimumab therapY

Rationale: The combination of ipilimumab and nivolumab induces relatively high response rates and promising response depth in late stage melanoma. Nevertheless, it takes time till responses occur and still a significant number of patients do not benefit from treatment, due to rapid progressive disease or resistance to therapy. In contrast to immunotherapies targeted therapies (BRAF or MEK inhibitors), can induce faster and higher response rates, but often of shorter duration, even when combined. Initial attempts of combining vemurafenib or dabrafenib + trametinib with ipilimumab failed due to toxicity. Patients with elevated levels of serum LDH are less likely to respond to immunotherapy compared to patients with normal LDH levels. This does not mean that such patients do not benefit at all from immunotherapy. This raises the question, whether response rates upon immunotherapy can be improved by upfront reduction of tumor burden and normalization of LDH. The investigators postulate that induction therapy with combined BRAF+MEK inhibition, and subsequent LDH normalization, can improve response rates to the rates seen in LDH normal patients. To address this question the investigators have setup a randomized phase 2 trial in metastatic melanoma patients with elevated serum LDH comparing the response rates upon ipilimumab + nivolumab versus ipilimumab + nivolumab preceded by 6 weeks of vemurafenib + cobimetinib induction. Furthermore, less than half of the patients treated with the combination of ipilimumab and nivolumab received maintenance nivolumab, and approximately 40% of all patients discontinued treatment for toxicity. In 70% of patients responses were ongoing despite discontinuation of treatment due to toxicity. This raises the question, to what extent does maintenance therapy add clinical benefit to an ongoing immune response. Preclinical data indicate even that continuous restimulation of T cells can result in activation induced non-responsiveness (anergy). Therefore, a secondary objective of this trial will be, to test a response-driven nivolumab scheme Objectives: Primary Objective • To compare efficacy of induction vemurafenib + cobimetinib followed by ipilimumab + nivolumab (Arm A) versus upfront ipilimumab + nivolumab treatment (Arm B). Secondary Objectives - To describe duration of response and overall survival induced by vemurafenib + cobimetinib followed by the combination of ipilimumab + nivolumab (Arm A) as compared to ipilimumab + nivolumab (Arm B) - To describe the rate and quality of toxicity observed in the two study arms - To describe the rate of ongoing responses upon response-driven flat dose (240mg q2w or 480mg q4w) nivolumab maintenance - To determine the immune-activating capacity of induction therapy with vemurafenib + cobimetinib followed by the combination of ipilimumab + nivolumab. - To evaluate the changes in systemic immune competence Study design: This is a two-arm phase 2 study consisting of 200 BRAFV600E/K mutation-positive late-stage melanoma patients with an elevated baseline LDH level (> ULN, < 3xULN) randomized 1:1 (stratified according to LDH) to receive either vemurafenib + cobimetinib directly followed by ipilimumab + nivolumab (Arm A) or standard first line ipilimumab + nivolumab (Arm B). Subsequently, patients in both arms will receive flat dose (240mg q2w or 480mg q4w) nivolumab maintenance in a response-driven manner. Study population: Stage IV, or unresectable stage III, BRAFV600E/K mutation positive melanoma patients, naïve for BRAF/MEK, PD-1/PD-L1 or CTLA-4 targeting therapy, 18 years and older. Intervention: Patients will be randomized 1:1 to receive either 6 weeks vemurafenib 960 mg bid + cobimetinib 60 mg QD 21-day on, 7-day off (21/7) schedule, directly followed by 4 courses of ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm A) or first line standard 4 courses of ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm B). Subsequently, patients in both arms will receive nivolumab maintenance flat dose (240mg q2w or 480mg q4w) in a response-driven manner according to their response at week 18. Main study parameters/endpoints: Primary Endpoints • Compare the best overall response rate (BORR) according to RECIST 1.1 of both arms at week 18 from start of treatment. Secondary Endpoints - Progression-free survival (PFS) according to RECIST 1.1 - Overall survival (OS) - Percentage of grade 3/4 toxicities according to CTCv4.03 - Percentage of ongoing response, percentage of patients requiring re-induction, response percentage upon re-induction - Changes in tumor-specific T cell responses

NCT02968303
Conditions
  1. Melanoma, Malignant, of Soft Parts
Interventions
  1. Drug: Vemurafenib and Cobimetinib
MeSH:Melanoma Sarcoma, Clear Cell
HPO:Cutaneous melanoma Melanoma

Phase 2 Study With COmbination of Vemurafenib With Cobimetinib in B-RAF V600E/K Mutated Melanoma Patients to Normalize LDH and Optimize Nivolumab and Ipilimumab therapY. --- V600E ---

Inclusion Criteria: - Adults 18 years and older - World Health Organization (WHO) Performance Status 0-2 - Histologically or cytologically confirmed Stage IV, or unresectable stage III, BRAF V600E/K mutated melanoma - Measurable disease according to RECIST 1.1 - Signed and dated informed consent form - No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 - No prior BRAFi and/ or MEKi therapy - No immunosuppressive medications - Screening laboratory values must meet the following criteria and should be obtained within 10 days prior to randomization: - WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.0 mmol/L - Creatinine ≤ 2x ULN or creatinine clearance (CrCl) ≥ 40 ml/min - AST, ALT ≤ 3.0 x ULN (≤5 x ULN for patients with liver metastases) - Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL ) - LDH > ULN, < 5.0 x ULN - No symptomatic brain metastases (asysmptomatic brain metastases, accidentally found during screening can be included) - No leptomeningeal metastases - No active autoimmune disease requiring systemic treatment in the past 3 months or a documented history of autoimmune disease, or history of syndrome that required systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or immunosuppressive medications. --- V600E ---

- No underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events Inclusion Criteria: - Adults 18 years and older - World Health Organization (WHO) Performance Status 0-2 - Histologically or cytologically confirmed Stage IV, or unresectable stage III, BRAF V600E/K mutated melanoma - Measurable disease according to RECIST 1.1 - Signed and dated informed consent form - No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 - No prior BRAFi and/ or MEKi therapy - No immunosuppressive medications - Screening laboratory values must meet the following criteria and should be obtained within 10 days prior to randomization: - WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.0 mmol/L - Creatinine ≤ 2x ULN or creatinine clearance (CrCl) ≥ 40 ml/min - AST, ALT ≤ 3.0 x ULN (≤5 x ULN for patients with liver metastases) - Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL ) - LDH > ULN, < 5.0 x ULN - No symptomatic brain metastases (asysmptomatic brain metastases, accidentally found during screening can be included) - No leptomeningeal metastases - No active autoimmune disease requiring systemic treatment in the past 3 months or a documented history of autoimmune disease, or history of syndrome that required systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or immunosuppressive medications. --- V600E ---

Primary Outcomes

Measure: Best overall response rate (BORR) according to RECIST 1.1

Time: Week 18 from start of treatment

Secondary Outcomes

Measure: Progression-free survival (PFS) according to RECIST 1.1

Time: 1 and 2 years from start of treatment

Measure: Overall survival (OS)

Time: 1 and 2 years from start of treatment

Measure: Grade 3/4 toxicities according to CTCv4.03

Time: Week 18 from start of treatment

Measure: Percentage of ongoing response

Time: 1 and 2 years from start of treatment

Measure: Response percentage upon re-induction

Time: Week 18 from start of treatment

Measure: Changes in tumor-specific T cell responses

Time: Week 18 from start of treatment

46 An Open-label Multicenter Study on the Efficacy of Continuous Oral Dosing of Vemurafenib on Tumour Response in Previously Treated Patients With Metastatic Melanoma

This open-label single arm study will assess the efficacy, safety and tolerability of Vemurafenib in previously treated patients with metastatic melanoma. Patients will receive oral Vemurafenib [RG7204; PLEXXIKON: PLX4032] at a dose of 960 mg b.i.d. continuously until disease progression or withdrawal from study and will be assessed at regular intervals for tumour response and tolerability. Target sample size is <100 patients.

NCT00949702
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

DTIC, temozolomide, etc.) - BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay) - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active CNS metastases on CT/MRI within 28 days prior to enrollment - history of or known carcinomatous meningitis - previous treatment with BRAF (sorafenib allowed) or MEK inhibitor - cardiac dysrhythmias >2 NCI CTCAE or treatment with drugs with dysrhythmic potential - uncontrolled hypertension(>150/100mmHg) despite optimal medical therapy - infectious disease including HIV, HBV and HCV Inclusion Criteria: - adult patients >/=18 years of age - histologically confirmed metastatic melanoma (Stage IV, AJCC) - patients must have completed and failed at least one prior standard of care regimen (e.g. --- V600E ---

DTIC, temozolomide, etc.) - BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay) - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active CNS metastases on CT/MRI within 28 days prior to enrollment - history of or known carcinomatous meningitis - previous treatment with BRAF (sorafenib allowed) or MEK inhibitor - cardiac dysrhythmias >2 NCI CTCAE or treatment with drugs with dysrhythmic potential - uncontrolled hypertension(>150/100mmHg) despite optimal medical therapy - infectious disease including HIV, HBV and HCV Malignant Melanoma Melanoma null --- V600E ---

Primary Outcomes

Description: BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.

Measure: Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Secondary Outcomes

Description: BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.

Measure: Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those patients whose best overall response was complete response or partial response. PD: At least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. For patients who were alive without progression, duration of response was censored on the date of the last evaluable tumor assessment.

Measure: Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed complete response (CR) or partial response (PR), whichever occurred first.

Measure: Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in patients without disease progression were considered to be a PFS event on the date of death. Patients who neither progressed nor died were censored on the date of the last evaluable tumor assessment prior to the data cutoff date.

Measure: Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: Overall survival was defined as the time from the date of the first treatment to the date of death, regardless of the cause of death. For patients who were alive at the time of analysis, overall survival was censored at the last date the patient was known to be alive prior to the data cutoff date.

Measure: Overall Survival

Time: From first treatment through September 27, 2010

Description: Three parameters were measured. (1) Improvement in the Physician's Assessment of Global Performance status on a 7-point scale (1=very much better to 7=very much worse). (2) Improvement in oxygen saturation requirements, defined as a clinically meaningful increase in oxygen saturation requirement (from a baseline value < 95% to ≥ 95% saturation using a pulse oximeter). (3) A decrease in total dose and frequency of narcotic pain analgesics. The percentage of patients showing improvement (1 and 2) or a decrease (3) are reported.

Measure: Improvement in Physical Symptoms (Improvement in Physician's Assessment of Global Performance Status and Oxygen Saturation Requirements, and Decrease in Total Dose and Frequency of Narcotic Pain Analgesics) During Treatment in Comparison to Baseline

Time: From first treatment through September 27, 2010

Description: Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin).

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1

Time: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1

Description: Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin). AUC0-8h was calculated using the linear trapezoidal rule.

Measure: Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1

Time: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1

Description: Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and 4 hours post-dose at Day 1 of Cycles 1, 2, 3, 4, 6, 8, and 10. Each Cycle was 3 weeks in duration.

Measure: Vemurafenib Plasma Levels at Various Treatment Cycles

Time: Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1

Description: Three electrocardiograms (ECG) were obtained pre-dose and 2, 4, 6, and 8 hours post-dose at Days 1 and 15 of Cycle 1 and again pre-dose and 4 hours post-dose at various Cycles throughout treatment. Five baseline triplicate ECGs were obtained before the start of treatment at the same time points used during treatment. Reported is the largest mean time-matched QTcP change from baseline. QTcP=QT/(60/heart rate)^β (β=mean [calculated separately for males and females] log-transformed QT versus log-transformed RR regression slopes using all available pre-treatment (baseline) ECG values.

Measure: Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP)

Time: Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1

Description: The intensity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a 5-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening, and Death).

Measure: Percentage of Patients With Adverse Event

Time: From first treatment through September 27, 2010

47 A Multicenter, Open-label, Dose-escalation, Phase I Study of TAK-733, an Oral MEK Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics and maximum tolerated dose of TAK-733 in patients with advanced, nonhematologic tumors. The expansion stage of the study will evaluate evidence of antitumor activity of TAK-733 in patients with advanced metastatic melanoma.

NCT00948467
Conditions
  1. Advanced Non-hematologic Malignancies
  2. Advanced Metastatic Melanoma
Interventions
  1. Drug: TAK-733
MeSH:Melanoma Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm

- Melanoma patients should have the V600E BRAF mutation status of their tumor documented, if available, and tumor tissue must be provided for confirmatory genotyping by a central laboratory. --- V600E ---

Primary Outcomes

Measure: Safety profile, dose-limiting toxicities, maximum tolerated dose and recommended phase 2 dose of TAK-733

Time: 12 months

Measure: Pharmacokinetic characterization of TAK-733

Time: 12 months

Secondary Outcomes

Measure: Effect of food on the pharmacokinetics of TAK-733

Time: 12 months

Measure: Antitumor activity of TAK-733 in patients with advanced nonhematologic malignancies

Time: 12 months

Measure: Antitumor activity of TAK-733 in melanoma patients

Time: 12 months

48 A Randomized Discontinuation, Blinded, Placebo-Controlled Phase II Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma

Uveal melanoma is the most common primary intra-ocular malignancy in adults with an incidence of 0.6 - 0.7 per 100,000 per year. Prognosis of metastatic uveal melanoma is poor. In retrospective analyses a median survival time after detection of metastases of 5 months (Flaherty et al, 1998) and 7 months (Kath et al, 1993) was reported. For patients receiving no treatment reported median survival was 2.0 months compared with 5.2 months for those receiving treatment for metastases (Gragoudas et al, 1991). Up to now there is no established treatment of metastatic uveal melanoma. Some therapeutic approaches with locoregional treatment or systemic chemotherapy have been undertaken: In case of metastatic disease which is confined to the liver in about 85% of patients with uveal melanoma surgical resection led to a median survival of 14 months (Mariani et al, 2009) or 19 months and a 5-year survival rate of 22% in a selected patient population (Adam et al, 2006). As locoregional treatment option treatment with fotemustine via direct intra-arterial hepatic infusion was investigated and led to a median survival of 15 months (Peters et al, 2006). This was not a randomized trial, but a report on 101 consecutive treated patients. Additional debulking surgery was performed whenever feasible. A randomized phase III trial comparing intra-arterial hepatic fotemustine administration with intravenous systemic fotemustine and overall survival as primary endpoint is still ongoing (EORTC 18021). Thus, no systemic chemotherapy is approved for metastatic uveal melanoma. Although no specific genes have been linked to the pathogenesis of uveal melanoma, preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Thus, sorafenib as inhibitor of b-Raf and Raf-1 (c-Raf or c-Raf-1), pro-angiogenic vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) may potentially lead to a benefit for patients with metastatic uveal melanoma in terms of disease control and prolongation of survival.

NCT01377025
Conditions
  1. Uveal Melanoma
Interventions
  1. Drug: Placebo
  2. Drug: Sorafenib
  3. Drug: Sorafenib
MeSH:Melanoma Uveal Neoplasms
HPO:Cutaneous melanoma Melanoma

Thus, sorafenib as oral multi-kinase inhibitor that targets the Raf/MEK/ERK signaling pathway (CRAF, BRAF, V600E BRAF) in the cell and receptor tyrosine kinases (RTKs) such as VEGFR-2, VEGFR-3, and PDGFR-ß involved in tumor cell proliferation and angiogenesis may potentially lead to a benefit for patients with metastatic uveal melanoma in terms of disease control and prolongation of survival. --- V600E ---

Primary Outcomes

Measure: Progression Free Survival

Time: Every 8 weeks for 1 year

Secondary Outcomes

Measure: Number of patients with adverse events

Time: Every 8 weeks for 1 year

Measure: Overall Survival

Time: Every 8 weeks for 2 years

49 A Phase 2 Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib for Patients Whose Tumors Harbor Pathogenic Alterations in BRAF, RAF1, MEK1/2, ERK1/2, and NF1.

The purpose of CTO-IUSCC-0730 study is to assess the clinical efficacy of LY3214996 in combination with abemaciclib at the recommended phase 2 dose of LY3214996 200 mg orally daily and abemaciclib 150 mg orally twice daily. Patients will be treated until evidence of disease progression, non-compliance with study protocol, unacceptable major toxicity, at subject's own request for withdrawal, or if the study closes for any reason.

NCT04534283
Conditions
  1. Cancer
  2. Cancer Metastatic
  3. BRAF V600E
  4. MEK1 Gene Mutation
  5. MEK2 Gene Mutation
  6. ERK Mutation
  7. RAF1 Gene Mutation
Interventions
  1. Drug: Abemaciclib
  2. Drug: LY3214996

i. Patients with NSCLC that harbor BRAF V600E treated with prior RAF and/or MEK inhibition therapy will be excluded. --- V600E ---

Patients with tumor types other than NSCLC that harbor BRAF V600E mutations who have been treated and progressed on prior BRAF and/or MEK inhibition will be included. --- V600E ---

Cancer Cancer Metastatic BRAF V600E MEK1 Gene Mutation MEK2 Gene Mutation ERK Mutation RAF1 Gene Mutation null --- V600E ---

Primary Outcomes

Description: the number of patients who achieve a best overall response of complete response (CR) or partial response (PR) divided by the total number of patients treated (safety population)

Measure: Overall response rate

Time: from cycle 1 day 1 until safety follow up visit (up to 1 year)

Secondary Outcomes

Description: CTCAE Version 5.0 will be used to summarize adverse events in the assessment of safety for incorporating LY3214996 in combination with abemaciclib. Summaries of treatment related adverse events in the population will be tabulated. All adverse events (AEs) will be presented in incidence tables coded by CTC term.

Measure: Incidence of Adverse Events

Time: baseline until safety follow up visit (up to 1 year)

Description: measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented

Measure: Duration of Overall Response Rate

Time: up to 1 year

Description: the time from the date of start of treatment to the first date of the observed clinical or radiologically documented PD or death due to any cause, whichever occurs first. For patients who are not known to have died or progressed as of the data-inclusion cut-off date, PFS time will be censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systematic anticancer therapy.

Measure: Duration of Progression free survival

Time: up to 1 year

50 An Open-Label, Single-arm Study to Evaluate the Safety and Efficacy of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer

The purpose of this study is to evaluate the safety and efficacy of dabrafenib in combination with trametinib in Chinese patients with BRAF V600E mutation-positive metastatic Non-Small Cell Lung Cancer. The general study design has been discussed and agreed with Chinese Health Authority and is applying a similar design used for global pivotal phase II study (BRF113928).

NCT04452877
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

An Open-Label, Single-arm Study to Evaluate the Safety and Efficacy of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer. --- V600E ---

A Study of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutant Metastatic NSCLC The purpose of this study is to evaluate the safety and efficacy of dabrafenib in combination with trametinib in Chinese patients with BRAF V600E mutation-positive metastatic Non-Small Cell Lung Cancer. --- V600E ---

A Study of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutant Metastatic NSCLC The purpose of this study is to evaluate the safety and efficacy of dabrafenib in combination with trametinib in Chinese patients with BRAF V600E mutation-positive metastatic Non-Small Cell Lung Cancer. --- V600E --- --- V600E ---

Incidence of Adverse Events and Serious Adverse events, including abnormal laboratory values or test results.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of Stage IV NSCLC (according to AJCC 8th edition) that is BRAF V600E mutation-positive by local test result from a qualified assay (NMPA and/or MOH-approved) - Previously treated or untreated for metastatic NSCLC: 1. Subjects previously treated should have received no more than 3 prior systemic therapies for metastatic disease, including one prior platinum based chemotherapy, and should have documented disease progression on a prior treatment regimen (i.e. --- V600E ---

The amount of time a patient must use a condom for 16 weeks post treatment discontinuation - Subjects with active Hepatitis B infection (HbsAg positive) - Subjects with positive test for hepatitis C ribonucleic acid (HCV RNA) - Concurrent participation in other clinical trials using experimental therapies Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of Stage IV NSCLC (according to AJCC 8th edition) that is BRAF V600E mutation-positive by local test result from a qualified assay (NMPA and/or MOH-approved) - Previously treated or untreated for metastatic NSCLC: 1. Subjects previously treated should have received no more than 3 prior systemic therapies for metastatic disease, including one prior platinum based chemotherapy, and should have documented disease progression on a prior treatment regimen (i.e. --- V600E ---

The amount of time a patient must use a condom for 16 weeks post treatment discontinuation - Subjects with active Hepatitis B infection (HbsAg positive) - Subjects with positive test for hepatitis C ribonucleic acid (HCV RNA) - Concurrent participation in other clinical trials using experimental therapies Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung This is a single arm, open label, multicenter phase II study evaluating the efficacy and safety of dabrafenib in combination with trametinib in Chinese subjects with BRAF V600E mutation positive AJCC v8 stage IV Non-Small Cell Lung Cancer. --- V600E ---

Subjects with stage IV BRAF V600E mutant Non-Small Cell Lung Cancer confirmed by local qualified assay (approved by China health authorities) will be enrolled in this study. --- V600E ---

Central confirmation testing for BRAF V600E will be performed. --- V600E ---

Primary Outcomes

Description: Overall Response Rate is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by central independent review as per RECIST v1.1 criteria

Measure: Overall Response Rate (ORR), central independent review assessed by RECIST v1.1

Time: From baseline until disease progression, death, lost to follow-up or withdrawal of consent, whichever occurs first, assessed up to approximately 12 months from treatment initiation

Secondary Outcomes

Description: ORR is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per RECIST 1.1 criteria

Measure: Overall response rate (ORR), investigator assessed by RECIST v1.1

Time: From baseline until disease progression, death, lost to follow-up or withdrawal of consent, whichever occurs first, assessed up to approximately 12 months from treatment initiation

Description: PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. PFS will be assessed via local review according to RECIST 1.1.

Measure: Progression Free Survival (PFS), investigator assessed by RECIST v1.1

Time: From baseline until disease progression or death due to any cause, whichever occurs first, assessed up to approximately 12 months from treatment initiation

Description: DoR is defined for the subset of subjects with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression according to RECIST v1.1 per local review or death due to any cause

Measure: Duration of Response (DoR), investigator assessed by RECIST v1.1

Time: From first documented response until first documented progression or death due to any cause, whichever occurs first, assessed up to approximately 12 months from treatment initiation

Description: OS is defined as the time from first dose until death due to any cause

Measure: Overall Survival (OS)

Time: From baseline until death due to any cause, assessed up to approximately 33 months from treatment initiation

Description: Mean trough concentration will be calculated at each timepoint

Measure: Trough concentration of dabrafenib

Time: Pre-dose sample at visits week 3, 6 and 12

Description: Mean trough concentration will be calculated at each timepoint

Measure: Trough concentration of dabrafenib metabolites

Time: Pre-dose sample at visits week 3, 6 and 12

Description: Mean trough concentration will be calculated at each timepoint

Measure: Trough concentration of trametinib

Time: Pre-dose sample at visits week 3, 6 and 12

Description: EQ-5D-5L is a standardized measure to assess the overall health-related quality of life in patients.

Measure: Mean change from baseline in the European Quality of Life (EuroQol)- 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score

Time: From baseline, every 3 weeks until end of treatment (up to approximately 32 months after treatment initiation)

Description: EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients.

Measure: Mean change from baseline in the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30) score

Time: From baseline, every 3 weeks until end of treatment (up to approximately 32 months after treatment initiation)

Description: EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire.

Measure: Mean Change from Baseline in the European Organization for Research and Treatment of Cancer lung cancer specific module (EORTC QLQ-LC13) score

Time: From baseline, every 3 weeks until end of treatment (up to approximately 32 months after treatment initiation)

Description: Safety profile of dobrafenib in combination with trametinib. Incidence of Adverse Events and Serious Adverse events, including abnormal laboratory values or test results.

Measure: Number of patients with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: From baseline until end of study, assessed up to approximately 33 months from treatment initiation

51 Combination of Targeted Therapy (Encorafenib and Binimetinib) Followed by Combination of Immunotherapy (Ipilimumab and Nivolumab) vs Immediate Combination of Immunotherapy in Patients With Unresectable or Metastatic Melanoma With BRAF V600 Mutation : an EORTC Randomized Phase II Study (EBIN)

This is a multicenter, 2-arm open-label, randomized comparative phase II study. The objective of this trial is to prospectively evaluate whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves progression free survival compared to combination immunotherapy nivolumab + ipilimumab alone in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

NCT03235245
Conditions
  1. Unresectable Stage III Melanoma
  2. Stage IV Melanoma
Interventions
  1. Drug: Nivolumab + Ipilimumab
  2. Drug: Encorafenib + Binimetinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Inclusion Criteria: - Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma - Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment - Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E ---

Note: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on binimetinib treatment - Impaired cardiovascular function or clinically significant cardiovascular diseases - Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100mmHg, despite current therapy - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to starting study treatment - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including stroke, transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis Inclusion Criteria: - Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma - Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment - Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E ---

Primary Outcomes

Description: PRS is defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. Progression will be assessed according to the RECIST criteria (version 1.1)

Measure: Progression Free Survival (PFS)

Time: 4.1 years from first patient in

Secondary Outcomes

Description: OS is defined as the time from the date of randomization to the date of death, whatever the cause.

Measure: Overall Survival (OS)

Time: 6 years from first patient in

Description: CR will be assessed according to the RECIST criteria (version 1.1)

Measure: Complete Response (CR) rate

Time: 4.1 years from first patient in

Description: Time to CR is defined as the time from the date of randomization until the occurrence of first CR.

Measure: Time to Complete Response (CR)

Time: 4.1 years from first patient in

Description: Duration of CR will be measured from the time measurement criteria for CR are first met until the first date that recurrence is objectively documented.

Measure: Duration of Complete Response (CR)

Time: 4.1 years from first patient in

Description: Best overall response will be assessed according to the RECIST criteria (version 1.1)

Measure: Best overall response rate

Time: 4.1 years from first patient in

Description: Time to best response is defined as the time from the date of randomization until the occurrence of the best response (CR or PR, whichever comes first). CR and PR will be assessed according to the RECIST criteria (version 1.1)

Measure: Time to best response

Time: 4.1 years from first patient in

Description: Best response duration will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. CR and PR will be assessed according to the RECIST criteria (version 1.1)

Measure: Duration of best response

Time: 4.1 years from first patient in

Description: This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.

Measure: Occurrence of adverse events

Time: 4.1 years from first patient in

Description: PFS2 is defined as the time from randomization to second objective disease progression, or death from any cause, whichever first. The second objective disease progression will be assessed according to the RECIST criteria (version 1.1)

Measure: Progression-free survival 2 (PFS2)

Time: 4.1 years from first patient in

52 Phase Ib Study to Test the Safety and Potential Synergy of Pembrolizumab (Anti-PD-1) and AMG386 (Angiopoietin-2 (Ang-2) in Patients With Advanced Solid Tumor

This research study is studying an investigational combination of drugs as a possible treatment for advanced solid tumors: melanoma, ovarian, renal, or colorectal cancer. The drugs involved in this study are: - Pembrolizumab - AMG386

NCT03239145
Conditions
  1. Advanced Solid Tumor
Interventions
  1. Drug: Pembrolizumab
  2. Drug: Trebananib
MeSH:Neoplasms
HPO:Neoplasm

Melanoma patients with BRAF V600E or V600K mutation-positive melanoma who have previously received a BRAF inhibitor with or without a MEK inhibitor) are eligible. --- V600E ---

Primary Outcomes

Measure: Dose Limiting Toxicity

Time: 2 years

Secondary Outcomes

Measure: Objective Response Rate

Time: 2 years

Measure: Progression Free Survival

Time: 2 years

Measure: Overall Survival

Time: 2 years

53 The TRIPLETE Study RANDOMIZED PHASE III STUDY OF TRIPLET mFOLFOXIRI PLUS PANITUMUMAB Versus mFOLFOX6 PLUS PANITUMUMAB AS INITIAL THERAPY FOR UNRESECTABLE RAS AND BRAF WILDTYPE METASTATIC COLORECTAL CANCER PATIENTS

- The association of FOLFOX (5-fluoruracil, folinic acid, and oxaliplatin) and pan is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients. - The phase III TRIBE trial recently demonstrated that FOLFOXIRI (5-fluoruracil, folinic acid, oxaliplatin and irinotecan) plus bev significantly prolongs PFS and OS and increases RECIST response rate, ETS and DoR, as compared to FOLFIRI (5-fluoruracil folinic acid, and irinotecan) plus bev. The advantage provided by the intensification of the upfront chemotherapy backbone is independent of RAS and BRAF mutational status. - Some phase II trials recently assessed the safety and activity of the combination of three-drugs chemotherapy regimens with an anti-EGFR monoclonal antibody. Promising activity results in terms of RECIST response rate and R0 resection rate have been achieved, with some safety concerns with special regards to gastrointestinal toxicity. - In the phase II randomized MACBETH study the combination of a modified schedule of FOLFOXIRI with cetuximab determined remarkable activity results, with an acceptable and manageable safety profile. - The optimal duration of the upfront treatment with chemotherapy plus anti-EGFRs is not established. The phase II MACRO-2 trial suggested that interrupting FOLFOX after 4 months while continuing cet alone as maintenance, is a reasonable option. - Activity parameters (RECIST response rate, ETS, DoR) are clinically relevant endpoints, associated with longer survival, in particular with anti-EGFR moAb-based treatment. On the basis of these considerations, we designed the present phase III randomized trial of first-line mFOLFOXIRI plus pan versus mFOLFOX6 plus pan in RAS and BRAF wt unresectable mCRC patients.

NCT03231722
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: Panitumumab
  2. Drug: Irinotecan
  3. Drug: Oxaliplatin
  4. Drug: l-leucovorin
  5. Drug: 5-fluorouracil
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

- RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of primary colorectal cancer or related metastasis (local or central laboratory assessment). --- V600E ---

Primary Outcomes

Description: the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria

Measure: Overall response rate

Time: 12 months

Secondary Outcomes

Description: the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 4.0)

Measure: Overall Toxicity Rate

Time: 24 months

Description: the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 4.0)

Measure: Toxicity Rate

Time: 24 months

Description: the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. Documentation of disease progressive disease is defined as per RECIST 1.1 criteria based on investigator assessment

Measure: Progression Free Survival

Time: 24 months

Description: the time from randomization to the date of death due to any cause

Measure: Overall Survival

Time: 48 months

Description: the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria based on central re-evaluation of CT scan images.

Measure: Centrally assessed Overall response rate

Time: 12 months

Description: the percentage of patients, relative to the total of the enrolled subjects, achieving a ≥20% decrease in the sum of diameters of RECIST target lesions at week 8 compared to baseline.

Measure: Early Tumour Shrinkage Rate

Time: up to 2 months from randomization

Description: the relative change in the sum of longest diameters of RECIST target lesions at the nadir, in the absence of new lesions or progression of non-target lesions, when compared with baseline.

Measure: Deepness of Response

Time: 12 months

Description: the percentage of patients, relative to the total of enrolled subjects, undergoing secondary R0 resection of metastases

Measure: R0 Resection Rate

Time: 12 months

54 Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer

The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer. Researchers also want to find out if the combination of nivolumab, ipilimumab and nintedanib is safe and tolerable.

NCT03377023
Conditions
  1. Non Small Cell Lung Cancer
  2. Lung Cancer, Nonsmall Cell
  3. Non Small Cell Lung Cancer Metastatic
Interventions
  1. Drug: Nivolumab
  2. Drug: Ipilimumab
  3. Drug: Nintedanib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy. --- T790M --- --- V600E ---

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy. --- T790M --- --- V600E ---

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy - At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. --- T790M --- --- V600E ---

Primary Outcomes

Description: Dose escalation to determine the MTD and Recommended Phase 2 Dose (RP2D) of concurrent administration of nivolumab, ipilimumab, and nintedanib. The maximum tolerated dose (MTD) is defined as the dose with the dose limiting toxicity (DLT) rate of 30%.

Measure: Phase 1 - Maximum Tolerated Dose (MTD)

Time: Up to 12 months

Description: Objective response is defined as confirmed CR or confirmed PR based on modified RECIST guidelines version 1.1. The ORR will be estimated by calculating the proportion of patients who achieve OR; the 80% Confidence Interval (CI) and 95% CI for the OR rate will be estimated using the exact binomial distribution. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Phase 2 - Objective Response Rate (ORR) per Treatment Arm

Time: Up to 36 months

Secondary Outcomes

Description: Disease control is defined as CR, PR, or SD based on RECIST guidelines version 1.1 with modifications. The disease control rate (DCR) will be estimated by the proportion of patients who achieve DC, and its 80% CI and 95% CI will be estimated using the exact binomial distribution. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Phase 2: Disease Control Rate (DCR)

Time: Up to 36 months

Description: Overall survival will be determined as the time from the start of treatment with nivolumab plus ipilimumab plus nintedanib until death due to any cause. For patients who are alive at the time of data cut-off, OS will be censored on the last date when patients are known to be alive. The Kaplan-Meier method will be used to estimate the OS curve and the OS rate at time points of interest.

Measure: Phase 2: Overall Survival (OS)

Time: Up to 36 months

Description: Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Measure: Phase 2: Progression-free Survival (PFS)

Time: Up to 36 months

55 A Phase 2 Study of AZD6244 in Biliary Cancers

This phase II trial is studying how well selumetinib works in treating patients with biliary cancer that cannot be removed by surgery. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT00553332
Conditions
  1. Liver and Intrahepatic Biliary Tract Cancer
  2. Recurrent Extrahepatic Bile Duct Cancer
  3. Unresectable Extrahepatic Bile Duct Cancer
Interventions
  1. Drug: selumetinib
  2. Other: laboratory biomarker analysis
MeSH:Bilia Biliary Tract Neoplasms Bile Duct Neoplasms Cholangiocarcinoma
HPO:Biliary tract neoplasm Cholangiocarcinoma

To genotype tumors for the presence of RAS mutations (i.e., NRAS, KRAS, HRAS) and BRAF mutations (e.g., V600E) in biliary tumor samples from these patients. --- V600E ---

Primary Outcomes

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Measure: Objective Response Rate (CR and PR)

Time: Every 8 weeks

Secondary Outcomes

Description: Toxicitity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0

Measure: Toxicity Profile of AZD6244

Time: From the time of first treatment with AZD6244, assessed up to 4 weeks

Description: Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Measure: Median Progression Free Survival for Patients

Time: Up to 6 months

Measure: Overall Survival

Time: Up to 12 months

Measure: RAS/RAF/MEK/ERK Signaling Pathway Activation

Time: At baseline

Description: Measure the proteins levels of RAS/RAF/MEK/ERK signaling pathway activation to AZD6244

Measure: Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation

Time: At baseline

56 Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression for Patients With Non-small Cell Lung Cancers Harboring Major Oncogenic Drivers

This phase II trial studies how well targeted therapy works in treating patients with incurable non-small cell lung cancer with a genetic mutation. Giving drugs that target other genetic mutations or other specific proteins may work better when a patient has cancer caused by a driver mutation and the treatment that targets that mutation stops working.

NCT02949843
Conditions
  1. EGFR Activating Mutation
  2. Recurrent Non-Small Cell Lung Carcinoma
  3. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Drug: Chemotherapy
  2. Biological: Immunotherapy
  3. Other: Laboratory Biomarker Analysis
  4. Biological: Nivolumab
  5. Biological: Pembrolizumab
  6. Drug: Targeted Molecular Therapy
  7. Drug: Tyrosine Kinase Inhibitor
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

These tests will be performed overall and then separately in the three arms.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued EGFR Activating Mutation Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To estimate the objective response rate among patients with high PD-L1 expressing cancers after failure of targeted therapy. --- V600E ---

These tests will be performed overall and then separately in the three arms.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued EGFR Activating Mutation Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To estimate the objective response rate among patients with high PD-L1 expressing cancers after failure of targeted therapy. --- V600E --- --- V600E ---

Primary Outcomes

Description: A Simon's two-stage design will be used.

Measure: Objective response rate in patients with high PD-L1 expressing cancers after failure of targeted therapy defined as complete or partial response according to the investigator's assessment

Time: Up to 3 years

Secondary Outcomes

Description: Toxicities for each group will be estimated and described using counts and frequencies by grade, location and relatedness.

Measure: Incidence of adverse events measured using Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 30 days after the last dose of study treatment

Measure: Incidence of mutations in secondary genes for patients with PD-L1 expression < 50%

Time: Up to 3 years

Description: Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table).

Measure: Objective response rates for patients without high PD-L1 expressing cancers

Time: Up to 3 years

Description: Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table).

Measure: Objective response rates for the combined population to historical controls receiving second or third line targeted agents

Time: Up to 3 years

Description: Estimated using Kaplan-Meier methods and survival rates will be compared using log-rank tests.

Measure: Overall survival

Time: From date of progression on primary targeted treatment to death, assessed up to 3 years

Measure: Rate of tobacco use and mutation burden based on PD-L1 expression at time of progression

Time: Up to 3 years

Description: Whether smoking status is related to the prevalence of any mutations identified (present/absent) will be examined using Cochran-Maentel Haenzel tests. These tests will be performed overall and then separately in the three arms.

Measure: Smoking status defined as current, former, never

Time: At baseline

57 An Exploratory Study of the Immunological Effects of Vemurafenib and Cobimetinib, Administered Alone and in Combination, in Subjects With Advanced BRAF V600E/K Mutant Melanoma

This trial explores the immunologic effects of vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), administered alone and in combination, to patients with advanced BRAF V600E/K mutant melanoma.

NCT02427893
Conditions
  1. Melanoma
Interventions
  1. Drug: Cobimetinib
  2. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

An Exploratory Study of the Immunological Effects of Vemurafenib and Cobimetinib, Administered Alone and in Combination, in Subjects With Advanced BRAF V600E/K Mutant Melanoma. --- V600E ---

Trial of Vemurafenib and Cobimetinib in Patients With Advanced BRAFV600 Mutant Melanoma This trial explores the immunologic effects of vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), administered alone and in combination, to patients with advanced BRAF V600E/K mutant melanoma. --- V600E ---

Primary Outcomes

Description: compare immunologic changes described above with the development of study treatment-related adverse events. For example, severity or extent of rash from cobimetinib (a well-described dermatologic toxicity of MEK inhibitors) may be compared to levels of intratumoral immune activation assessed by one or more of the parameters.

Measure: Safety and tolerability of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma.

Time: 2 years

Secondary Outcomes

Description: compare immunologic changes described above with therapeutic outcomes, including CR, PR, SD, and PD measured by RECIST 1.1. For example, tumor regression may be correlated with levels of intratumoral immune activation or expression of immune checkpoints assessed by one or more of the parameters

Measure: Anti-tumor activity of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma.

Time: 2 years

58 Phase II Study of Clofarabine in Patients With Recurrent or Refractory Langerhans Cell Histiocytosis and LCH-related Disorders

This research study is evaluating a drug called clofarabine as a possible treatment for Langerhans Cell Histiocytosis (LCH) and and other histiocytic disorders.

NCT02425904
Conditions
  1. Langerhans Cell Histiocytosis
Interventions
  1. Drug: Clofarabine
MeSH:Histiocytosis, Langerhans-Cell Histiocytosis
HPO:Histiocytosis

ECD patients who have confirmed BRAF V600E mutation must have failed treatment with a BRAF inhibitor or are not considered to be eligible for such treatment. --- V600E ---

Primary Outcomes

Description: Responses will be assessed using the standard criteria proposed by the Histiocyte Society

Measure: Overall Response Rate

Time: Week 7

Secondary Outcomes

Measure: Progression Free Survival

Time: At three and five years

Measure: Overall Survival

Time: At three and five years

Measure: The proportion of patients who experience a toxicity-event requiring stopping clofarabine

Time: Baseline, Up to 24 weeks

Measure: Proportion of participants with grade 3-4 toxicity

Time: Baseline, Up to 24 Weeks

59 Immunohistochemical Detection of the BRAFV600E Mutation on Cytological Specimen in PTC

Immunohistochemical detection of the BRAF-V600E mutation on pre-operative fine needle aspiration biopsy (FNAB) from patients suspected for papillary thyroid carcinoma, using the mutation specific antibody VE1.

NCT02561533
Conditions
  1. Papillary Thyroid Carcinoma
Interventions
  1. Other: BRAF detection on fine needle aspiration biopsy (FNAB)
MeSH:Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Detection of BRAF Mutation on FNAB From Papillary Thyroid Carcinoma Immunohistochemical detection of the BRAF-V600E mutation on pre-operative fine needle aspiration biopsy (FNAB) from patients suspected for papillary thyroid carcinoma, using the mutation specific antibody VE1. --- V600E ---

Therefore, pre-operative detection of the BRAF-V600E mutation may be of clinical interest in order to individualize treatment of patients with BRAF positive PTC. --- V600E ---

FNABs are performed immediately before the thyroid operation, and BRAF-V600E detection using VE1 is performed on clots. --- V600E ---

Primary Outcomes

Description: Mutations status correlated to histological diagnoses and mutation status on histological samples

Measure: Immunohistochemical detection of BRAF mutation on fine needle aspiration biopsy (FNAB)

Time: 1 day

60 Dose-seeking Study of Pembrolizumab Plus Vemurafenib and Cobimetinib for Therapy of Advanced Melanoma

The study plans to treat patients with pembrolizumab and thus blocking the PD-1/PD-L1 axis would render tumor-infiltrating lymphocytes (TILs) in the tumor parenchyma more functional as a consequence of BRAF inhibition, such that T cell activation by BRAFi would not be dampened by the PD-1/PD-L1 interaction. This combination would reverse dysfunction among T cells in the tumor parenchyma, maximizing T cell mediated immune anti-tumor efficacy. Progression free survival (PFS) with pembrolizumab in KEYNOTE-001 was 57% at 6 months, and 46.4% in the more recently reported phase III trial. PFS with vemurafenib treatment in BRIM-3 was ~50% at 6 months. Combined treatment with pembrolizumab, cobimetinib and vemurafenib for BRAF mutant melanoma is hypothesized to be safe and to improve the PFS compared to these recent historical controls. Because this combination has not yet been tested, and because the primary objective is to assess safety, the investigators are staging accrual in the first phase of the trial. The study aims to accrue up to 30 patients to the mTPI design of this study with the expectation that there will be at least 30 patients treated at RP2D. In case there are less than 30 patients on the RP2D, additional patients will be accrued. Patients will continue to receive treatment with pembrolizumab, vemurafenib and cobimetinib until disease progression or dose limiting toxicity. Patients with treatment response and no dose limiting toxicity may receive treatment with pembrolizumab for up to 24 months.

NCT02818023
Conditions
  1. Melanoma
Interventions
  1. Drug: Pembrolizumab
  2. Drug: Vemurafenib
  3. Drug: Cobimetinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Only patients with BRAF V600E or V600K mutated tumors will be enrolled. --- V600E ---

Primary Outcomes

Description: determine the safety and maximum tolerated dose of vemurafenib and cobimetinib with pembrolizumab

Measure: Percentage of participants that experience a dose-limiting toxicity

Time: Up to 2 years

Secondary Outcomes

Measure: overall response rate (ORR)

Time: Up to 2 years

Measure: progression free survival

Time: Up to 2 years

Measure: overall survival

Time: up to 2 years

Other Outcomes

Measure: assessment of tumor microenvironment and immune response via biomarker level measurement

Time: Up to 2 years

61 A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX4032 in Patients With Solid Tumors

The primary objective of this FIH study is to assess the safety and pharmacokinetics of PLX4032 in patients with solid tumors. The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation.

NCT00405587
Conditions
  1. Malignant Melanoma
  2. Colorectal Carcinoma
Interventions
  1. Drug: PLX4032
MeSH:Melanoma Colorectal Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the large intestine

The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation. --- V600E ---

Two extension cohorts of patients with confirmed V600E mutations will be recruited, consisting of advanced melanoma and metastatic colorectal carcinoma. --- V600E ---

Primary Outcomes

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16

Measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

Measure: Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation

Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Description: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

Measure: Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Measure: Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Measure: Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16

Measure: Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Description: BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Secondary Outcomes

Description: Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment.

Measure: Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.

Measure: Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort

Time: Month 1, 3, 4, 6, 9, and Last event (350) days

Description: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment.

Measure: PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)

Measure: Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Description: OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used.

Measure: Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Description: Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1.

Measure: Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, and up to 168 days

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16

Description: Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)

Measure: Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG)

Time: BL and Day 15

Measure: Cmax of RO5185426 - Food Effect

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16

Description: The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining.

Measure: Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67

Time: BL and Day 15

62 A Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01089101
Conditions
  1. Low Grade Glioma
  2. Recurrent Childhood Pilocytic Astrocytoma
  3. Recurrent Neurofibromatosis Type 1
  4. Recurrent Visual Pathway Glioma
  5. Refractory Neurofibromatosis Type 1
  6. Refractory Visual Pathway Glioma
Interventions
  1. Other: Laboratory Biomarker Analysis
  2. Other: Pharmacological Study
  3. Drug: Selumetinib
MeSH:Glioma Astrocytoma Neurofibromatoses Neurofibromatosis 1 Neurofibroma Optic Nerve Glioma
HPO:Astrocytoma Glioma Neurofibromas Optic nerve glioma Subependymal giant-cell astrocytoma

It is unlikely that sufficient numbers of subjects will be followed until death to statistically support estimation of the survival distributions but survival estimation will also be considered.. Presence or absence of BRAF V600E mutations or BRAF KIAA1549 fusion (phase II). --- V600E ---

To assess the sustained response rate of AZD6244 administered at 25 mg/m^2/dose twice daily (BID), in a single arm Phase II setting in patients assigned to strata based on neurofibromatosis (NF)-1 status and presence or absence of v-raf murine sarcoma viral oncogene homolog B (BRAF) aberrations, specifically BRAF V600E mutations and/or BRAF KIAA1549 fusion identified by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. --- V600E ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Measure: Maximum tolerated dose and recommended phase 2 dose of selumetinib determined by dose-limiting toxicities (phase I)

Time: 28 days

Description: For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. In addition, the confirmed sustained objective response rate observed during treatment by cumulative incidence functions will be estimated. This provides not only an overall estimate of the response rate but also an estimate of the timing of responses as a function of number of months of treatment.

Measure: Stratum-specific objective response (complete response + partial response) rate sustained for 8 weeks (phase II)

Time: 40 weeks

Description: Exact confidence interval estimates will be provided.

Measure: Objective response (objective response = complete response + partial response) (re-treatment study)

Time: Up to 48 weeks

Description: Disease stabilization rates will be measured.

Measure: Disease stabilization rates (re-treatment study)

Time: At 1 year

Secondary Outcomes

Description: Plasma drug concentrations and pharmacokinetic parameters volume of the central compartment, elimination rate constant, half-life, apparent oral clearance, and area under the plasma concentration time curve.

Measure: Plasma drug concentrations and pharmacokinetic parameters (Phase I)

Time: Day 1 of cycle 1

Description: Kaplan-Meier estimates of distributions of PFS all eligible subjects who received at least one dose of selumetinib will be provided separately for each stratum. It is unlikely that sufficient numbers of subjects will be followed until death to statistically support estimation of the survival distributions but survival estimation will also be considered.

Measure: Stratum-specific progression-free survival distribution (PFS) (phase II)

Time: From the date of initial treatment to the earliest date of disease progression, second malignancy or death for subjects who fail; and to the date of last contact for subjects who remain at risk for failure assessed for up to 30 days

Description: Will be assessed by immunohistochemistry and fluorescence in situ hybridization, respectively. Frequency tables summarizing the presence and absence of BRAF aberrations in all patients from whom tissue is available will be provided. The association of presence/absence and type of BRAF aberrations versus PFS will be explored via Kaplan-Meier-plots. Log-rank tests and/or Cox regression models may also be used to assess statistical associations between BRAF and PFS provided more than 10 events are observed in a given strata to make such assessments meaningful.

Measure: Presence or absence of BRAF V600E mutations or BRAF KIAA1549 fusion (phase II)

Time: Up to 30 days

Description: Kaplan-Meier estimates of progression-free survival distributions for all eligible patients will be provided. Exact confidence interval estimates will be provided.

Measure: Progression-free survival (retreatment study)

Time: From the date of re-treatment initiation to the earliest date of disease progression, second malignancy or death for patients who fail; and the last contact for patients who remain at risk for failure, assessed up to 30 days

63 A Phase 1/2 Study of BMS-908662 (XL281) Alone or in Combination With Cetuximab in Subjects With K-RAS or B-RAF Mutation Positive Advanced or Metastatic Colorectal Cancer

The purpose of the study is to identify a safe and tolerable dose of BMS-908662 in combination with cetuximab; and then to evaluate the tumor response to BMS-908662 when administered alone or in combination with cetuximab

NCT01086267
Conditions
  1. Colorectal Cancer
Interventions
  1. Drug: BMS-908662
  2. Drug: BMS-908662
  3. Drug: Cetuximab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Inclusion Criteria: - Subjects with K-RAS (codon 12 or 13) or B -RAF (V600E) mutation positive advanced or metastatic colorectal cancer who have relapsed or are refractory to 2 or more standard systemic anticancer regimes for metastatic disease, or are intolerant to existing therapies. --- V600E ---

Primary Outcomes

Measure: Toxicity will be evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3

Time: Assessments every 1-2 weeks while receiving study drug

Secondary Outcomes

Measure: Efficacy as determined by estimates of objective response rates and response duration

Time: Efficacy measured at least every 8 weeks while receiving study drug

Measure: Pharmacodynamics (PD) will be assessed by evaluating markers of RAS/RAF pathway activity

Time: PD assessed during the first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by minimum observed concentrations [Cmin].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by maximum observed concentrations [Cmax].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by time of maximum observed concentration [Tmax].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by area under the concentration-curve for one dosing interval [AUC(TAU)].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by accumulation index [AI].

Time: PK measured during first 4 weeks on study

64 Association Between BRAF V600E and Redifferentiation Therapy in Patients With Radioiodine-refractory Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is the most common neoplasia in the thyroid gland. The combination of surgery, followed by radioiodine therapy (RIT) and thyroid-stimulating hormone (TSH) suppressive therapy is usually a curative option for differentiated thyroid cancer (DTC). Although DTC has a good prognosis generally, it is problematic when dedifferentiation is suspected and radioiodine refractoriness presumed. One possible therapy option for redifferentiation is the pretreatment with retinoids. From 2008 to 2014 there were 13 patients with PTC who were treated with retinoids after thyroidectomy before a further course of radioiodine. A recent study has shown that the efficacy of Selumetinib, another option for redifferentiation depends on the mutational status of the treated patient. In this retrospective study the investigators looked for a similar association between BRAF V600E and redifferentiation therapy with retinoids. As retinoids have fewer side effects compared to TKI, it is worth performing studies to assess the importance of genetic marker for the response and to estimate the chances of this specific patient collective. BRAF V600E seems to be associated with better long-term response after redifferentiation therapy with 13-cis RA in RAI-R PTC. Therefore, evaluation of BRAF mutational status prior to redifferentiation therapy could be beneficial for predicting response.

NCT03363347
Conditions
  1. Thyroid Cancer
Interventions
  1. Drug: Redifferentiation with retinoid acid
MeSH:Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Association Between BRAF V600E and Redifferentiation Therapy in Patients With Radioiodine-refractory Papillary Thyroid Cancer. --- V600E ---

BRAF V600E and Redifferentiation Therapy in Radioiodine-refractory Papillary Thyroid Cancer Papillary thyroid cancer (PTC) is the most common neoplasia in the thyroid gland. --- V600E ---

In this retrospective study the investigators looked for a similar association between BRAF V600E and redifferentiation therapy with retinoids. --- V600E ---

BRAF V600E seems to be associated with better long-term response after redifferentiation therapy with 13-cis RA in RAI-R PTC. --- V600E ---

Primary Outcomes

Description: Redifferentiation therapy was performed using 13-cis RA (Isotretinoin, Roaccutan®) with a daily dose of orally 1,5mg/kg for up to two months. For assessment of clinical outcome of 13-cis retinoic acid treatment three parameters, tumor size, thyroglobulin levels and radioiodine uptake were considered in a graduated model.

Measure: Response to radioiodine therapy after redifferentiation

Time: 7 years

Secondary Outcomes

Description: Tumor size was evaluated form CT, MRI, or FDG-PET/CT imaging, comparing results before and after redifferentiation and RIT, results were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).

Measure: Parameter tumor size

Time: 7 years

Description: Non-stimulated serum Tg level (in ng/ml) before redifferentiation therapy was compared with the first Tg level after redifferentiation and RIT. A stable Tg level was defined as ≤10% difference.

Measure: Parameter thyroglobulin levels (serum Tg)

Time: 7 years

Description: Recovery of RI-Uptake was evaluated from the post-therapy whole body scan in comparison to the lesions in CT, MRI, or FDG-PET/CT imaging before redifferentiation. Optimal uptake was defined as intensive accumulation of radioiodine in all tumor lesions. When not all lesions accumulate radioiodine or the signal was weak it was considered as suboptimal uptake.

Measure: Parameter radioiodine-uptake (RI-Uptake)

Time: 7 years

65 S1613, A Randomized Phase II Study of Trastuzumab and Pertuzumab (TP) Compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) With HER-2 Amplification

This randomized phase II trial studies how well trastuzumab and pertuzumab work compared to cetuximab and irinotecan hydrochloride in treating patients with HER2/neu amplified colorectal cancer that has spread from where it started to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as trastuzumab and pertuzumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cetuximab and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trastuzumab and pertuzumab may work better compared to cetuximab and irinotecan hydrochloride in treating patients with colorectal cancer.

NCT03365882
Conditions
  1. Colon Adenocarcinoma
  2. ERBB2 Gene Amplification
  3. Rectal Adenocarcinoma
  4. Recurrent Colon Carcinoma
  5. Recurrent Rectal Carcinoma
  6. Stage III Colon Cancer AJCC v7
  7. Stage III Rectal Cancer AJCC v7
  8. Stage IIIA Colon Cancer AJCC v7
  9. Stage IIIA Rectal Cancer AJCC v7
  10. Stage IIIB Colon Cancer AJCC v7
  11. Stage IIIB Rectal Cancer AJCC v7
  12. Stage IIIC Colon Cancer AJCC v7
  13. Stage IIIC Rectal Cancer AJCC v7
  14. Stage IV Colon Cancer AJCC v7
  15. Stage IV Rectal Cancer AJCC v7
  16. Stage IVA Colon Cancer AJCC v7
  17. Stage IVA Rectal Cancer AJCC v7
  18. Stage IVB Colon Cancer AJCC v7
  19. Stage IVB Rectal Cancer AJCC v7
Interventions
  1. Biological: Cetuximab
  2. Drug: Irinotecan Hydrochloride
  3. Other: Laboratory Biomarker Analysis
  4. Biological: Pertuzumab
  5. Biological: Trastuzumab
  6. Device: HER-2 testing
MeSH:Carcinoma Adenocarcinoma Rectal Neoplasms Colonic Neoplasms
HPO:Carcinoma Colon cancer Neoplasm of the colon Neoplasm of the rectum

The associations between HER-2/CEP17 signal ratio and response will be explored via Logistic regression.. Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Colon Adenocarcinoma ERBB2 Gene Amplification Rectal Adenocarcinoma Recurrent Colon Carcinoma Recurrent Rectal Carcinoma Stage III Colon Cancer AJCC v7 Stage III Rectal Cancer AJCC v7 Stage IIIA Colon Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Colon Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Colon Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IV Colon Cancer AJCC v7 Stage IV Rectal Cancer AJCC v7 Stage IVA Colon Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Colon Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7 Carcinoma Adenocarcinoma Rectal Neoplasms Colonic Neoplasms PRIMARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP compared to control arm (Arm 2) of cetuximab and irinotecan hydrochloride (irinotecan) (CETIRI). --- V600E ---

The associations between HER-2/CEP17 signal ratio and response will be explored via Logistic regression.. Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Colon Adenocarcinoma ERBB2 Gene Amplification Rectal Adenocarcinoma Recurrent Colon Carcinoma Recurrent Rectal Carcinoma Stage III Colon Cancer AJCC v7 Stage III Rectal Cancer AJCC v7 Stage IIIA Colon Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Colon Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Colon Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IV Colon Cancer AJCC v7 Stage IV Rectal Cancer AJCC v7 Stage IVA Colon Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Colon Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7 Carcinoma Adenocarcinoma Rectal Neoplasms Colonic Neoplasms PRIMARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP compared to control arm (Arm 2) of cetuximab and irinotecan hydrochloride (irinotecan) (CETIRI). --- V600E --- --- V600E ---

Primary Outcomes

Description: Analysis of PFS will be conducted using the stratified log rank test upon the observation of 115 PFS events. PFS among patients who register to Arm 3 will be summarized using descriptive statistics.

Measure: Progression-free survival (PFS)

Time: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Secondary Outcomes

Description: Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Measure: Incidence of adverse events

Time: Up to 3 years

Description: ORR including confirmed complete and partial responses per Response Evaluation Criteria in Solid Tumors 1.1 will be compared using using the Cochran-Mantel-Haenszel test. ORR among patients who register to Arm 3 will be summarized using descriptive statistics.

Measure: Overall response rate (ORR)

Time: Up to 3 years

Description: Distributions of OS in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test. OS among patients who register to Arm 3 will be summarized using descriptive statistics.

Measure: Overall survival (OS)

Time: From date of registration to date of death due to any cause, assessed up to 3 years

Other Outcomes

Description: The associations between GCN and PFS will be explored via Kaplan-Meier curves and Cox regression.

Measure: Association between HER-2 gene copy number (GCN) and PFS

Time: Up to 3 years

Description: The associations between GCN and response will be explored via logistic regression.

Measure: Association between HER-2 gene copy number (GCN) and response

Time: Up to 3 years

Description: The associations between HER-2/CEP17 signal ratio and PFS will be explored via Kaplan-Meier curves and Cox regression.

Measure: Association between HER-2/CEP17 signal ratio and PFS

Time: Up to 3 years

Description: The associations between HER-2/CEP17 signal ratio and response will be explored via Logistic regression.

Measure: Association between HER-2/CEP17 signal ratio and response

Time: Up to 3 years

66 A Phase 2 Study of Trametinib for Patients With Pediatric Glioma or Plexiform Neurofibroma With Refractory Tumor and Activation of the MAPK/ERK Pathway.

This is a phase 1/2, open-label, interventional clinical trial that will study the response rate of pediatric glioma and plexiform neurofibroma (PN) to oral administration of trametinib. Patients meeting all inclusion criteria for a given study group will receive the study medication at a daily dose of 0.025 mg/kg up to a total of 18 cycles, in 28-day cycles. A total of 150 patients will be recruited as part of this clinical study. Patients aged between 1 month (corrected age) and 25 years old will be eligible, in order to include a maximum of patients affected by low-grade glioma (LGG) and PN. This study includes four groups: patients with neurofibromatosis type 1 (NF1) and LGG, NF1 patients with PN, patients with LGG with a B-Raf Serine/Threonine-protein Kinase/Proto-oncogene Encoding B-Raf (BRAF) fusion and patients with glioma of any grade with activation of the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinases (MAPK/ERK) pathway. All patients except patients with PN must have failed at least one line of treatment. The study will also explore the molecular mechanisms behind tumor development, progression and resistance to treatment. Furthermore, this study will also explore important aspects for patients with brain tumors by including assessment of quality of life and neuropsychological evaluation.

NCT03363217
Conditions
  1. Low-grade Glioma
  2. Plexiform Neurofibroma
  3. Central Nervous System Glioma
Interventions
  1. Drug: Trametinib
MeSH:Glioma Neurofibroma Neurofibromatoses Neurofibroma, Plexiform
HPO:Glioma Neurofibromas Plexiform neurofibroma

5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation. --- V600E ---

5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation. --- V600E --- --- V600E ---

Primary Outcomes

Description: Determination of the objective response rate of daily trametinib as a single agent for treatment of progressing/refractory low-grade tumors with MAPK/ERK pathway activation.

Measure: Objective Response Rate

Time: From date of study inclusion until the date of first documented progression, up to 504 treatment days.

Secondary Outcomes

Description: Time from registration to progression, or censored at the date of last disease evaluation for those without progression reported. Applicable to group 1-2-3-4.

Measure: Time to Progression (time from registration to progression)

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at the date of last disease evaluation. Applicable to group 1-2-3-4.

Measure: Progression Free Survival (time from registration to the earlier of progression or death).

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Time from registration to death due to any cause, or censored at date last known alive. Applicable to group 1-2-3-4.

Measure: Overall Survival (time from registration to death)

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Determination of the safety and tolerability of trametinib by assessment of toxicity associated with trametinib (Adverse Events (AEs), Serious Adverse Events (SAEs)). Applicable to group 1-2-3-4.

Measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).

Time: At treatment week 2, 3, 4, 5, 9, 13, 17, 21, 25, 48, 72; at the end of 504 treatment days and every 6 months for up to 3 years.

Description: Determination of the serum level of trametinib by assessment of the through level. Applicable to group 1-2-3-4.

Measure: Determination of the Serum Level of Trametinib.

Time: At day 22 and at tumor progression up to the end of treatment day 504.

Description: Evaluation of the quality of life during treatment with the PedsQL cancer/brain tumor modules. Applicable to group 1-2-3-4.

Measure: Evaluation of the Quality of Life During Treatment.

Time: At screening, week 13, week 25, week 37, week 49, week 61 and at the end of treatment day 504.

Other Outcomes

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib. The areas of development assessed to calculate the composite score are: cognition, communication, physical, social/emotional and adaptative. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 1 and 42 months using the Bayley Scales of Infant and Toddlers Development, Third Edition (Bailey-III).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 2 years and 6 years using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 6 years and 16 years and 11 months using the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, perceptual reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 16 years 11 months and 25 years using the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determination of trametinib usefulness in patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1. Applicable to group 4

Measure: Response rate of patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Comparison of the best response rate using the RECIST 1.1 criteria and volumetric measurement. Applicable to group 2.

Measure: Comparison of responses with RECIST 1.1 and volumetric measurement for plexiform neurofibroma

Time: At the achievement of best response to treatment up to treatment day 504.

Description: Gene expression profiling on fresh frozen tissue and mutational analysis on paraffin-embedded tissue. Circulating tumor DNA (ctDNA) evolution through treatment.

Measure: Investigation and correlation of biological features to tumor response.

Time: Within 14 days prior to treatment start for investigations of tumor tissue. At screening, week 13, week 25, week 37, week 49, week 61, at the end of treatment day 504 and every 6 months up to 3 years for ctDNA evaluation.

67 Managed Access Program (MAP) to Provide Access to Trametinib and Dabrafenib Combination Therapy for Patients With BRAF V600 Mutation-positive Advanced Non-Small Cell Lung Cancer (NSCLC)

The purpose of this Cohort Treatment Plan is to allow access to trametinib and dabrafenib for eligible patients diagnosed with BRAF V600activating mutation-positive advanced NSCLC. The patient's Treating Physician should follow the suggested treatment guidelines and comply with all local health authority regulations.

NCT04507919
Conditions
  1. Small Cell Lung Carcinoma
Interventions
  1. Drug: Dabrafenib and Trametinib
  2. Drug: Dabrafenib
  3. Drug: Trametinib
MeSH:Carcinoma Lung Neoplasms Small Cell Lung Carcinoma
HPO:Carcinoma Neoplasm of the lung Small cell lung carcinoma

Stage IIIB, Stage IV) NSCLC (Non-Small Cell Lung Cancer) with confirmed BRAF V600E/K activating mutation. --- V600E ---


68 A Phase II Trial of Rechallenge With Panitumumab Driven by RAS Clonal-mediated Dynamic of Resistance

Open label, single-arm, multiple centers, Phase II trial. The trial has been designed to prove or disprove whether a third line rechallenge with panitumumab can achieve an objective response rate (ORR= CR+PR) of 30% or more in a population of RAS wild type mCRC patients selected on the basis of RAS extended clonal evolution in their plasma.

NCT03227926
Conditions
  1. Colorectal Cancer
Interventions
  1. Drug: Panitumumab 20 MG/ML Intravenous Solution [VECTIBIX]
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

INCLUSION CRITERIA Molecular Screening - Histologically confirmed diagnosis of metastatic colorectal cancer; - Age ≥ 18 years; - Documented WT RAS exons 2, 3 and 4 (KRas and NRas) and WT BRAF V600E; - Complete or partial response to frontline chemotherapy including anti-EGFR mAb. --- V600E ---

Primary Outcomes

Measure: Overall response rate (ORR) to panitumumab according to RECIST v1.1.

Time: Tumor assessments every 8 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

Secondary Outcomes

Measure: Progression Free Survival

Time: every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

Measure: Overall Survival

Time: every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

Measure: Toxicity according to CTCAE version 4.03.

Time: every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

69 VECODUE A Phase II Trial of Vemurafenib Plus Cobimetinib in Patients Treated With Prior First-line Systemic Immunotherapy for Inoperable Locally Advanced or Metastatic Melanoma

In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively. As suggested by National Comprehensive Cancer Network (NCCN) guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting. The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.

NCT03224208
Conditions
  1. Melanoma
  2. Melanoma (Skin)
  3. Melanoma Stage
Interventions
  1. Drug: Vemurafenib
  2. Drug: Cobimetinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Vemurafenib Plus Cobimetinib in Advanced or Metastatic Melanoma Patients In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. --- V600E ---

Melanoma Melanoma (Skin) Melanoma Stage Melanoma In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged OS and PFS compared to dacarbazine. --- V600E ---

As evidenced above, vemurafenib inhibits the BRAF V600E kinase, (this mutation is found in 50% to 60% of melanomas), and enables a remarkable clinical response rate, more than 50% and a statistically significant improvement in OS in patients with unresectable stage III and IV melanoma. --- V600E ---

Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. --- V600E ---

Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. --- V600E --- --- V600E ---

Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: OS will be calculated from the first day of treatment until the date of death from any cause.Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive.

Measure: Overall Survival

Time: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

Secondary Outcomes

Description: PFS will be defined as the time from initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first.PFS will be calculated based on disease status evaluated bythe investigator according to RECIST v1.1

Measure: PFS

Time: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

Description: ORR, defined as the proportion of patients with a best overall response of either complete response (CR) or partial response (PR), will be calculated based on disease status evaluated by the investigator accordingto RECIST v1.1

Measure: ORR

Time: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

70 Phase II Trial of BRAF/MEK Inhibitors in Papillary Craniopharyngiomas

This phase II trial studies how well vemurafenib and cobimetinib work in treating patients with BRAF V600E mutation positive craniopharyngioma. Vemurafenib and cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03224767
Conditions
  1. BRAF V600E Mutation Present
  2. Papillary Craniopharyngioma
Interventions
  1. Drug: Vemurafenib
  2. Drug: Cobimetinib
  3. Other: Laboratory Biomarker Analysis
  4. Other: Quality-of-Life Assessment
MeSH:Craniopharyngioma Adamantinoma
HPO:Craniopharyngioma

Vemurafenib and Cobimetinib in Treating Patients With BRAF V600E Mutation Positive Craniopharyngioma This phase II trial studies how well vemurafenib and cobimetinib work in treating patients with BRAF V600E mutation positive craniopharyngioma. --- V600E ---

Vemurafenib and Cobimetinib in Treating Patients With BRAF V600E Mutation Positive Craniopharyngioma This phase II trial studies how well vemurafenib and cobimetinib work in treating patients with BRAF V600E mutation positive craniopharyngioma. --- V600E --- --- V600E ---

Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.. - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E ---

Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.. - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E --- --- V600E ---

- Prior treatment - Cohort A: No prior therapy received other than surgery - Cohort B: Prior radiation therapy required (any type of prior radiation is allowed) - For patients treated with external beam radiation therapy, interstitial brachytherapy or radiosurgery, an interval of >= 3 months must have elapsed from completion of radiation therapy to registration - Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity attributed to radiation with exception of alopecia, fatigue - For patients enrolling on Cohort A or Cohort B: - For patients treated with surgery, an interval of >= 21 days must have elapsed prior to registration - No prior treatment with BRAF or MEK inhibitors - Steroid dosing stable for at least 4 days prior to registration - Not pregnant and not nursing; for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required - ECOG performance status =< 2 - Comorbid conditions - No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) =< 8 weeks prior to registration - No evidence of intracranial hemorrhage =< 4 weeks prior to registration - Patients who have experienced thromboembolic event within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 4 weeks prior to registration - No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration - No current unstable angina or uncontrolled arrhythmia - No uncontrolled hypertension at time of registration (blood pressure [BP] > 150/95 despite antihypertensive therapy) - No known history of prolonged QT syndrome - No known history of ventricular arrhythmia within 6 months of registration - No known history of uveitis or iritis =< 4 weeks prior to registration - No known history of or evidence of retinal pathology that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration within 12 months of registration - No known history of chronic lung disease - Concomitant medications - Chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Chronic concomitant treatment with CYP1A2 substrate is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Absolute neutrophil count >= 1500/mm^3 - Platelets >= 100,000/mm^3 - Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45mL/min - Bilirubin =< 1.5 upper limit of normal (ULN) - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 ULN - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E ---

- Prior treatment - Cohort A: No prior therapy received other than surgery - Cohort B: Prior radiation therapy required (any type of prior radiation is allowed) - For patients treated with external beam radiation therapy, interstitial brachytherapy or radiosurgery, an interval of >= 3 months must have elapsed from completion of radiation therapy to registration - Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity attributed to radiation with exception of alopecia, fatigue - For patients enrolling on Cohort A or Cohort B: - For patients treated with surgery, an interval of >= 21 days must have elapsed prior to registration - No prior treatment with BRAF or MEK inhibitors - Steroid dosing stable for at least 4 days prior to registration - Not pregnant and not nursing; for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required - ECOG performance status =< 2 - Comorbid conditions - No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) =< 8 weeks prior to registration - No evidence of intracranial hemorrhage =< 4 weeks prior to registration - Patients who have experienced thromboembolic event within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 4 weeks prior to registration - No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration - No current unstable angina or uncontrolled arrhythmia - No uncontrolled hypertension at time of registration (blood pressure [BP] > 150/95 despite antihypertensive therapy) - No known history of prolonged QT syndrome - No known history of ventricular arrhythmia within 6 months of registration - No known history of uveitis or iritis =< 4 weeks prior to registration - No known history of or evidence of retinal pathology that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration within 12 months of registration - No known history of chronic lung disease - Concomitant medications - Chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Chronic concomitant treatment with CYP1A2 substrate is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Absolute neutrophil count >= 1500/mm^3 - Platelets >= 100,000/mm^3 - Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45mL/min - Bilirubin =< 1.5 upper limit of normal (ULN) - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 ULN - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E --- --- V600E ---

- Prior treatment - Cohort A: No prior therapy received other than surgery - Cohort B: Prior radiation therapy required (any type of prior radiation is allowed) - For patients treated with external beam radiation therapy, interstitial brachytherapy or radiosurgery, an interval of >= 3 months must have elapsed from completion of radiation therapy to registration - Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity attributed to radiation with exception of alopecia, fatigue - For patients enrolling on Cohort A or Cohort B: - For patients treated with surgery, an interval of >= 21 days must have elapsed prior to registration - No prior treatment with BRAF or MEK inhibitors - Steroid dosing stable for at least 4 days prior to registration - Not pregnant and not nursing; for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required - ECOG performance status =< 2 - Comorbid conditions - No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) =< 8 weeks prior to registration - No evidence of intracranial hemorrhage =< 4 weeks prior to registration - Patients who have experienced thromboembolic event within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 4 weeks prior to registration - No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration - No current unstable angina or uncontrolled arrhythmia - No uncontrolled hypertension at time of registration (blood pressure [BP] > 150/95 despite antihypertensive therapy) - No known history of prolonged QT syndrome - No known history of ventricular arrhythmia within 6 months of registration - No known history of uveitis or iritis =< 4 weeks prior to registration - No known history of or evidence of retinal pathology that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration within 12 months of registration - No known history of chronic lung disease - Concomitant medications - Chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Chronic concomitant treatment with CYP1A2 substrate is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Absolute neutrophil count >= 1500/mm^3 - Platelets >= 100,000/mm^3 - Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45mL/min - Bilirubin =< 1.5 upper limit of normal (ULN) - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 ULN BRAF V600E Mutation Present Papillary Craniopharyngioma Craniopharyngioma Adamantinoma PRIMARY OBJECTIVES: I. To determine the activity of BRAF and MEK inhibitor combination in untreated papillary craniopharyngiomas as measured by best response at any time during the first four cycles of BRAF and MEK inhibitor treatment. --- V600E ---

Primary Outcomes

Description: Defined as the number of responses achieved during treatment with BRAF and MEK inhibitors divided by the total number of evaluable patients and assessed by contrast-enhanced magnetic resonance imaging or computed tomography. Point estimates will be generated for response rates within each cohort with corresponding 95% binomial confidence intervals. Simon's two-stage design with one interim analysis for futility will be applied to evaluate response rate within each cohort.

Measure: Response rate

Time: Up to 5 years

Secondary Outcomes

Description: Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.

Measure: Progression-free survival

Time: Up to 5 years

Description: Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.

Measure: Overall survival

Time: Up to 5 years

71 QUILT-3.055: A Phase IIb, Multicohort, Open-Label Study of Combination Immunotherapies in Patients Who Have Previously Received Treatment With PD-1/PD-L1 Immune Checkpoint Inhibitors

This is a Phase IIb, multicohort, open-label multicenter study of combination immunotherapies in patients who have previously received treatment with PD-1/PD-L1 immune checkpoint inhibitors. All patients in Cohorts 1-4 will receive the combination treatment of PD-1/PD-L1 checkpoint inhibitor plus N-803 for up to 17 cycles. Each cycle is six weeks in duration. Some patients who experience disease progression while on study in Cohorts 1-4 may roll over into Cohort 5 and receive combination therapy with a PD-1/PD-L1 checkpoint inhibitor, N-803, and PD-L1 t-haNK cellular therapy for up to an additional 17 cycles. Each cycle is six weeks in duration. All patients will receive N-803 once every 3 weeks. Patients will also receive the same checkpoint inhibitor that they received during their previous therapy. Radiologic evaluation will occur at the end of each treatment cycle. Treatment will continue for up to 2 years, or until the patient experiences confirmed progressive disease or unacceptable toxicity, withdraws consent, or if the Investigator feels it is no longer in the patient's best interest to continue treatment. Patients will be followed for disease progression, post-therapies, and survival through 24 months past administration of the first dose of study drug.

NCT03228667
Conditions
  1. Non-Small Cell Lung Cancer
  2. Small Cell Lung Cancer
  3. Urothelial Carcinoma
  4. Head and Neck Squamous Cell Carcinoma
  5. Merkel Cell Carcinoma
  6. Melanoma
  7. Renal Cell Carcinoma
  8. Gastric Cancer
  9. Cervical Cancer
  10. Hepatocellular Carcinoma
  11. Microsatellite Instability
  12. Mismatch Repair Deficiency
  13. Colorectal Cancer
Interventions
  1. Drug: N-803 + Pembrolizumab
  2. Drug: N-803 + Nivolumab
  3. Drug: N-803 + Atezolizumab
  4. Drug: N-803 + Avelumab
  5. Drug: N-803 + Durvalumab
  6. Drug: N-803 + Pembrolizumab + PD-L1 t-haNK
  7. Drug: N-803 + Nivolumab + PD-L1 t-haNK
  8. Drug: N-803 + Atezolizumab + PD-L1 t-haNK
  9. Drug: N-803 + Avelumab + PD-L1 t-haNK
  10. Drug: N-803 + Durvalumab + PD-L1 t-haNK
MeSH:Carcinoma, Merkel Cell Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Melanoma Colorectal Neoplasms Carcinoma, Squamous Cell Carcinoma, Hepatocellular Stomach Neoplasms Uterine Cervical Neoplasms Carcinoma, Renal Cell Small Cell Lung Carcinoma Carcinoma, Transitional Cell Squamous Cell Carcinoma of Head and Neck Microsatellite Instability
HPO:Carcinoma Cervical polyp Cervix cancer Clear cell renal cell carcinoma Cutaneous melanoma Hepatocellular carcinoma Melanoma Merkel cell skin cancer Neoplasm of the large intestine Neoplasm of the lung Neoplasm of the stomach Non-small cell lung carcinoma Papillary renal cell carcinoma Renal cell carcinoma Small cell lung carcinoma Squamous cell carcinoma

Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy; OR unresectable or metastatic melanoma with progression, refractory to ≥ 2 doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor, and disease progression within 24 weeks following the last dose of ipilimumab. --- V600E ---

Primary Outcomes

Description: Assess ORR, defined as Investigator-assessed CR + PR, per RECIST 1.1.

Measure: Objective Response Rate

Time: 24 months

Secondary Outcomes

Description: Assess time from first treatment to death resulting from cancer.

Measure: Disease-specific Survival

Time: 24 months

Description: Assess time from first treatment to death resulting from any cause.

Measure: Overall Survival

Time: 24 months

Description: Assess time to response

Measure: Time to Response

Time: 24 months

Description: Assess duration of response

Measure: Duration of Response

Time: 24 months

Description: Assess incidence of adverse events.

Measure: Incidence of Adverse Events

Time: 24 months

Description: Compare changes in QOL scores from baseline.

Measure: Quality of Life (QOL)

Time: 24 months

Description: Assess time from first treatment to disease progression or death from any cause, whichever occurs first.

Measure: Progression Free Survival

Time: 24 months

72 Study of Tilsotolimod in Combination With Nivolumab and Ipilimumab for the Treatment of Solid Tumors

A Phase 2 study intended to see efficacy of tilsotolimod in combination with immunotherapy drugs ipilimumab and nivolumab in different solid tumors.

NCT03865082
Conditions
  1. Solid Tumor
Interventions
  1. Drug: Tilsotolimod
  2. Drug: Nivolumab
  3. Drug: Ipilimumab
MeSH:Neoplasms
HPO:Neoplasm

2. Subjects with BRAF V600E mutations. --- V600E ---

Primary Outcomes

Description: Efficacy measure by objective response rate

Measure: Demonstrate the efficacy of intratumoral tilsotolimod in combination with ipilimumab and nivolumab for each cohort

Time: ORR defined as a CR or partial response (PR) according to RECIST v1.1, confirmed by imaging ≥ 4 weeks after the initial documentation of response (to occur up to 24 months).

Description: Durability or response per RECIST v1.1

Measure: Duration of response

Time: DOR will be evaluated every 8 weeks starting Cycle3 Day1 (each cycle is 28 days) for year 1 then every 12 weeks after the first year through study completion until all study participants have either progressive disease or start new anticancer treatment.

Secondary Outcomes

Description: Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms(ECGs), safety and laboratory parameters as assessed by CTCAE v4.03 or higher.

Measure: Safety and tolerability of the combination of tilsotolimod with nivolumab and ipilimumab

Time: At every study visit (up to 48 months)

73 An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of Agents Co-Administered With Encorafenib and Binimetinib in Patients With BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors

This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.

NCT03864042
Conditions
  1. Advanced Solid Tumors
  2. Metastatic Melanoma
Interventions
  1. Drug: losartan
  2. Drug: dextromethorphan
  3. Drug: caffeine
  4. Drug: omeprazole
  5. Drug: midazolam
  6. Drug: rosuvastatin
  7. Drug: bupropion immediate release (IR)
  8. Drug: encorafenib
  9. Drug: binimetinib
  10. Drug: modafinil
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E ---

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K --- --- V600E ---

- Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; - ARM 1 ONLY: Positive urine cotinine test at screening - ARM 3 ONLY: - History of psychosis, depression or mania; - History of angioedema; - History of mitral valve prolapse; - History of left ventricular hypertrophy; Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E ---

- Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; - ARM 1 ONLY: Positive urine cotinine test at screening - ARM 3 ONLY: - History of psychosis, depression or mania; - History of angioedema; - History of mitral valve prolapse; - History of left ventricular hypertrophy; Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K --- --- V600E ---

Primary Outcomes

Measure: Probe substrate peak plasma concentration (Cmax) in Arms 1 and 2

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Probe substrate concentration from time zero to the time of last quantifiable concentration (AUClast) in Arms 1 and 2

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Changes in the amount of probe eliminated via urine over an 8-hour period (Ae0-8) in Arm 1

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Changes in plasma encorafenib and LHY746 Cmax and area under the concentration time curve (AUC) in Arm 3.

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 (Drug-Drug Interaction (DDI) phase)

Secondary Outcomes

Measure: Metabolite ratio (MRAUC) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Metabolite ratio (MRCmax) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Metabolite ration (MRAe0-8) for E-3174/losartan and dextrorphan/dextromethorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (time to reach Cmax [Tmax]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUC from time zero extrapolated to infinity [AUCinf]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (percent of AUC extrapolated [AUC%extrap]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent terminal elimination half-life [T1/2]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent terminal elimination rate constant [Kel]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent total body clearance after extravascular administration [CL/F]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent total volume of distribution after extravascular administration [Vz/F]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (urine concentration [Curine]) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day-7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (quantity of urine excreted during each collection interval) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (cumulative amount excreted in urine during each collection interval [CumA]e) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (percentage of dose recovered in urine [Fe] %) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: Safety will be evaluated by monitoring adverse events (AEs)

Time: From first dose of study intervention/treatment until the end of DDI phase (through 28 days)

74 A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600 Mutation Positive Lesions in Erdheim Chester Disease

This phase II trial studies the side effects and how well dabrafenib and trametinib work in treating patients with Erdheim Chester disease that have BRAF V600 gene mutations. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03794297
Conditions
  1. Erdheim-Chester Disease
Interventions
  1. Drug: Dabrafenib Mesylate
  2. Other: Quality-of-Life Assessment
  3. Other: Questionnaire Administration
  4. Drug: Trametinib Dimethyl Sulfoxide
MeSH:Erdheim-Chester Disease

These potential risks may also apply to other agents used in this study - History of retinal vein occlusion (RVO) - Interstitial lung disease or pneumonitis not secondary to ECD - Central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or visible pathology (e.g., evidence of optic disc cupping, evidence of new visual field defects on automated perimetry, or intraocular pressure > 21 mmHg as measured by tonography) as assessed by ophthalmic examination - Inability to travel to the treating center - Patients with confirmed diagnosis of ECD that are asymptomatic and with no visceral involvement are not eligible for this trial (patients with no target lesions as per RECIST 1.1 criteria) Erdheim-Chester Disease Erdheim-Chester Disease PRIMARY OBJECTIVES: I. To study the efficacy and safety of dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) as combination therapy in patients with BRAF V600E positive Erdheim Chester disease. --- V600E ---

To determine the clinical response rate to dabrafenib and trametinib combination therapy in patients with BRAF V600E positive Erdheim Chester disease. --- V600E ---

V. To establish duration of treatment-endpoints in patients with BRAF V600E positive Erdheim-Chester disease (ECD) lesions. --- V600E ---

Primary Outcomes

Description: Measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response to therapy will be evident on follow up imaging studies revealing a decrease in lesion size of 30% or more, which is defined as a partial response as per RECIST criteria, when compared to baseline studies.

Measure: Clinical response rate

Time: Up to 48 weeks after completion of study treatment

Description: Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Measure: Incidence of toxicities

Time: Up to 48 weeks after completion of study treatment

Secondary Outcomes

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Time to response

Time: Up to 48 weeks after completion of study treatment

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Duration of response

Time: From the time measurement criteria are met for complete or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 48 weeks after completion of study treatment

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 48 weeks after completion of study treatment

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Overall survival

Time: Up to 48 weeks after completion of study treatment

Measure: Degree of histiocytic infiltration using fludeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and bone scans

Time: Up to 48 weeks after completion of study treatment

Measure: Levels of C-reactive protein

Time: Up to 48 weeks after completion of study treatment

Measure: Levels of estrogen receptor (ESR)

Time: Up to 48 weeks after completion of study treatment

Measure: Levels of cytokines

Time: Up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the multi-dimensional fatigue inventory.

Measure: Change in fatigue

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the 6 minute walk test, single leg stance, and functional reach and grip strength using a dynamometer.

Measure: Change in level of functioning

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the human activity profile and activity card sort.

Measure: Change in ability to perform routine activities

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the comparative pain scale.

Measure: Change in pain

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the the group peg board test.

Measure: Change in fine motor dexterity

Time: Baseline up to 48 weeks after completion of study treatment

Description: Improvement of patients' overall quality of life will be evidence of response, and assessments will be made at baseline and throughout the trial, as well as at the conclusion of the trial, to evaluate for any improvement in quality of life. Patients will be evaluated using the National Institute of Neurological Disorders and Stroke-Neuro-Quality of Life scale.

Measure: Change in overall quality of life

Time: Baseline up to 48 weeks after completion of study treatment

Description: Resistance to therapy will be evaluated through imaging studies and patient follow up for at least one year, but this is not expected with the combination therapy.

Measure: Resistance to therapy

Time: Up to 1 year

75 A Pilot Study of the Addition of Cemiplimab, an Antibody to PD-1, to the Treatment of Subjects With BRAF-Mutant Anaplastic Thyroid Cancer Who Are No Longer Responding to Dabrafenib and Trametinib

This study is being done to see if adding the study drug, cemiplimab, to the standard therapy with dabrafenib and trametinib is an effective treatment against anaplastic thyroid cancer.

NCT04238624
Conditions
  1. Anaplastic Thyroid Cancer
  2. Thyroid Cancer
  3. BRAF Gene Mutation
  4. BRAF Mutation-Related Tumors
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Thyroid Neoplasms Thyroid Carcinoma, Anaplastic Thyroid Diseases
HPO:Abnormality of the thyroid gland Anaplastic thyroid carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Response and progression will be evaluated by using criteria proposed in RECIST 1.1.. Inclusion Criteria: - Pathological (histologically or cytologically) proven diagnosis of BRAF-V600E mutant ATC (a diagnosis that is noted to be consistent with ATC is acceptable) - Either Metastatic disease or locoregional disease that is considered not resectable for cure - Ideally a surgeon should determine that the disease is not resectable for cure, but this can also be done by any investigator - Patients must have measurable disease according to RECIST 1.1 criteria, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as >/= 20 mm with conventional techniques or as >/= 10 mm with spiral CT scan, MRI, or calipers by clinical exam - Age >/= 18 years - Eastern Cooperative Oncology Group (ECOG) performance status /= 60) - Able to swallow and retain orally administered medication - Patient must have normal organ and marrow function as defined below: - Absolute neutrophil count >/=1.5 x 10^9/L - Hemoglobin >/=8 g/dL - Platelets >/=100 x 10^9/L - Serum bilirubin V600E ---

Sherman) - Active inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) - History of primary immunodeficiency - History of allogeneic organ transplant - Known history of previous clinical diagnosis of active tuberculosis (this does not include a history of being PPD positive) Inclusion Criteria: - Pathological (histologically or cytologically) proven diagnosis of BRAF-V600E mutant ATC (a diagnosis that is noted to be consistent with ATC is acceptable) - Either Metastatic disease or locoregional disease that is considered not resectable for cure - Ideally a surgeon should determine that the disease is not resectable for cure, but this can also be done by any investigator - Patients must have measurable disease according to RECIST 1.1 criteria, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as >/= 20 mm with conventional techniques or as >/= 10 mm with spiral CT scan, MRI, or calipers by clinical exam - Age >/= 18 years - Eastern Cooperative Oncology Group (ECOG) performance status /= 60) - Able to swallow and retain orally administered medication - Patient must have normal organ and marrow function as defined below: - Absolute neutrophil count >/=1.5 x 10^9/L - Hemoglobin >/=8 g/dL - Platelets >/=100 x 10^9/L - Serum bilirubin V600E ---

Primary Outcomes

Description: Response and progression will be evaluated by using criteria proposed in RECIST 1.1.

Measure: Overall Response Rate per RECIST 1.1 Criteria

Time: 2 years

76 Phase I/II Study of the Human Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine (AR), Combined With the PD-L1 Inhibitor Atezolizumab in Non-Small Cell Lung Cancer

This phase I/II trial studies the best dose and side effects of anetumab ravtansine when given together with atezolizumab and how well they work in treating participants with non-small cell lung cancer that has spread to other places in the body. Monoclonal antibodies, such as anetumab ravtansine and atezolizumab, may interfere with the ability of tumor cells to grow and spread.

NCT03455556
Conditions
  1. Mesothelin Positive
  2. Stage III Non-Small Cell Lung Cancer AJCC v7
  3. Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  4. Stage IIIB Non-Small Cell Lung Cancer AJCC v7
  5. Stage IV Non-Small Cell Lung Cancer AJCC v7
Interventions
  1. Biological: Anetumab Ravtansine
  2. Biological: Atezolizumab
  3. Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

INCLUSION CRITERIA - Phase I only: Diagnosis of advanced/metastatic NSCLC for which no standard treatment option; Phase II only: Advanced NSCLC patients who have received at least 1 platinum-based systemic chemotherapy regimen - Patients with tumors having actionable genomic alterations should have received prior therapy with Food and Drug Administration (FDA) approved agents targeting these aberrations (ie EGFR, ALK, ROS1, BRAF V600E) - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Phase II only: Must have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria - Ability to understand and the willingness to sign a written informed consent document - Histological or cytologically confirmed NSCLC that shows moderate or stronger mesothelin expression in 30% of tumor cells by a companion assay; MSLN expression score using Ventana immunohistochemistry (IHC) SP74 assay; Phase I only: In addition 5- 30% tumor cells and 1, 2, or 3+ MSLN score; Phase II only: 30% tumor cells and either 2+/3+ - Life expectancy of >= 12 weeks - Absolute neutrophil count >= 1.5 ? --- V600E ---

Primary Outcomes

Description: Maximum tolerated dose (MTD) of anetumab ravtansine combined with atezolizumab defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I)

Measure: Maximum Tolerated Dose (MTD) (Phase I)

Time: Up to 21 days

Description: Defined as a patient who has achieved a partial response (PR) or complete response (CR) on two consecutive evaluations at least 4 weeks apart. Will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.

Measure: Rate of Confirmed Response (Phase II)

Time: 6 months

Secondary Outcomes

Description: Will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.

Measure: Clinical Activity (Phase I)

Time: Up to 6 months

Description: The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population.

Measure: Incidence of Adverse Events According to Common Terminology Criteria for Adverse Events Version 4.0 (Phase I)

Time: Up to 21 days after last dose

Description: Defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier.

Measure: Overall Survival (Phase II)

Time: Up to 2 years

Description: Defined as the time from registration to the earliest date of documentation of disease progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan Meier. Will also report the 1-year progression free survival (PFS) rate for the combination of anetumab ravtansine and atezolizumab in 2nd-line non-small cell lung cancer (NSCLC).

Measure: Progression-free Survival (Phase II)

Time: 1 year and up to 2 years

77 A Phase I/II Study of MCS110 With BRAF/MEK Inhibition in Patients With Melanoma After Progression on BRAF/MEK Inhibition

This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation. The interventions involved in this study are: - MCS110 - Dabrafenib - Trametinib

NCT03455764
Conditions
  1. Melanoma
Interventions
  1. Drug: MCS110
  2. Drug: Dabrafenib
  3. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

MCS110 With BRAF/MEK Inhibition in Patients With Melanoma This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation. --- V600E ---

Inclusion Criteria: - For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. --- V600E ---

- For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and have had progression of disease on prior BRAF and MEK inhibitor therapy. --- V600E ---

Primary Outcomes

Description: Any side effects or severe side effects that require the drug to be held or reduced

Measure: Dose Limiting Toxicity

Time: 2 years

Secondary Outcomes

Description: The percentage of patients that have a reduction of their disease on imaging that meets RECIST criteria

Measure: Overall Response Rate

Time: 2 years

Description: The percentage of patients who have a reduction of their disease on imaging to the point that it can no longer be measured.

Measure: Complete Response rate

Time: 2 years

Description: The percentage of patients who have meet RECIST criteria for having a reduction in their disease on imaging but still have measurable disease.

Measure: Partial Response rate

Time: 2 years

Description: The length of time between participants starting study treatment and having growth of their disease

Measure: Progression Free Survival

Time: 2 years

Description: The amount of time between participants starting study therapy and death

Measure: Overall Survival

Time: 2 years

Description: Any side effects or severe side effects associated with study therapy

Measure: Toxicity (Safety and Tolerability)

Time: 2 years

78 An Open Label, Multicenter, Phase I Extension Study of an Oral Cdk Inhibitor P1446A-05 Administered With an Oral BRAF Inhibitor Vemurafenib (Zelboraf®) in Patients With Advanced or Inoperable Malignant Melanoma With BRAF Mutation

- An Open Label, Multicenter, Phase I Extension Study of an Oral Cdk Inhibitor P1446A-05 Administered with an Oral BRAF Inhibitor Vemurafenib (Zelboraf®) in Patients with Advanced or Inoperable Malignant Melanoma with BRAF Mutation - The primary objective is to determine the safety, maximum tolerated dose (MTD), and dose limiting toxicity (DLT) of the co-administration of P1446A-05 with vemurafenib, in melanoma patients with BRAF mutation

NCT01841463
Conditions
  1. Advanced or Inoperable Malignant Melanoma With BRAF Mutation
Interventions
  1. Drug: P1446A-05
  2. Drug: Vemurafenib (Zelboraf®)
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

In the 'Extension' phase, sixty patients with BRAF V600E/K mutations (forty patients naïve to selective BRAF inhibitor therapy, and twenty progressing on selective BRAF inhibitor therapy) will be treated at the MTD on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity to determine efficacy of the co-administration.. Tumor Response. --- V600E ---

Primary Outcomes

Description: The study will be conducted in two phases- Phase I (Dose escalation phase), and Extension phase. In the Dose escalation' phase patients will be co-administered P1446A-05 (150, 250, 350 mg qd) and vemurafenib (720, 960 mg bid) in a cohort of three to six patients on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity. Escalation to the next higher dose during the dose escalation phase will depend upon demonstrated safety in the previous dose group. The maximum tolerated dose (MTD) of P1446A-05 and vemurafenib co-administered will be determined. In the 'Extension' phase, sixty patients with BRAF V600E/K mutations (forty patients naïve to selective BRAF inhibitor therapy, and twenty progressing on selective BRAF inhibitor therapy) will be treated at the MTD on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity to determine efficacy of the co-administration.

Measure: Maximum Tolerated Dose and Dose Limiting Toxicity

Time: Until disease progression or unacceptable toxicity (expected to be 6-8 months)

Secondary Outcomes

Description: - To determine best Overall Response Rate (ORR), Duration of response (DOR), Progression Free Survival (PFS), and Overall Survival (OS) of the co-administration of P1446A 05 and vemurafenib using RECIST version 1.1 in melanoma patients with BRAF mutation

Measure: Tumor Response

Time: Until disease progression or unacceptable toxicity (expected to be 6-8 months)

Description: PK parameters such as Cmax, Tmax, AUC0-t, AUC0-inf, Kel, CL, Vz and t1/2 will be determined using standard non-compartmental and population pharmacokinetic approach (wherever possible). Blood samples (6 mL at each time point) for pharmacokinetic assessment will be collected at the following time points in Dose Escalation Phase- Cycle 1- Day 15: pre-dose (within 30 min before swallowing the capsule/s, 1, 2, 4, 6, 8hr; Day 19: pre-dose (within 30 min before swallowing the capsule/s, 1, 2, 4, 8hr; and within one hour post dose on Day 22. Additionally, blood samples for PK analysis may be collected should patient develop SAE at the earliest feasible time point.

Measure: Pharmacokinetic (PK)

Time: Cycle1 (Day 15 and 22) and Cycle 2 (Day1,15 and 28)

Description: The biomarkers will be assessed pre- and post-treatment and will focus on (a) inhibition of the MAPK pathway as a target of vemurafenib, a RAF inhibitor; (b) cell cycle pathways as an effect of P1446A-05, a Cdk inhibitor; (c) mechanisms of resistance; and (d) markers for senescence and apoptosis as evidence of target engagement/drug response. During phase I dose escalation, optional tumor samples will be collected at screening, within 4 to 6 hours of drug administration on Day 14 of Monotherapy and between Cycle 1 Day 15 and Cycle 1 Day 21, and at disease progression After the MTD is determined, 10 additional patients will be enrolled in "Serial Tumor biopsy cohort" During the Extension phase, tumor samples will be collected at screening, Cycle 1 Day 15 and Cycle 1 Day 21 within 4 to 6 hours of drug administration, and at disease progression.

Measure: Biomarker Analysis

Time: Until disease progression or unacceptable toxicity (expected to be 6-8 months)

79 A 2-part Phase III Randomized, Open Label, Multicenter sSudy of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. A total of approximately 900 patients will be randomized. Part 1: Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms: 1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm) 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or 3. vemurafenib 960 mg BID (denoted as vemurafenib arm) Part 2: Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms: 1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)

NCT01909453
Conditions
  1. Melanoma
Interventions
  1. Drug: LGX818
  2. Drug: MEK162
  3. Drug: vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Change from baseline in the EQ-5D.. Inclusion Criteria: - Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV) - Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization - Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. --- V600E ---

IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), except the administration of BRAF or MEK inhibitors - Evidence of at least one measurable lesion as detected by radiological or photographic methods - ECOG performance status of 0 or 1 - Adequate bone marrow, organ function, cardiac and laboratory parameters - Normal functioning of daily living activities Exclusion Criteria: - Any untreated central nervous system (CNS) lesion - Uveal and mucosal melanoma - History of leptomeningeal metastases - History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease - Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients who have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at least 6 weeks prior to randomization - History of Gilbert's syndrome - Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor - Impaired cardiovascular function or clinically significant cardiovascular diseases - Uncontrolled arterial hypertension despite medical treatment - HIV positive or active Hepatitis B, and/or active Hepatitis C - Impairment of gastrointestinal function - Patients with neuromuscular disorders that are associated with elevated CK - Pregnant or nursing (lactating) women - Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: - Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV) - Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization - Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. --- V600E ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. The local Investigator's assessments will be used as supportive analyses.

Measure: Progression free survival (PFS)

Time: Approximately 2 years after first patient randomized

Secondary Outcomes

Description: OS is calculated as the time from date of randomization to date of death due to any cause.

Measure: Overall Survival (OS)

Time: Up to approximately 5 years after first patient randomized

Description: PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. The local Investigator's assessments will be used as supportive analyses.

Measure: Progression Free Survival (PFS)

Time: Approximately 2 years with update around 3 years after first patient randomized

Description: ORR calculated as the proportion of patient with a best overall response of complete response (CR) or partial response (PR). ORR will be calculated for confirmed and unconfirmed responses separately.

Measure: Objective Response Rate (ORR)

Time: Approximately 2 years after first patient randomized

Description: TTR calculated as the time from date of randomization until first documented complete response (CR) or partial response (PR).

Measure: Time To Response (TTR)

Time: Approximately 2 years after first patient randomized

Description: DCR calculated as the proportion of patient with a best overall response of CR, PR or stable disease (SD).

Measure: Disease Control Rate (DCR)

Time: Approximately 2 years after first patient randomized

Description: DOR calculated as the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer.

Measure: Duration of objective response (DOR)

Time: Approximately 2 years after first patient randomized

Description: Number of patients with adverse events and serious adverse events, changes in laboratory values, vital signs, electrocardiograms (ECGs), MUGA (Multi Gated Acquisition Scan)/ echocardiogram and assessment of physical,dermatological and ocular examinations graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.

Measure: Safety and tolerability of combination and LGX818

Time: Up to approximately 4 years after first patient randomized

Description: Change from baseline in the ECOG PS.

Measure: ECOG Performance status (PS)

Time: Approximately 2 years after first patient randomized

Description: Time to definitive 1 point deterioration in the ECOG PS is defined as the time form date of randomization to definitive deterioration, where deterioration is considered as definitive if no improvement in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.

Measure: Time to definitive 1 point deterioration in ECOG performance status

Time: Approximately 2 years after first patient randomized

Description: Plasma concentration-profiles of LGX818 and MEK162 and model based PK parameters.

Measure: Pharmacokinetics of LGX818 and MEK162

Time: Approximately 2 years after first patient randomized

Description: Time to definitive 10% deterioration in the global health status score of the EORTC QLQ-C30 is the time from the date of randomization to the date of at least 10% relative to baseline worsening with no later improvement above this threshold observed during the course of the study or death due to any cause.

Measure: Time to definitive 10% deterioration in global health status (EORTC QLQC30)

Time: Approximately 2 years after first patient randomized

Description: Change from baseline in the global health status score of the EORTC QLQ-C30.

Measure: Global health status (EORTC QLQC30)

Time: Approximately 2 years after first patient randomized

Description: Time to definitive 10% deterioration in the FACT-M melanoma (subscale) is the time from the date of randomization to the date of at least 10% relative to baseline worsening with no later improvement above this threshold observed during the course of the study or death due to any cause.

Measure: Time to definitive 10% deterioration in the FACT-M melanoma subscale

Time: Approximately 2 years after first patient randomized

Description: Change from baseline in the EQ-5D.

Measure: Global health status (EQ-5D)

Time: Approximately 2 years after first patient randomized

80 A Single Center Phase II Trial of Vemurafenib (R05185426) in Poor Performance Status Patients With Unresectable Locally Advanced or Metastatic Melanoma Harboring a V600E/K Mutation

The purpose of this study is to find out what effects, good and/or bad, vemurafenib has on the patient and the melanoma. Specifically, the investigators want to know how well vemurafenib shrinks melanoma. The investigators also want to find out how well vemurafenib can improve how well the patient functions.

NCT01474551
Conditions
  1. Melanoma
Interventions
  1. Drug: vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Single Center Phase II Trial of Vemurafenib (R05185426) in Poor Performance Status Patients With Unresectable Locally Advanced or Metastatic Melanoma Harboring a V600E/K Mutation. --- V600E ---

Vemurafenib (R05185426) in Poor Performance Status Patients With Unresectable Locally Advanced or Metastatic Melanoma Harboring a V600E/K Mutation The purpose of this study is to find out what effects, good and/or bad, vemurafenib has on the patient and the melanoma. --- V600E ---

Primary Outcomes

Description: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response. In order to be considered evaluable for response, a patient must have completed at least 1 cycle of therapy. Patients who do not complete a cycle of therapy can be replaced.

Measure: Overall Objective Response

Time: 2 years

81 Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436

Radioactive iodine therapy is often part of the standard treatment for Papillary Thyroid Carcinoma (PTC) patients. However, in many patients, tumors develop a resistance or no longer respond to radioactive iodine therapy (iodine-refractory). Several lines of evidence suggest that blocking the BRAF gene may help to re-sensitize the tumors to radioactive iodine. BRAF is a protein that plays a central role in the growth and survival of cancer cells in some types of PTC. The investigational drug GSK2118436 may work by blocking the BRAF protein in cancer cells lines and tumors that have a mutated BRAF gene. In this research study, the investigators are looking to see if GSK2118436 can re-sensitize iodine-refractory PTC to radioactive iodine therapy. The investigators are also looking at the safety of adding GSK2118436 to radioactive iodine therapy.

NCT01534897
Conditions
  1. Papillary Thyroid Carcinoma
Interventions
  1. Drug: GSK2118436
MeSH:Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436. --- V600E ---

Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436 Radioactive iodine therapy is often part of the standard treatment for Papillary Thyroid Carcinoma (PTC) patients. --- V600E ---

Number of patients with radioiodine-refractory metastatic BRAF V600E-mutant PTC who have increased radioiodine uptake in their disease sites while on dabrafenib. --- V600E ---

To determine the feasibility of: (a) administering GSK2118436 for 28 days in patients with BRAF V600E-mutant PTC, prior to whole body iodine scanning (all patients); and (b) administering GSK2118436 for an additional 14 days, prior to administering treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake after 28 days of treatment).. Clinical Benefit as Measured by Change in Thyroglobulin Level. --- V600E ---

Rising thyroglobulin is generally indicative of tumor growth.. Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Papillary Thyroid Carcinoma Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases You will take GSK2118436 capsules by mouth for 28 straight days. --- V600E ---

Rising thyroglobulin is generally indicative of tumor growth.. Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Papillary Thyroid Carcinoma Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases You will take GSK2118436 capsules by mouth for 28 straight days. --- V600E --- --- V600E ---

Primary Outcomes

Description: Number of patients with radioiodine-refractory metastatic BRAF V600E-mutant PTC who have increased radioiodine uptake in their disease sites while on dabrafenib. Radioiodine uptake is assessed by whole body scan and areas of interest are identified by nuclear medicine physicians.

Measure: Increased Radioiodine Uptake

Time: 25 days after start of Dabrafenib (GSK2118436)

Secondary Outcomes

Description: To evaluate the safety and tolerability, as determined by adverse event and serious adverse event reporting, of GSK2118436 in combination with whole body iodine scans (all patients) and treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake).

Measure: Safety Analysis as Number of Participants With Adverse Events

Time: 2 years

Description: To evaluate clinical benefit as measured by objective response rate per modified RECIST 1.1, which assesses changes in size of measurable tumors. (per RECIST, a partial response (PR) = at least 30% decrease in size of tumor; progressive disease (PD) = at least 20% increase in size of tumor; stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD).

Measure: Clinical Benefit as Measured by Change in Tumor Size

Time: 2 years

Description: To determine the feasibility of: (a) administering GSK2118436 for 28 days in patients with BRAF V600E-mutant PTC, prior to whole body iodine scanning (all patients); and (b) administering GSK2118436 for an additional 14 days, prior to administering treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake after 28 days of treatment).

Measure: Number of Participants Who Complete the Study With Minimal Delays and no Dose Reductions

Time: 2 years

Description: To evaluate clinical benefit as measured by change in serum tumor marker, thyroglobulin. Rising thyroglobulin is generally indicative of tumor growth.

Measure: Clinical Benefit as Measured by Change in Thyroglobulin Level

Time: 3 months after radioiodine therapy

82 A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma

This phase II trial studies how well dabrafenib and trametinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery and contains a B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02196181
Conditions
  1. Stage III Cutaneous Melanoma AJCC v7
  2. Stage IIIA Cutaneous Melanoma AJCC v7
  3. Stage IIIB Cutaneous Melanoma AJCC v7
  4. Stage IIIC Cutaneous Melanoma AJCC v7
  5. Stage IV Cutaneous Melanoma AJCC v6 and v7
  6. Unresectable Melanoma
Interventions
  1. Drug: Dabrafenib Mesylate
  2. Drug: Trametinib Dimethyl Sulfoxide
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma. --- V600E ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVE: I. To compare progression-free survival with intermittent dosing and continuous dosing of dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma. --- V600E ---

Primary Outcomes

Description: Testing of the superiority of intermittent dosing of dabrafenib and trametinib compared to continuous dosing with these two same agents will be based on progression-free survival. Stratified Cox regression models stratified by stratification factors will be used for all analyses.

Measure: Progression-free survival (PFS)

Time: Measured from date of randomization, assessed up to 5 years

Secondary Outcomes

Description: Overall survival between patients on each arm and survival after progression will be compared using Cox regression models.

Measure: Overall survival

Time: Up to 5 years

Description: Response rates between arms will be compared using Fisher's exact test.

Measure: Response rates

Time: Up to 5 years

Description: Defined as >= grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 with attribution possibly, probably, or definitely related to treatment; or any >= grade 1 per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment with chills, dehydration, hypotension, dizziness, or muscle weakness per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment reported during the same course. Rates of fever between arms will also be compared using Fisher's exact test.

Measure: Rates of fever

Time: Up to 5 years

Other Outcomes

Description: Compared between patients of the two treatment groups.

Measure: Molecular events leading to reactivation of the MAPK pathway

Time: Up to 5 years

Description: Cox regression analyses will be used to evaluate biomarkers' associations with PFS.

Measure: Change in biomarkers associated with PFS of archived tissue

Time: Baseline up to 5 years

Description: Cox regression analyses will be used to evaluate biomarkers' associations with PFS.

Measure: Interaction between baseline biomarkers and treatment arm

Time: Baseline up to 5 years

83 A Phase II Study of Cetuximab Rechallenge in Combination With Irinotecan in Advanced Metastatic Colorectal Cancer Without KRAS or NRAS or BRAF Mutation (All Wild Type) for Patients Pretreated With FOLFIRI and Cetuximab in First Line With Stopping Cetuximab for Progressive Disease After a Previous Response (Partial Response or Complete Response) and After Treatment With a Fluoropyrimidine, Oxaliplatin Plus Bevacizumab Regimen

The main objective of this study is to evaluate the objective response rate at two months (complete disappearance of the disease and partial disappearance of the disease) obtained after administration of combination therapy with cetuximab and irinotecan in the patients with metastatic colorectal cancer. Secondaries objectives will be assessed progression-free survival, overall survival, toxicity, quality of life.

NCT02316496
Conditions
  1. Colorectal Cancer Metastatic
Interventions
  1. Drug: cetuximab
  2. Drug: Irinotecan
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Colorectal Cancer Metastatic Colorectal Neoplasms null --- V600E ---

Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Colorectal Cancer Metastatic Colorectal Neoplasms null --- V600E --- --- V600E ---

Primary Outcomes

Measure: Objective response rate (ORR)

Time: At 2 months

Secondary Outcomes

Description: Best response observed during investigational treatment combination. From the start of treatment until treatment failure

Measure: Objective response rate (ORR)

Time: up to 27 months

Description: The proportion of patients with tumor response (Complete response or partial response) or tumor stabilization as best response during study treamtent

Measure: Disease control rate (DCR)

Time: up to 27 months

Description: Time from the date of inclusion to the date of the first progressive disease (RECIST criteria) or death (any cause)

Measure: Progression-free survival (PFS)

Time: up to 27 months

Description: Only for patients with tumor response (complete reposne or partial response) , from first confirmed response to first observed progression (PD) or death due to PD during study treatment

Measure: Duration of response (DOR)

Time: up to 27 months

Description: Time from the date of inclusion to the date of the first confirmed CR or PR during study treatment

Measure: Time to response (TTR)

Time: up to 27 months

Description: Time from the date of inclusion to the date of the first obseved progression (PD), or death due to progression during the study treatment

Measure: Time to progression (TTP)

Time: up to 27 months

Description: Time from the date of inclusion to the date the decision was made to end the study treatment for any reason

Measure: Time to treatment failure (TTF)

Time: up to 27 months

Description: Only for patient with a stable disease (SD) as best response during the study treatment, from date of inclusion to the first observed progression (PD) or death due to progression

Measure: Duration of stable disease (DoSD)

Time: up to 27 months

Description: From the date of inclusion to the date of patient death, due to any cause, or to the last date the patient was known to be alive

Measure: Overall survival (OS)

Time: up to 27 months

Measure: Adverse Events (CTCAE v.4.03)

Time: Up to 27 months

Description: Using EORTC Quality of Life Questionnaire - C30 (QLQ-C30) and the Dermatology Life Quality Index (DLQI ) questionnaires

Measure: Quality of life

Time: Up to 27 months

Description: RAS and BRAF status in circulating tumoral DNA

Measure: Respose rate

Time: up to 27 months

Description: RAS and BRAF status in circulating tumoral DNA

Measure: PFS

Time: up to 27 months

84 Phase II Biomarker Study Evaluating The Upfront Combination Of BRAF Inhibitor Dabrafenib With MEK Inhibitor Trametinib Versus The Combination After Eight Weeks Of Monotherapy With Dabrafenib Or Trametinib In Patients With Metastatic And Unresectable Stage III Or IV Melanoma Harbouring An Activating BRAF Mutation

This is a three-arm, open-label, randomised Phase II study to evaluate whether the different sequencing of dabrafenib and trametinib monotherapies and the upfront combination has an impact on translational or clinical activity in subjects with BRAF mutant metastatic unresectable stage IIIc or IV melanoma. Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and in combination in BRAF-mutant melanoma. However, duration of responses seem to be limited due to acquired drug resistance. The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition on skin, blood and tumour biomarkers and to study the correlation between biomarkers and response to treatment and intrapatient toxicity. Approximately 54 eligible subjects will be randomised in the ratio of 1:1:1 to one of the three treatment arms.

NCT02314143
Conditions
  1. Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- BRAF (proto-oncogene B-Raf) V600E/K mutation-positive confirmed by a local laboratory. --- V600E ---

Primary Outcomes

Description: Intra-tumoral expression levels of ERK measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 [no staining], 1+ [weak staining], 2+ [medium staining] and 3+ [strongest staining]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for combination therapy calculated from Week 0 to Week 2. The analysis was based on the biomarker Population which included all participants with biopsy performed at screening and at least once during treatment.

Measure: Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2

Time: Baseline (Week 0) and up to 2 weeks

Description: Intra-tumoral expression levels of ERK were measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 [no staining], 1+ [weak staining], 2+ [medium staining] and 3+ [strongest staining]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for dabrafenib followed by combination therapy and trametinib followed by combination therapy, calculated from Week 8 to Week 10.

Measure: Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10

Time: Week 8 and up to 10 weeks

Secondary Outcomes

Description: Clinical response was evaluated by ORR, which was defined as the number of participants with a confirmed or an unconfirmed complete response (CR) or partial response (PR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30 percent decrease in the sum of the diameters of target lesions. Number of participants with ORR (CR+PR) has been presented. The analysis was based on the Intent-to-Treat Population (ITT) which included all the randomized participants whether or not randomized treatment was administered.

Measure: Number of Participants With Overall Response Rate (ORR)

Time: Up to 3.2 years

Description: Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heat rate (HR) were measured. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus the Baseline value. The number of participants with heart rate "decrease to < 60" and "increase to >100" have been presented. For SBP and DBP, "any grade increase" have been presented. Any grade increase in SBP, including grade 0 (<120), grade 1 (120-139), grade 2 (140-159), grade 3 (>=160) and DBP including grade 0 (<80), grade 1 (80-89), grade 2 (90-99), grade 3 (>=100) have been presented. The analysis was based on the Safety Population which included all participants who received at least one dose of randomized treatment and was based on the actual treatment received. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

Measure: Number of Participants With Change in Vital Signs From Baseline

Time: Baseline and up to 3.2 years

Description: Complete physical examination included assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.

Measure: Number of Participants With Clinically Significant Abnormal Findings Undergoing Physical Examinations

Time: Up to 3.2 years

Description: The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The Baseline performance status of participants with respect to worst-case on-therapy performance status has been presented.

Measure: Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline

Time: Baseline and up to 3.2 years

Description: Single measurements of 12-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, corrected QT interval (QTc), Bazett's Corrected QT interval (QTcB), Friderica's Corrected QT interval (QTcF). Number of participants with abnormal ECG findings (Abnormal - Not Clinically Significant and Abnormal - Clinically Significant ) at any time post-Baseline visit have been presented.

Measure: Number of Participants With Abnormal Electrocardiograms (ECG) Findings

Time: Up to 3.2 years

Description: Echocardiograms (ECHO) was performed to assess cardiac ejection fraction and cardiac valve morphology. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on-therapy value has been presented.

Measure: Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline

Time: Baseline and up to 3.2 years

Description: Blood samples were collected for evaluation of clinical chemistry parameters including sodium, potassium, calcium, albumin, total protein, blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GCT), phosphate, C-reactive protein (CRP), hypercalcemia, hyperkalemia, hypernatremia, hypocalcemia, hypokalemia, hyponatremia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin and estimated creatinine clearance (CRTCE). Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in clinical chemistry parameters for has been presented. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

Measure: Number of Participants With Change in Clinical Chemistry Parameters From Baseline

Time: Baseline and up to 3.2 years

Description: Blood samples were collected for evaluation of hematology parameters including hemoglobin, white blood cell (WBC), platelet count, basophils, eosinophils, lymphocytes, monocytes, total neutrophils, lymphocytopenia and lymphocytosis. Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in hematology parameters for has been presented.

Measure: Number of Participants With Change in Hematology Parameters From Baseline

Time: Baseline and up to 3.2 years

Description: The safety profile of dabrafenib and trametinib in monotherapy as well as in combination therapy was characterized by determining the number of participants with incidence of squamous cell carcinoma and keratoacanthoma.

Measure: Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma

Time: Up to 3.2 years

Description: An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.

Measure: Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs

Time: Up to 3.2 years

Description: Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.

Measure: Plasma Pharmacokinetic Concentration of Trametinib

Time: 4 to 8 hours post-dose at Weeks 2, 8 and 10

Description: Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.

Measure: Plasma Pharmacokinetic Concentration of Dabrafenib

Time: 4 to 8 hours post-dose at Weeks 2, 8 and 10

85 BRAF, Autophagy and MEK Inhibition in Metastatic Melanoma: A Phase I/II Open-Label Trial of Dabrafenib, Trametinib and Hydroxychloroquine in Patients With Advanced BRAF Mutant Melanoma

The primary purpose of this study is to determine the maximum tolerated dose (MTD) and preliminary safety of hydroxychloroquine (HCQ) when administered in conjunction with oral dabrafenib and trametinib (D+T) in patients with advanced BRAF mutant melanoma.

NCT02257424
Conditions
  1. Advanced BRAF Mutant Melanoma
Interventions
  1. Drug: Trametinib 2 mg daily
  2. Drug: hydroxychloroquine (HCQ)
  3. Drug: dabrafenib 150 mg orally twice a day
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- Patients must have histologically confirmed melanoma unresectable Stage III or Stage IV positive for BRAF V600E, V600K, V600R or V600D by a CLIA approved assay. --- V600E ---

Primary Outcomes

Description: Phase 1: Maximum tolerated dose (MTD) = a) the dose producing Dose Limiting Toxicity (DLT) in 2/6 patients, or b) the dose level below the dose which produced DLT in ≥ 2/3 patients, or in ≥ 3/6 patients

Measure: Phase 1: To determine the maximum tolerated dose

Time: 5 weeks

Description: Phase 2: Progression free survival (PFS) is defined as the duration of time from start of treatment to time of first progression, death due to any cause or last patient contact alive and progression-free

Measure: Phase 2: To assess the clinical efficacy of HCQ+D+T by 1 year PFS rate.

Time: 1 year

86 Culture and Characterization of Circulating Tumor Cells (CTC) From Patients With Malignant Melanoma and Other Cancers

The purpose of this study is to determine if circulating tumor cells (CTC) can be accurately detected and isolated from the blood of participants with melanoma using novel laboratory techniques. Blood samples will be collected from participants with melanoma, and also from participants with other solid tumor cancers and healthy volunteers for purposes of comparison. Relevant information will be collected from participant's medical record and stored in a coded manner in a password-protected format. This information will be used to look for correlations of research results on blood samples to participant's medical condition. Test results will not be given to participants or their physicians. In some cases, CTC may be grown for long-term cell lines for further research.

NCT01528774
Conditions
  1. Melanoma
Interventions
  1. Other: Blood Draw
MeSH:Melanoma Neoplastic Cells, Circulating
HPO:Cutaneous melanoma Melanoma

- Isolate plasma RNA and DNA to assess expression tumor-specific markers (e.g., tyrosinase, B-FRAF, V600E, etc.) and metastasis-associated genes (e.g., MSH-1, thymidylate synthase, etc.). --- V600E ---

B-RAF V600E in melanoma patients) mitotic rate of tumor, date of tumor diagnosis, treatment history, date of regional and metastatic progression and date of death (if applicable). --- V600E ---

Primary Outcomes

Measure: Circulating tumor cell (CTC) isolation and colony counts

Time: 2 years

Secondary Outcomes

Measure: Immunophenotyping, somatic (tumor-specific) DNA mutation analysis

Time: 2 years

87 A Phase 1, Open-label, Dose-escalation, Safety and Pharmacokinetic Study of CDX-1127 in Patients With Selected Refractory or Relapsed Hematologic Malignancies or Solid Tumors

This is a study of CDX-1127, a therapy that targets the immune system and may act to promote anti-cancer effects. The study enrolls patients with hematologic cancers (certain leukemias and lymphomas), as well as patients with select types of solid tumors.

NCT01460134
Conditions
  1. CD27 Expressing B-cell Malignancies for Example Hodgkin's Lymphoma
  2. Chronic Lymphocytic Leukemia
  3. Mantle Cell Lymphoma
  4. Marginal Zone B Cell Lymphoma)
  5. Any T-cell Malignancy
  6. Solid Tumors (Metastatic Melanoma, Renal (Clear) Cell Carcinoma
  7. Hormone-refractory Prostate Adenocarcinoma, Ovarian Cancer
  8. Colorectal Adenocarcinoma, Non-small Cell Lung Cancer)
  9. Burkett's Lymphoma
  10. Primary Lymphoma of the Central Nervous System
Interventions
  1. Drug: CDX-1127
  2. Drug: CDX-1127
  3. Drug: CDX-1127
MeSH:Lymphoma Neoplasms Carcinoma, Non-Small-Cell Lung Melanoma Adenocarcinoma Ovarian Neoplasms Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, B-Cell Lymphoma, Mantle-Cell Lymphoma, B-Cell, Marginal Zone
HPO:B-cell lymphoma Chronic lymphatic leukemia Cutaneous melanoma Lymphoid leukemia Lymphoma Melanoma Neoplasm Non-small cell lung carcinoma Ovarian neoplasm

4. Tumor must be recurrent or treatment refractory with no remaining alternative, approved therapy options, with the following exception: melanoma patients enrolled in the expansion phase must have previously received ipilimumab and, for patients with the BRAF V600E mutation, vemurafenib, or have been offered such therapies and refused, and patients must have progressive disease subsequent to previous therapies. --- V600E ---

Primary Outcomes

Description: Analysis of adverse events along with the results of vital sign measurements, physical examinations, and clinical laboratory tests will be used to determine the safety profile of CDX-1127.

Measure: Characterize the adverse events associated with CDX-1127 administration

Time: Safety follow up is 70 days from last dose.

Secondary Outcomes

Measure: Levels of anti-CD27 antibodies in circulating blood.

Time: Until end of treatment

Measure: Levels of CDX-1127 in circulating blood.

Time: Until end of treatment

Description: Determine the anti-malignant cell activity of CDX-1127 based on change from baseline in tumor measurements every 12 weeks.

Measure: Activity Evaluations

Time: Until disease progression

Measure: Immune system effects (eg: lymphoid cell populations and serum cytokine levels)

Time: Until end of treatment

88 A Multicenter Phase II Study of the Combination of AZD6244 Hydrogen Sulfate and MK-2206 in Patients With Refractory Advanced Biliary Cancers

This phase II trial studies how well selumetinib and Akt inhibitor MK-2206 work in treating patients with refractory or advanced gallbladder or bile duct cancer that cannot be removed by surgery. Selumetinib and Akt inhibitor MK-2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01859182
Conditions
  1. Adenocarcinoma of the Gallbladder
  2. Adenocarcinoma With Squamous Metaplasia of the Gallbladder
  3. Adult Primary Cholangiocellular Carcinoma
  4. Advanced Adult Primary Liver Cancer
  5. Cholangiocarcinoma of the Extrahepatic Bile Duct
  6. Localized Unresectable Adult Primary Liver Cancer
  7. Metastatic Extrahepatic Bile Duct Cancer
  8. Recurrent Adult Primary Liver Cancer
  9. Recurrent Extrahepatic Bile Duct Cancer
  10. Stage II Gallbladder Cancer
  11. Stage IIIA Gallbladder Cancer
  12. Stage IIIB Gallbladder Cancer
  13. Stage IVA Gallbladder Cancer
  14. Stage IVB Gallbladder Cancer
  15. Unresectable Extrahepatic Bile Duct Cancer
Interventions
  1. Drug: selumetinib
  2. Drug: Akt inhibitor MK2206
  3. Other: laboratory biomarker analysis
  4. Other: pharmacogenomic studies
  5. Procedure: quality-of-life assessment
MeSH:Adenocarcinoma Liver Neoplasms Cholangiocarcinoma Gallbladder Neoplasms Bile Duct Neoplasms Metaplasia
HPO:Cholangiocarcinoma Neoplasm of the gallbladder Neoplasm of the liver

To determine the presence of genetic mutations of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathway genes (other than v-raf murine sarcoma viral oncogene homolog [BRAF] V600E) relevant to biliary cancer and how these correlate with and may predict objective response to treatment with AZD6244 hydrogen sulfate and MK-2206. --- V600E ---

Primary Outcomes

Description: Calculated with corresponding 95% binomial confidence intervals.

Measure: Proportion of patients who have a response (PR or CR), assessed by the RECIST v1.1

Time: 6 months

Secondary Outcomes

Description: Frequency and severity of adverse events and tolerability of the regimen in each of the patient groups will be collected and summarized by descriptive statistics.

Measure: Frequency and severity of adverse events as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

Time: Up to 4 weeks

Description: Changes in overall quality of life will be explored in relation to severe toxicity incidence and in particular to incidence of cachexia. Graphical analyses will be used to assess patterns in these patient reported outcomes in relation to the clinical and tolerability outcomes of incidence.

Measure: Changes in QOL evaluated using the Functional Assessment of Cancer Therapy - General (FACT-G)

Time: Baseline to 8 weeks

89 Enhanced Melanoma Vaccine Against Neoantigen and Shared Antigens by CD40 Activation and TLR Agonists in Patients With Melanoma

This study evaluates whether it is safe to administer a peptide vaccine made of 6MHP and a mutated neoantigen peptide (BRAF585-614-V600E) combined with adjuvants. The adjuvants that will be used in this trial are a CD40 antibody (CDX-1140) and a toll-like receptor (TLR) 3 agonist (Poly-ICLC). The study will also investigate the effects of the vaccine and the adjuvants on the immune response. The investigators will monitor these effects by performing tests in the laboratory on participants' blood and skin tissue.

NCT04364230
Conditions
  1. Melanoma
Interventions
  1. Drug: 6MHP
  2. Drug: NeoAg-mBRAF
  3. Drug: PolyICLC
  4. Drug: CDX-1140
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Melanoma Vaccine Against Neoantigen and Shared Antigens by CD40 Activation and TLR Agonists In Patients With Melanoma This study evaluates whether it is safe to administer a peptide vaccine made of 6MHP and a mutated neoantigen peptide (BRAF585-614-V600E) combined with adjuvants. --- V600E ---

Primary Outcomes

Description: Number of participants with dose-limiting toxicities based on CTCAE v5.0

Measure: Safety of CDX-1140 + melanoma peptide vaccine (6MHP and NeoAg-mBRAF) + PolyICLC

Time: 30 days after receiving the last dose of study drug

Description: Number of participants with persistent C4+ Th1 responses to the melanoma vaccine at either day 127 or day 176, or both

Measure: Immunogenicity: Impact of addition of CDX-1140 to a melanoma vaccine on persistence of CD4+ Th1 responses

Time: Day 127 and/or Day 176

Secondary Outcomes

Description: Number of FoxP3+ CD4+ T cells per mm^2 in vaccine site biopsies

Measure: Immunogenicity: Impact of CDX-1140 on regulatory T cells

Time: Day 8 and Day 22

Description: Number of participants with circulating Tregs (CD4+ FoxP3+) as a proportion of circulating CD4 T cells

Measure: Immunogenicity: Impact of addition of CDX-1140 to melanoma vaccine on circulating regulatory T cells

Time: Through Day 85

Description: Number of participants with CD4+ T cell response; maximum increase after vaccination at any time point.

Measure: Immunogenicity: Impact of addition of CDX-1140 to melanoma vaccine on frequency of CD4+ Th1 responses to vaccine antigens

Time: Through Day 176

Description: Number of participants with CD4+ T cell response to the melanoma peptides

Measure: Immunogenicity: Impact of addition of CDX-1140 to melanoma vaccine on CD4+ Th1 memory response to vaccine antigens

Time: Day 176

90 Predictive Value of Progastrin Titer at Diagnosis and of Progastrin Kinetics During Treatment in Cancer Patients

Progastrin is a pro-hormone that, in physiological conditions, is maturated in gastrin in G cells of the stomach. The role of the gastrin is to stimulate the secretion of gastric acids during digestion. It is also important for the regulation of cell growth of the gastric mucosal. In a healthy person, progastrin is not detectable in the peripheral blood. However, progastrin is abnormally released in the blood of patients with different cancers (colorectal, gastric, ovarian, breast, cervix uterus, melanoma…) The gene GAST coding for progastrin is a direct target gene of the WNT/ß-catenin oncogenic pathway. The activation of this oncogenic pathway is an early event in cancer development. Chronic activation of the WNT/ß-catenin oncogenic pathway occurs in almost all human solid tumors and is a central mechanism in cancer biology that induces cellular proliferation, blocking of differentiation leading to primary tumor growth and metastasis formation. Progastrin measured in the peripheral blood of patients on treatments, could be a new powerful marker for diagnosis and prognosis at different stages.

NCT03787056
Conditions
  1. Cancer
  2. Breast Cancer
  3. Gastric Cancer
  4. Renal Cancer
  5. Prostate Cancer
  6. Melanoma
  7. Lung Cancer
  8. Hepatocellular Cancer
  9. Colorectal Cancer
  10. Head and Neck Cancer
  11. Pancreatic Cancer
  12. Ovarian Cancer
  13. Glioblastoma
  14. Endometrial Cancer
  15. Bladder Cancer
  16. Esophageal Cancer
  17. B-cell Lymphoma
Interventions
  1. Other: Blood draws
MeSH:Glioblastoma Endometrial Neoplasms Kidney Neoplasms Liver Neoplasms Carcinoma, Hepatocellular
HPO:Endometrial carcinoma Glioblastoma multiforme Hepatocellular carcinoma Neoplasm of the liver Renal neoplasm

Lung carcinoma: - SCLC for curative-intent cohort - Stage IV NSCLC with EGFR activating mutation, BRAF V600E mutation, ALK or ROS1 fusion. --- V600E ---

Primary Outcomes

Description: Progastrin concentration in plasma samples will be measured with an ELISA Kit (CancerREAD LAB) provided by ECS Progastrin.

Measure: ROC curve AUC regarding diagnostic accuracy of progastrin levels at baseline in cancer patients compared to non-cancer controls

Time: At baseline

Secondary Outcomes

Description: A nonlinear mixed effect model will be used to model the progastrin measurements done during treatments and follow-up of patients.The effect of each event (chemotherapy, surgery…) on the progastrin value and in the inter-individual variability of production and/or elimination rates of progastrin will be analyzed. Progastrin will be measured by ELISA, and the values will be expressed in pM. Measures will be done depending on the treatment received. Chemotherapy, every 3 or 4 weeks. Oral treatments: every 3 to 12 weeks. Surgery or radiotherapy: before and after the treatment. Follow up: concomitantly to the visits scheduled for the regular follow up of the patients.

Measure: Longitudinal kinetic of progastrin values during treatments, assessed by modeled kinetic parameters of interest

Time: 6 years

Description: 24 patients will be selected, upon their agreement and serum high levels, to enter in nychtemer (12 patients) or weekly (12 patients) cohorts. For the Nychtemer cohort, progastrin will be assayed at d1 at 8:00 am; 11:00 am; 2:00 pm; 5:00 pm; 8:00 pm and at d2 at 8:00 For the weekly cohort, progastrin will be assayed Day 1; Day 8; Day 15 and +/- Day 22; ideally on the same hour times. Progastrin will be measured by ELISA, and the values will be expressed in pM.

Measure: Nycthemeral and weekly progastrin variations

Time: every 3 hours within 24 hours for the Nycthemeral cohort, and every week for 2 or 3 weeks for the weekly cohort

Description: A nonlinear mixed effect model will be used to correlate individual values of progastrin (expressed in pM) with individual characteristic on the patient (hepatic function, as measured by the concentration of AST, ALT and bilirubin). Measures will be done Chemotherapy, every 3 or 4 weeks. Oral treatments: every 3 to 12 weeks. Surgery or radiotherapy: before and after the treatment. Follow up: concomitantly to the visits scheduled for the regular follow up of the patients

Measure: Determinants of progastrin serum values: hepatic function

Time: 6 years

Description: A nonlinear mixed effect model will be used to correlate individual values of progastrin (expressed in pM) with individual characteristic on the patient (renal function, as measured by creatinin concentration and creatinin clearance). Measures will be done Chemotherapy, every 3 or 4 weeks. Oral treatments: every 3 to 12 weeks. Surgery or radiotherapy: before and after the treatment. Follow up: concomitantly to the visits scheduled for the regular follow up of the patients

Measure: Determinants of progastrin serum values: renal function

Time: 6 years

Description: A nonlinear mixed effect model will be used to correlate the individual characteristics of the patient (age and gender) with progastrin concentration at the inclusion.

Measure: Determinants of progastrin serum values: age

Time: at the inclusion

Description: A nonlinear mixed effect model will be used to correlate genders with progastrin concentrations at the inclusion.

Measure: Determinants of progastrin serum values: gender

Time: at the inclusion

Description: The relationships between the progastrin kinetics during and after treatment and overall survival will be analyzed. Analyses will be performed separately on patients with curative intent treatment and on patients with palliative intent treatment. Measures wil be done At the end of the study (6 years for patients enrolled in curative intent and 5 years for patients enrolled in non-curative intent) or alternatively at the occurrence of progression or relapse.

Measure: Overall survival

Time: 6 years

Description: The relationships between the progastrin kinetics during and after treatment and recurrence free survival will be analyzed. Analyses will be performed separately on patients with curative intent treatment and on patients with palliative intent treatment. Measures wil be done At the end of the study (6 years for patients enrolled in curative intent and 5 years for patients enrolled in non-curative intent) or alternatively at the occurrence of progression or relapse.

Measure: recurrence free survival

Time: 6 years

Description: The relationships between the progastrin kinetics during and after treatment and progression free survival will be analyzed. Analyses will be performed separately on patients with curative intent treatment and on patients with palliative intent treatment. Measures wil be done At the end of the study (6 years for patients enrolled in curative intent and 5 years for patients enrolled in non-curative intent) or alternatively at the occurrence of progression or relapse.

Measure: progression free survival

Time: 6 years

Description: The size of the tumor will be correlated to progastrin concentration at the time of cancer diagnosis

Measure: The tumor size at cancer diagnosis

Time: At baseline

Description: The ability of progastrin kinetics during the neoadjuvant period to predict the outcome of the surgery (complete or not) will be analyzed by a ROC curve. If applicable.

Measure: Complete surgery

Time: 6 years

Description: The ability of the progastrin kinetics to predict recurrence free survival (curative cohorts), will be based on parameters estimated with a PK/PD model able to characterize the early kinetics of progastrin during and after the end of treatment and during follow up.

Measure: time to recurrence (for patients enrolled in curative intent cohorts).

Time: 6 years

Description: The ability of the progastrin kinetics to predict progression-free survival (non-curative cohorts) will be based on parameters estimated with a PK/PD model able to characterize the early kinetics of progastrin during and after the end of treatment and during follow up

Measure: time to progression (for patients enrolled in non-curative intent cohorts)

Time: 6 years

Description: The ability of the progastrin kinetics to predict time to death will be based on parameters estimated with a PK/PD model able to characterize the early kinetics of progastrin during and after the end of treatment and during follow up

Measure: time to death (whenever it occurred)

Time: 6 years

Description: The ROC AUC will be compared between classical markers and the prograstrin. Logistic regression will be used to combine the classical marker(s) and the progastrin in order to estimate the diagnostic value of the marker combination. progastrin, CA15-3, CA19-9, CA125, CEA, PSA and AFP concentration will be measured on blood sample taken at the inclusion.

Measure: Comparison of the initial values and of the kinetics of other serum tumor markers (CA15-3, CA 19-9, CA125, CEA, PSA, AFP) with those of progastrin

Time: at the baseline

91 A Multicenter, Open-label Phase 1b Study of the Combination of Binimetinib and Encorafenib in Adolescent Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma

This is a multicenter Phase 1b, open-label study to evaluate the pharmacokinetic, safety and efficacy of binimetinib and encorafenib co-administered to adolescent patients with BRAF V600-mutant advanced/metastatic melanoma. The study consists of a Safety Run-in Phase to determine the RDE (recommended dose in expansion), followed by an Expansion Phase.

NCT03878719
Conditions
  1. Melanoma
Interventions
  1. Drug: binimetinib
  2. Drug: encorafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer Stage IIIB, IIIC, or IV. - Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or central laboratory - Adequate cardiac function: - Left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO or multi-gated acquisition (MUGA) scan and above the institutional lower limit of normal (LLN); - Triplicate average baseline QTcF value ≤ 450 ms. - Adequate bone marrow, organ function, and laboratory parameters: - Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; - Hemoglobin ≥ 9 g/dL with or without transfusions; - Platelets ≥ 75 × 10⁹/L without transfusions; - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN); in patients with liver metastases ≤ 5 × ULN; - Total bilirubin ≤ 1.5 × ULN; - Creatinine ≤ 1.5 × institutional ULN for age, or calculated creatinine clearance ≥ 70 mL/min/1.73 --- V600E ---

Primary Outcomes

Measure: Pharmacokinetic (PK) parameter (time to reach the maximum observed plasma concentration Cmax [Tmax]) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (time of last PK sample [Tlast]) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (area under the plasma concentration-time curve from time zero to Tlast [AUClast]) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tmax) for binimetinib's active metabolite (AR00426032)

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for AR00426032

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tlast) for AR00426032

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (AUClast) for AR00426032

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tmax) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tlast) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (AUClast) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tmax) for encorafenib's metabolite (LHY746)

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for LHY746

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tlast) for LHY746

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (AUClast) for LHY746

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (trough concentration [Ctrough]) for binimetinib

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (trough concentration [Ctrough]) for binimetinib

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (trough concentration [Ctrough]) for binimetinib

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Measure: PK parameter (Ctrough) for AR00426032

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Ctrough) for AR00426032

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (Ctrough) for AR00426032

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Measure: PK parameter (Ctrough) for encorafenib

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Ctrough) for encorafenib

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (Ctrough) for encorafenib

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Measure: PK parameter (Ctrough) for LHY746

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Ctrough) for LHY746

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (Ctrough) for LHY746

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Secondary Outcomes

Measure: Incidence and severity of adverse events (AEs)

Time: From informed consent up to 30 days following last dose of study drug

Measure: Incidence of dose-limiting toxicities (DLTs)

Time: Duration of treatment for safety run-in phase, approximately 6 months, 28 day cycles

Description: Five-point Hedonic scale from 1 to 5, 5=really good

Measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for binimetinib

Time: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles

Description: Five-point Hedonic scale from 1 to 5, 5=really good

Measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for encorafenib

Time: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles

Measure: Objective response rate (ORR) assessed by the investigator, based on Response Criteria Evaluation in Solid Tumors (RECIST) v1.1

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Duration of response (DOR)

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Time to response

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Progression-free survival (PFS)

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: One-year survival rate

Time: From first dose up to 1 year after treatment initiation

Measure: Change from baseline bone age and the difference in bone age and chronological age

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Change from Baseline in bone densitometry based on dual energy X-ray absorptiometry (DEXA) scan.

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Change from Baseline in calcium-phosphorus product (Ca × P)

Time: Duration of treatment, approximately 6 months, 28 day cycles

92 LUNGMAP: A Master Protocol To Evaluate Biomarker-Driven Therapies And Immunotherapies In Previously-Treated Non-Small Cell Lung Cancer (Lung-Map Screening Study)

This screening and multi-sub-study randomized phase II/III trial will establish a method for genomic screening of similar large cancer populations followed by assigning and accruing simultaneously to a multi-sub-study hybrid Master Protocol (Lung-MAP). The type of cancer trait (biomarker) will determine to which sub-study, within this protocol, a participant will be assigned to compare new targeted cancer therapy, designed to block the growth and spread of cancer, or combinations to standard of care therapy with the ultimate goal of being able to approve new targeted therapies in this setting. In addition, the protocol includes non-match sub-studies which will include all screened patients not eligible for any of the biomarker-driven sub-studies.

NCT03851445
Conditions
  1. Previously Treated Non-Small Cell Lung Cancer
Interventions
  1. Drug: Screening Platform
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients must agree to have any tissue that remains after testing retained for the use of sub-study Translational Medicine (TM) studies at the time of consent the patient is enrolled in. 5. Patients with known EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, or BRAF V600E mutation are not eligible unless they have progressed following all standard of care targeted therapy. --- T790M --- --- V600E ---

Primary Outcomes

Description: The tissue submission will be measured by the proportion of patients who register to this screening study for whom a tissue sample is submitted.

Measure: Screening Success (Tissue Submission)

Time: Up to 3 years

Description: Adequate tissue will be measured by the proportion of patients who submitted a specimen for whom genomic results were successfully obtained, if multiple platforms are being used (e.g. both FMI and IHC), these rates will be summarized by the individual assays and combined. These rates are summarized for the entire screened population and by screening type (screened at progression versus pre-screened prior to progression). The rates are evaluated for both the initial submission success rates and the overall success rate accounting for new tissue submissions following an unsuccessful result.

Measure: Screening Success (Adequate Tissue)

Time: Up to 3 years

Description: Pre-screening-to-sub-study assignment will be measured among pre-screened patients and the proportion of patients assigned to a sub-study (which is triggered by the submission of the notice of progression form, see Section 14.0). Note: Patients screened at progression are notified of their sub-study assignment within 1 day of the biomarker results being reported to SWOG.

Measure: Screening Success (Prescreening-to-sub-study Assignment)

Time: Up to 3 years

Description: Screening success will be measured by the reasons for non-participation collection on the LungMAP Notice of Intention not to Register Form. The proportions of patients with this form submitted are summarized overall and by screening type. The reasons for submission are summarized overall and by screening type.

Measure: Screening Success (Notice of Intention Not to Register Submission)

Time: Up to 3 years

Description: Match to Biomarker-Driven Sub-Study will be measured by successful biomarker screening, the proportion assigned to a biomarker-driven substudy.

Measure: Screening Success (Match to Biomarker-Driven Sub-Study)

Time: Up to 3 years

Description: Assignment Success will be measured by the proportion of patients assigned to a sub-study who are registered to a sub-study, these rates are summarized overall and among biomarker-driven and non-match sub-study assignments, separately. In addition, these rates are summarized by screening type.

Measure: Screening Success (Assignment Success)

Time: Up to 3 years

93 A Phase 2 Study of Erdafitinib in Subjects With Advanced Solid Tumors and FGFR Gene Alterations

The purpose of this study is to evaluate the efficacy of erdafitinib in terms of overall response rate (ORR) in participants with advanced solid tumors with fibroblast growth factor receptor (FGFR) mutations and gene fusions.

NCT04083976
Conditions
  1. Advanced Solid Tumor
Interventions
  1. Drug: Erdafitinib
MeSH:Neoplasms
HPO:Neoplasm

The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).. Inclusion Criteria: - Histologic demonstration of an unresectable, locally advanced, or metastatic solid tumor malignancy with an fibroblast growth factor receptor (FGFR) mutation or FGFR gene fusion - Measurable disease - Participant must have received at least one prior line of systemic therapy in the advanced, unresectable, or metastatic setting - Documented progression of disease, defined as any progression that requires a change in treatment, prior to full study screening Exclusion Criteria: - Has had prior chemotherapy, targeted therapy, or treatment with an investigational anticancer agent within 15 days or greater than or equal to (>=) 5 half-lives of the agent (whichever is longer) and up to a maximum of 30 days before the first dose of erdafitinib - The presence of FGFR gatekeeper and resistance mutations - Histologic demonstration of urothelial carcinoma - Hematologic malignancy (i.e., myeloid and lymphoid neoplasms - For non-small cell lung cancer participants only: pathogenic somatic mutations or gene fusions in the following genes: EGFR, ALK, ROS1, NTRK, and BRAF V600E - Active malignancies other than for disease requiring therapy Inclusion Criteria: - Histologic demonstration of an unresectable, locally advanced, or metastatic solid tumor malignancy with an fibroblast growth factor receptor (FGFR) mutation or FGFR gene fusion - Measurable disease - Participant must have received at least one prior line of systemic therapy in the advanced, unresectable, or metastatic setting - Documented progression of disease, defined as any progression that requires a change in treatment, prior to full study screening Exclusion Criteria: - Has had prior chemotherapy, targeted therapy, or treatment with an investigational anticancer agent within 15 days or greater than or equal to (>=) 5 half-lives of the agent (whichever is longer) and up to a maximum of 30 days before the first dose of erdafitinib - The presence of FGFR gatekeeper and resistance mutations - Histologic demonstration of urothelial carcinoma - Hematologic malignancy (i.e., myeloid and lymphoid neoplasms - For non-small cell lung cancer participants only: pathogenic somatic mutations or gene fusions in the following genes: EGFR, ALK, ROS1, NTRK, and BRAF V600E - Active malignancies other than for disease requiring therapy Advanced Solid Tumor Neoplasms Erdafitinib is a selective and potent pan FGFR 1-4 inhibitor with demonstrated clinical activity in participants with metastatic urothelial cancer and cholangiocarcinoma identified to have alterations in the FGFR pathway. --- V600E ---

The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).. Inclusion Criteria: - Histologic demonstration of an unresectable, locally advanced, or metastatic solid tumor malignancy with an fibroblast growth factor receptor (FGFR) mutation or FGFR gene fusion - Measurable disease - Participant must have received at least one prior line of systemic therapy in the advanced, unresectable, or metastatic setting - Documented progression of disease, defined as any progression that requires a change in treatment, prior to full study screening Exclusion Criteria: - Has had prior chemotherapy, targeted therapy, or treatment with an investigational anticancer agent within 15 days or greater than or equal to (>=) 5 half-lives of the agent (whichever is longer) and up to a maximum of 30 days before the first dose of erdafitinib - The presence of FGFR gatekeeper and resistance mutations - Histologic demonstration of urothelial carcinoma - Hematologic malignancy (i.e., myeloid and lymphoid neoplasms - For non-small cell lung cancer participants only: pathogenic somatic mutations or gene fusions in the following genes: EGFR, ALK, ROS1, NTRK, and BRAF V600E - Active malignancies other than for disease requiring therapy Inclusion Criteria: - Histologic demonstration of an unresectable, locally advanced, or metastatic solid tumor malignancy with an fibroblast growth factor receptor (FGFR) mutation or FGFR gene fusion - Measurable disease - Participant must have received at least one prior line of systemic therapy in the advanced, unresectable, or metastatic setting - Documented progression of disease, defined as any progression that requires a change in treatment, prior to full study screening Exclusion Criteria: - Has had prior chemotherapy, targeted therapy, or treatment with an investigational anticancer agent within 15 days or greater than or equal to (>=) 5 half-lives of the agent (whichever is longer) and up to a maximum of 30 days before the first dose of erdafitinib - The presence of FGFR gatekeeper and resistance mutations - Histologic demonstration of urothelial carcinoma - Hematologic malignancy (i.e., myeloid and lymphoid neoplasms - For non-small cell lung cancer participants only: pathogenic somatic mutations or gene fusions in the following genes: EGFR, ALK, ROS1, NTRK, and BRAF V600E - Active malignancies other than for disease requiring therapy Advanced Solid Tumor Neoplasms Erdafitinib is a selective and potent pan FGFR 1-4 inhibitor with demonstrated clinical activity in participants with metastatic urothelial cancer and cholangiocarcinoma identified to have alterations in the FGFR pathway. --- V600E --- --- V600E ---

Primary Outcomes

Description: ORR as assessed by IRC is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR).

Measure: Overall Response Rate (ORR) as Assessed by Independent Review Committee (IRC)

Time: Up to 6 Years

Secondary Outcomes

Description: ORR as assessed by investigator is defined as the percentage of participants who achieve a CR or PR.

Measure: Overall Response Rate as Assessed by Investigator

Time: Up to 6 Years

Description: DOR is the duration from the date of initial documentation of a response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study), or death, whichever comes first.

Measure: Duration of Response (DOR)

Time: Up to 6 Years

Description: DCR is defined as the percentage of participants with CR, PR or stable disease (SD).

Measure: Disease Control Rate (DCR)

Time: Up to 6 Years

Description: PFS is the duration from the date of the first dose of study drug until the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death, whichever comes first.

Measure: Progression Free Survival (PFS)

Time: Up to 6 Years

Description: OS will be measured from the date of first dose of study drug to the date of the participant's death.

Measure: Overall Survival (OS)

Time: Up to 6 Years

Description: Plasma concentrations of erdafitinib will be reported.

Measure: Plasma Concentrations of Erdafitinib

Time: Predose and 2-4 hours postdose

Description: An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An adverse event does not necessarily have a causal relationship with the relevant investigational product.

Measure: Number of Participants with Adverse Events (AEs)

Time: Up to 6 Years

Description: An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Adverse event severity is a clinical determination of the intensity of an adverse event.

Measure: Number of Participants with Adverse Events by Severity

Time: Up to 6 Years

Description: The EORTC QLQ-C30 includes 30 items in 5 functional scales, 1 global health status scale, 3 symptom scales, and 6 single symptom items. The responses are reported using a verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms.

Measure: Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQ-C30) Scale Score

Time: Baseline up to 6 Years

Description: The PGIS is a single question regarding the patient report of disease severity: considering all aspects of your cancer symptoms right now would you say your cancer symptoms are none, mild, moderate, severe, or very severe?

Measure: Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Symptom Severity (PGIS) Scale Score

Time: Baseline up to 6 Years

Description: The PGIC is the patient-reported outcome (PRO) counterpart to the clinical global impressions (CGI) scale. The PGIC is a single verbal rating scale ranging from 1 = a lot better now to 7 = a lot worse now.

Measure: Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Change (PGIC) Scale

Time: Baseline up to 6 Years

Description: The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).

Measure: Change from Baseline in Health-Related Quality of Life as Assessed by European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) Scale Score

Time: Baseline up to 6 Years

94 A Phase I Trial of Atezolizumab and Varlilumab in Combination With Radiation in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC)

This phase I trial studies the side effects of atezolizumab, varlilumab, and radiation therapy in treating patients with non-small cell lung cancer that has spread to other places in the body (advanced) and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies such as atezolizumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies such as varlilumab may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving atezolizumab, varlilumab, and radiation therapy may increase the amount of time the disease is not active or does not spread to another part of the body.

NCT04081688
Conditions
  1. Refractory Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Cancer AJCC v8
Interventions
  1. Drug: Atezolizumab 1200 MG in 20 ML Injection
  2. Radiation: Stereotactic Body Radiation Therapy
  3. Drug: Varlilumab 3 mg/kg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Treatment should be initiated at least 4 weeks since last dose of systemic therapy - Subjects with an actionable molecular alteration (such as EGFR mutation, ALK or ROS1 rearrangement, BRAF V600E mutation) are eligible only after failing standard-of-care targeted therapy with tyrosine kinase inhibitor (TKI). --- V600E ---

Primary Outcomes

Description: Will include grade 3 and 4 toxicities as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Measure: Assess the safety and tolerability of combined therapy in patients with metastatic NSCLC who have progressed on prior PD-1/PD-L1 therapy

Time: Up to 30 days after the last dose of treatment

Secondary Outcomes

Description: Will be defined as the proportion of all subjected confirmed with an immune-related partial response (irPR) or immune-related complete response (irCR) divided by the number of assigned patients according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Measure: To determine objective response rate (ORR) of therapy

Time: From the start of treatment until disease progression/recurrence, assessed up to 1 year

Description: Will be defined as the percentage of patients who achieve irCR, irPR, and immune-related stable disease.

Measure: To estimate clinical benefit rate of the combination

Time: Up to 1 year

Description: The log-rank test will be used to analyze PFS for comparison of treatment effects, i.e., the only covariate that will be used is the treatment arm. Distributions of PFS times will be estimated using the Kaplan- Meier product-limit method. The median PFS times with two-sided 95% confidence intervals will be estimated for each treatment group.

Measure: To estimate median progression-free survival (PFS) of the combination

Time: From cycle 1, day 1 (each cycle is 21 days) of treatment until the criteria for disease progression is met as defined by irRECIST or death as a result of any cause, assessed up to 1 year

Description: irAE's are defined as any treatment-related AE that is inflammatory in nature, consistent with the mechanism of action of immunotherapy and generally medically manageable with topical and/or systemic immunosuppressants.

Measure: To compare the frequency of immune-related adverse events (irAEs)

Time: Up to 30 days after the last dose of treatment

Other Outcomes

Description: Will be assessed by immunohistochemistry (IHC) and will score the percentage of cells staining positively for PD-L1 incrementally. Scoring will be performed for the percentage of malignant tumor cells and for the percentage of nonmalignant inflammatory cell compartment that express PD-L1, separately.

Measure: To compare pre- and post-treatment tumor PD-L1 expression

Time: Baseline up to cycle 2, day 8 (each cycle is 21 days)

Description: Will be assessed by IHC staining to identify tumor infiltrating lymphocytes at the tumor stroma interface.

Measure: To compare pre- and post-treatment tumor levels of infiltrating CD3+, CD8+ T-cells

Time: Baseline up to cycle 2, day 8 (each cycle is 21 days)

95 A Phase III Study of RAMucirumab in Combination With TAS102 vs. TAS102 Monotherapy in Chemotherapy Refractory Metastatic Colorectal Cancer Patients

Interventional, prospective, randomized (1:1), controlled, open label, multicenter phase IIb study in patients with advanced metastatic colorectal cancer. The scope of the trial is to evaluate overall survival of either regimen (TAS102 +/- Ramucirumab) and evaluate safety and tolerability.

NCT03520946
Conditions
  1. Colorectal Cancer
Interventions
  1. Drug: Ramucirumab
  2. Drug: TAS 102
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Intolerance is defined as a permanent discontinuation of the respective treatment resulting from toxicity 2. Signed informed consent before start of specific protocol procedure 3. Histologically or cytologically documented diagnosis of adenocarcinoma of the colon or rectum 4. Presence of at least one measurable site of disease following RECIST 1.1 criteria 5. ECOG (Eastern Cooperative Oncology Group) performance 0-1 6. Known RAS and BRAF V600E mutational status 7. Life expectancy of at least 3 months 8. Adequate hematological, hepatic and renal function parameters: 1. Leukocytes ≥3000/mm³, platelets ≥100,000/mm³, neutrophil count (ANC) ≥1500/μL, hemoglobin ≥9 g/dL (5.58 mmol/L) 2. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5, and a partial thromboplastin time (PTT) ≤5 seconds above the ULN (upper limit of normal) (unless receiving anticoagulation therapy). --- V600E ---

Patients will be stratified by the duration of previous anti-angiogenic therapy ≥ or <12 months in total, BRAF V600E mutation status (mutation vs. wildtype), RAS mutation status (mutation vs. wildtype), and randomized 1:1 to receive either ramucirumab/TAS102 (arm A) or TAS102 (arm B). --- V600E ---

Primary Outcomes

Description: Overall survival according to Kaplan-Meier

Measure: Overall survival

Time: Up to 4 years

Secondary Outcomes

Description: ORR defined as the proportion of patients with complete or partial remission according to RECIST 1.1

Measure: Overall response rate (ORR)

Time: Up to 4 years

Description: DCR defined as the proportion of patients with complete or partial remission and stable disease according to RECIST 1.1

Measure: Disease control rate (DCR)

Time: Up to 4 years

Description: PFS, defined as the time from enrollment/randomization to the first occurrence of progression, as determined by the investigator using CT criteria, or death from any cause

Measure: Progression-free survival (PFS)

Time: Up to 4 years

Description: OS rate at 6 and 12 months, defined as patients who are alive after at 6 and 12 months, respectively

Measure: Overall survival (OS) rate at different time points

Time: 6 months and 1 year

Description: Efficacy (ORR) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

Measure: Efficacy (ORR) subgroup

Time: Up to 4 years

Description: Efficacy (PFS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

Measure: Efficacy (PFS) subgroup

Time: Up to 4 years

Description: Efficacy (OS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

Measure: Efficacy (OS) subgroup

Time: Up to 4 years

Description: Quality of life (QoL) as measured by EORTC-QLQ-C30 at d1 of each cycle and on EOT (end of treatment).

Measure: Quality of life I (QoL)

Time: Up to 1 year

Description: Quality of life (QoL) as measured by EQ-5D-5L at d1 of each cycle and on EOT.

Measure: Quality of life II (QoL)

Time: Up to 1 year

Other Outcomes

Description: ORR according to gene expression, mutational profiles, plasma biomarkers and radiologic analysis

Measure: Explorative: Overall response rate (ORR)

Time: Up to 4 years

Description: OS according to gene expression, mutational profiles, plasma biomarkers and radiologic analysis

Measure: Explorative: Overall survival (OS)

Time: Up to 4 years

Description: PFS according to gene expression, mutational profiles, plasma biomarkers and radiologic analysis

Measure: Explorative: Progression-free survival (PFS)

Time: Up to 4 years

96 Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine (HCQ) for BRAF V600E-mutant or Trametinib and HCQ for BRAF Fusion/Duplication Positive or NF1-associated Recurrent or Progressive Gliomas in Children and Young Adults

This phase I/II trial is designed to study the side effects, best dose and efficacy of adding hydroxychloroquine to dabrafenib and/or trametinib in children with low grade or high grade brain tumors previously treated with similar drugs that did not respond completely (progressive) or tumors that came back while receiving a similar agent (recurrent). Patients must also have specific genetic mutations including BRAF V600 mutations or BRAF fusion/duplication, with or without neurofibromatosis type 1. Neurofibromatosis type 1 is an inherited genetic condition that causes tumors to grow on nerve tissue. Hydroxychloroquine, works in different ways to stop the growth of tumor cells by killing the cells or stopping them from dividing. Trametinib and dabrafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine with trametinib and/or dabrafenib may lower the chance of brain tumors growing or spreading compared to usual treatments.

NCT04201457
Conditions
  1. Low Grade Glioma (LGG) of Brain With BRAF Aberration
  2. High Grade Glioma (HGG) of the Brain With BRAF Aberration
  3. Low Grade Glioma of Brain With Neurofibromatosis Type 1
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
  3. Drug: Hydroxychloroquine
MeSH:Glioma Neurofibromatoses Neurofibromatosis 1 Neurofibroma
HPO:Glioma Neurofibromas

Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine (HCQ) for BRAF V600E-mutant or Trametinib and HCQ for BRAF Fusion/Duplication Positive or NF1-associated Recurrent or Progressive Gliomas in Children and Young Adults. --- V600E ---

Patients enrolled will be stratified as follows: - Phase I: - Stratum 1 LGG or HGG with BRAF V600E/D/K mutation - Stratum 2 LGG with BRAF duplication or fusion with any partner or LGG with neurofibromatosis type 1 - Phase II: - Stratum 3 LGG with BRAF V600E/D/K mutation - Stratum 4 HGG with BRAF V600E/D/K mutation - Stratum 5 LGG with BRAF duplication or fusion with any partner - Stratum 6 LGG with neurofibromatosis type 1 - BRAF alterations will be locally determined using molecular methods in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. --- V600E ---

Patients enrolled will be stratified as follows: - Phase I: - Stratum 1 LGG or HGG with BRAF V600E/D/K mutation - Stratum 2 LGG with BRAF duplication or fusion with any partner or LGG with neurofibromatosis type 1 - Phase II: - Stratum 3 LGG with BRAF V600E/D/K mutation - Stratum 4 HGG with BRAF V600E/D/K mutation - Stratum 5 LGG with BRAF duplication or fusion with any partner - Stratum 6 LGG with neurofibromatosis type 1 - BRAF alterations will be locally determined using molecular methods in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. --- V600E --- --- V600E ---

Patients enrolled will be stratified as follows: - Phase I: - Stratum 1 LGG or HGG with BRAF V600E/D/K mutation - Stratum 2 LGG with BRAF duplication or fusion with any partner or LGG with neurofibromatosis type 1 - Phase II: - Stratum 3 LGG with BRAF V600E/D/K mutation - Stratum 4 HGG with BRAF V600E/D/K mutation - Stratum 5 LGG with BRAF duplication or fusion with any partner - Stratum 6 LGG with neurofibromatosis type 1 - BRAF alterations will be locally determined using molecular methods in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. --- V600E --- --- V600E --- --- V600E ---

Immunohistochemistry for BRAF V600E alone is not adequate and must be confirmed molecularly - Phase II patients must have bi-dimensionally measurable disease defined as at least one lesion that can be accurately measured in at least two planes. --- V600E ---

The goal of this study is to optimize the clinical effect of dabrafenib and trametinib by addressing intrinsic and acquired resistance that is well-described in V600E-mutant melanoma and for which there is preclinical and clinical evidence in pediatric gliomas. --- V600E ---

Patients with BRAF V600E LGG or HGG will receive the combination of D+T+HCQ given orally in the form of capsules which must be taken whole, or an oral solution made from tablets. --- V600E ---

Primary Outcomes

Description: Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib

Measure: Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D)

Time: Approximately 28 days from start of therapy

Description: Maximum plasma concentration Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine

Measure: Maximum Plasma Concentration

Time: 1-4 days

Description: AUC for Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine

Measure: Area under the curve (AUC)

Time: 1-4 days

Description: Number of patients who meet the "better response" criteria, which is a comparison of response on this current protocol therapy versus their best response to previous RAF and/or MEK inhibitor therapy

Measure: Phase II: Sustained objective response rate.

Time: Up to approximately 2 years from the start of therapy

Secondary Outcomes

Measure: Phase I: Dose limiting toxicities of D + T HCQ or T + HCQ

Time: course 1 of therapy, approximately 28 days from start of therapy

Measure: Phase I: Response Rate

Time: Up to approximately 2 years from start of therapy

Measure: Phase II: Progression-free survival

Time: Start of protocol therapy until progression or last follow-up, up to approximately 2 years from start of treatment

Description: Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway

Measure: Phase II: Visual outcome based on Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway

Time: Throughout study therapy, up to approximately 2 years from start of therapy

Description: Accumulation of LC3II in peripheral blood mononuclear cells

Measure: Phase I and II: Autophagy inhibition as assessed by the accumulation of LC3II in peripheral blood mononuclear cells

Time: Approximately 2 years from start of therapy]

Description: Accumulation of p62 in peripheral blood mononuclear cells

Measure: Phase I and II: Autophagy inhibition as assessed by the accumulation of p62 in peripheral blood mononuclear cells

Time: Approximately 2 years from start of therapy

Description: MAPK pathway aberrations (other than BRAF) assessed by whole exome sequencing

Measure: Phase I and II: Presence of MAPK pathway aberrations (other than BRAF) as assessed by whole exome sequencing

Time: At time of study enrollment

Description: Evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)

Measure: Phase I and II: biomarker of resistance to RAF or MEK inhibitor therapy by evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)

Time: At enrollment and at the time of every MRI study up to approximately 2 years from the start of therapy

97 An Open-Label, Phase 1/1b, Single-Agent Study of RXDX-105 in Patients With Advanced Solid Tumors

This is a first-in-human, multicenter, open-label study consisting of 2 phases. Phase 1 is a dose escalation study of RXDX-105 (formerly known as CEP-32496) in patients with advanced solid tumors aimed at defining the recommended Phase 2 dose (RP2D) and schedule for administration. Phase 1b is a dose expansion in approximately 90 patients with advanced solid tumors with specific histologies and/or molecular alterations of interest. Patients in Phase 1b will be treated at the RP2D determined in Phase 1.

NCT01877811
Conditions
  1. Solid Tumors
Interventions
  1. Drug: RXDX-105
MeSH:Neoplasms
HPO:Neoplasm

Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E ---

Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E ---

Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E --- --- V600E ---

Known hypersensitivity to any of the components of RXDX-105 Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E ---

Known hypersensitivity to any of the components of RXDX-105 Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E ---

Known hypersensitivity to any of the components of RXDX-105 Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: From signing of the informed consent up to approximately 12 months

Measure: Phase 1: Dose Limiting Toxicities

Time: Approximately 12 months

Description: From signing of the informed consent up to approximately 12 months

Measure: Phase 1: Occurrence of Adverse Events

Time: Approximately 12 months

Description: To further assess the safety profile and tolerability of RXDX-105 at the RP2D

Measure: Phase 1b: Occurrence of Adverse Events

Time: Approximately 12 months

Secondary Outcomes

Measure: Phase 1: Maximum observed plasma drug concentration (Cmax)

Time: Day 1 to Day 16

Measure: Phase 1: Time of maximum observed plasma drug concentration (tmax)

Time: Day 1 to Day 16

Measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to infinity (AUC0-∞)

Time: Day 1 to Day 16

Measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to the last measureable drug concentration (AUC0-t)

Time: Day 1 to Day 16

Measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to 24 hours after study drug administration (AUC0-24)

Time: Day 1 to Day 16

Measure: Phase 1: Terminal elimination rate constant (λz)

Time: Day 1 to Day 16

Measure: Phase 1: Terminal elimination half-life (t1/2)

Time: Day 1 to Day 16

Measure: Phase 1: Apparent clearance of study drug from plasma (CL/F)

Time: Day 1 to Day 16

Description: Objective response rate is defined as the proportion of patients with advanced solid tumors achieving best overall response of complete response (CR), or partial response (PR), as assessed using RECIST v1.1

Measure: Phase 1b: Objective Response Rate

Time: Approximately 12 months

Description: The duration of objective response is defined as the time interval from the date of first documented response (CR or PR) to disease progression or death, whichever occurs first

Measure: Phase 1b: Duration of Objective Response

Time: Approximately 12 months

Description: Clinical benefit rate is defined as the proportion of patients achieving a complete response (CR), partial response (PR) or stable disease (SD) for 6 months

Measure: Phase 1b: Clinical Benefit Rate

Time: Approximately 12 months

98 Phase III, Randomized, Double-Blind, Multicenter Trial of Autologous Dendritic Cells and Irradiated Autologous Tumor Cells In Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) vs. Autologous Peripheral Blood Mononuclear Cells (PBMCs) In GM-CSF for The Treatment Of Metastatic Melanoma

The purpose of this research is to evaluate the safety and effectiveness of tumor cell therapy. This research study is evaluating if a patient-specific experimental therapy for metastatic melanoma will lengthen survival with minimal harmful effects. It is called an experimental therapy (or "study therapy") because it is not yet approved by the U.S. Food and Drug Administration (FDA). This research study will use the patient's own tumor cells,the patient's own dendritic cells (a type of immune cell), and a granulocyte-macrophage colony stimulating factor (GM-CSF, a type of growth factor). GM-CSF is a natural growth factor that stimulates growth of white blood cells in the body. Since 1991, GM-CSF has been used as a standard treatment to help increase the number of white blood cells after chemotherapy. The patient's dendritic cells are grown in a test-tube with the patient's tumor cells and the growth factor. The resulting solution is called the study therapy. The intent of the study therapy is to make the dendritic cells more effective at fighting the tumor when they are injected back into the patient.

NCT01875653
Conditions
  1. Stage IV Melanoma
  2. Stage III Melanoma
Interventions
  1. Biological: Autologous Dendritic Cell-Tumor Cell Immunotherapy (DC-TC)
  2. Biological: Autologous PBMCs in GM-CSF (MC)
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

2. Patients with multiple depots of distant metastatic disease must have previously received at least one or more of the following standard treatments: interleukin 2 (IL-2), or ipilimumab, or vemurafenib (if tumor expresses the V600E mutation), or dacarbazine or temozolomide, if not mutated for the V600E mutation, and not felt to be medically appropriate for IL-2 or ipilimumab. --- V600E ---

2. Patients with multiple depots of distant metastatic disease must have previously received at least one or more of the following standard treatments: interleukin 2 (IL-2), or ipilimumab, or vemurafenib (if tumor expresses the V600E mutation), or dacarbazine or temozolomide, if not mutated for the V600E mutation, and not felt to be medically appropriate for IL-2 or ipilimumab. --- V600E --- --- V600E ---

Primary Outcomes

Description: The time frames are estimated time in months (rounded up to the nearest month) from the start of study. The time estimates for the analyses are based on enrolling approximately 250 patients over a 34.8 months period and having a follow up of approximately 17 months after the last patient is enrolled.

Measure: Overall survival

Time: 52 months

Secondary Outcomes

Description: Adverse Events monitoring to assess safety and tolerability History & physical examination, vital signs, clinical laboratory tests (safety), and other tests as clinically indicated adverse event monitoring to assess safety and toxicity

Measure: Adverse Events as a Measure of Safety and Tolerability

Time: 52 months

99 A Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases, Whose Tumors Harbor B-raf Mutations

The purpose of this trial is to study the activity of vemurafenib in untreated melanoma brain metastases harboring B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations that are not amenable to stereotactic radiosurgery based on size, number of lesions or location, to measure cerebrospinal fluid (CSF) levels of vemurafenib as an indicator of central nervous system penetrance and to measure levels of vemurafenib in normal brain tissue and brain metastases in those in whom surgical management is feasible.

NCT01781026
Conditions
  1. Melanoma
Interventions
  1. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.. Inclusion Criteria: - Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations. --- V600E ---

Inclusion Criteria: - Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations. --- V600E ---

Primary Outcomes

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Measure: Activity of Vemurafenib in Untreated Brain Metastases

Time: 1 year

100 APPLICATION OF MOLECULAR TECHNIQUES FOR IMPROVING THE DIAGNOSIS AND TREATMENT OF NODULAR THYROID LESIONS.

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System)

NCT02323724
Conditions
  1. Papillary Thyroid Carcinoma
Interventions
  1. Genetic: BRAF V600E mutation by pyrosequencing technique
MeSH:Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System) Improvement in diagnosis. --- V600E ---

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System).. Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Papillary Thyroid Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases Aim of the study To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System). --- V600E ---

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System).. Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Papillary Thyroid Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases Aim of the study To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System). --- V600E --- --- V600E ---

Methodology: - Identification of cases - Detection of BRAF V600E mutation, initially in histological material from the surgical specimen, and if present, detection in cytological material. --- V600E ---

Primary Outcomes

Description: To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System).

Measure: Improvement in diagnosis

Time: 6 months

101 A Prospective Study of Plasma Genotyping as a Noninvasive Biomarker for Genotype-directed Cancer Care

Tumor genotyping has become an essential biomarker for the care of advanced lung cancer and melanoma, and is currently used to identify patients for treatment with targeted kinase inhibitors like erlotinib and vemurafenib. However, tumor genotyping can be slow and cumbersome, and is limited by availability of tumor biopsy tissue for testing. The aim of this study is to prospectively evaluate a blood-based genotyping tool that can quantify the presence of oncogenic mutations (EGFR, KRAS, BRAF) in patients with lung cancer and melanoma. This assay is being studied both as a diagnostic tool for classifying patient genotype, and a serial measurement tool for quantification of response and progression on therapy.

NCT02279004
Conditions
  1. NSCLC
  2. Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.. Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- L858R --- --- T790M --- --- V600E ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M --- --- L858R --- --- T790M --- --- V600E ---

Primary Outcomes

Description: We will determine the accuracy of a droplet digital PCR (ddPCR)-based plasma genotyping assay in performing noninvasive tumor genotyping.

Measure: Accuracy of Plasma Genotyping Assay

Time: 2 years

Secondary Outcomes

Description: The amount of time required to perform this noninvasive genotyping assay.

Measure: Turnaround Time of Plasma Genotyping Assay

Time: 2 years

Description: The ability of serial quantitative ddPCR-based plasma genotyping to predict early treatment failure in patients initiating a new line of therapy.

Measure: Early Treatment Failure

Time: 2 years

Description: We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.

Measure: Accuracy of Plasma NGS

Time: 2 years

102 A Pilot Study of Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer

The purpose of this study is to test a new drug combination consisting of two drugs, vemurafenib (also known as ZelborafTM) and panitumumab (also known as VectibixTM). This treatment is being tested in a subgroup of patients with colorectal cancer whose tumors have changes in the BRAF gene that may make them more likely to respond to this new drug combination.

NCT01791309
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: combination panitumumab and vemurafenib
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

A Pilot Study of Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer. --- V600E ---

Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer The purpose of this study is to test a new drug combination consisting of two drugs, vemurafenib (also known as ZelborafTM) and panitumumab (also known as VectibixTM). --- V600E ---

using pre- and post-vemurafenib tumor biopsies obtained from the first 10 patients participating in this trial.. Inclusion Criteria: - Patient must have metastatic colorectal cancer with a V600E BRAF mutation that has been histologically or cytologically-confirmed at MSKCC and has failed to respond to appropriate standard therapy regimens. --- V600E ---

Inclusion Criteria: - Patient must have metastatic colorectal cancer with a V600E BRAF mutation that has been histologically or cytologically-confirmed at MSKCC and has failed to respond to appropriate standard therapy regimens. --- V600E ---

Primary Outcomes

Description: Overall response will be estimated based on best response to this combination in six months of treatment.

Measure: objective response rate (ORR)

Time: 6 months

Secondary Outcomes

Description: Progression free survival (PFS) is defined as the period elapsing between the date of initiation of therapy and the date of either disease progression or date of death, whichever is earlier.

Measure: progression-free survival (PFS)

Time: 2 years

Description: OS is defined as the interval between the time of initiation of therapy and the date of death from any cause. Patients who are alive at the time of study completion will be censored at the time the patient was last known to be alive.

Measure: overall survival (OS)

Time: 2 years

Description: The safety endpoints will include all types of adverse experiences, laboratory safety measurements, ECOG performance scale status, and vital signs. Adverse experiences will be graded and recorded throughout the study according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0.

Measure: safety, tolerability, and adverse event profile

Time: 1 year

Description: using pre- and post-vemurafenib tumor biopsies obtained from the first 10 patients participating in this trial.

Measure: efficacy

Time: 2 years

103 A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).

This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part).

NCT01928940
Conditions
  1. Solid Tumours
Interventions
  1. Drug: dabrafenib
  2. Drug: trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E --- --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E --- --- V600E --- --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Solid Tumours Melanoma This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E ---

Solid Tumours Melanoma This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E ---

Phase I part is designed to primarily assess the safety and tolerability of GSK2118436 and GSK1120212 combination therapy in subjects with BRAF V600E/K mutation positive advanced solid tumors. --- V600E ---

Phase II part is designed to primarily evaluate ORR of the combination as first-line therapy in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation positive cutaneous melanoma. --- V600E ---

Primary Outcomes

Description: An AE is defined as any untoward medical occurrence (MO) in a part. temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. SAE is defined as any untoward MO that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect and protocol-specific SAEs:ALT>=3xupper limit of normal(ULN) and bilirubin>=2xULN(>35% direct) (or ALT>=3xULN, international normalized ratio>1.5), any new primary cancers, treatment emergent malignancies except basal cell carcinoma, symptomatic or asymptomatic LVEF decrease, retinal pigment epithelial detachment or retinal vein occlusion, pyrexia with hypotension,or dehydration or renal insufficiency,or severe (>=G3) rigor/chills.

Measure: Phase I: Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)

Time: From the start of study treatment until 30 days after study treatment discontinuation (average of 1.38 year)

Description: A DLT was defined as an event occurred during the first 21 days after the first dose of study drugs and met any of the following criteria, according to National Cancer Institutes (NCI) common terminology criteria for AE (CTCAE) grade (G) version 4.0: G4 hematological toxicity; G3 or G4 non-hematologic toxicity (including rash, nausea, vomiting and diarrhea only if uncontrolled with supportive therapy); rash >=G3 that required dose reduction despite supportive care; a G2 or greater non-hematological toxicity that in the judgment of the investigator and medical monitor; dose interruption of greater than 14 consecutive days due to unresolved toxicity; any new G2 or greater valvular heart disease and significant alteration in cardiac valve morphology from Baseline.

Measure: Phase I: Number of Participants With a Dose-limiting Toxicity (DLT)

Time: From the start of study treatment until 21 days

Description: CCPs were graded according to NCI CTCAE grade version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters (para) for which an increase to G3 or G4 from BL G occurred. CCPs that were not G according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those para for which the category decreased to Low or increased to High relative to the BL category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. CCPs included: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, calcium, creatinine, glucose, potassium, magnesium, sodium, inorganic phosphorus, chloride, lactate dehydrogenase (LDH), total protein, urea/blood urea nitrogen (BUN) and uric acid.

Measure: Phase I: Number of Participants With the Indicated Worst-case Change From Baseline (BL) in the Indicated Clinical Chemistry Parameters (CCPs)

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Hematology parameters were summarized according to NCI CTCAE G, version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 from Baseline G occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those parameters for which the category decreased to Low or increased to High relative to the Baseline category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Hematology parameters included: hemoglobin, lymphocytes, total neutrophils, platelet count, white blood cell (WBC) counts, basophils, eosinophils, hematocrit, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), monocytes and red blood cell (RBC) count.

Measure: Phase I: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Hematology Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Urine samples were collected for urine dipstick analysis at Baseline and at the post-treatment Visit. The number of participants with negative (absence) and positive (presence: trace, 1+, 2+, 3+, 4+ or 5+) results for urine occult blood (UOB), urine glucose (UGLU), urine ketones (UKET), urine protein (UP) and urine urobilinogen (UUBIL) were summarized. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase I: Number of Participants With the Indicated Urinalysis Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: The ECOG pef status 5-point scale is used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the par. and to determine appropriate treatment and prognosis: G0, fully active, able to carry on all pre-disease pef without restriction. G1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, example, light house work, office work. G2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about >50 percent (%) of waking hrs. G3, capable of only limited selfcare; confined to bed or chair >50% of waking hrs. G4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. G5, dead. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Number of par. who improved, had no change, or deteriorated in pef status from BL is summarized.

Measure: Phase I: Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance (Pef) Status

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were graded using (NCI CTCAE version 4.0). SBP was categorized as: G1 (Increase to >=120 to 140 millimeters of mercury [mmHg]), G2 (Increase to >=140 to <160 mmHg), and G3 (Increase to >=160 mmHg). DBP was categorized as: G1 (Increase to >=80 to <90 mmHg), G2 (Increase to >=90 to <100 mmHg), and G3 (Increase to >=100 mmHg). The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of G0.

Measure: Phase I: Number of Participants With Worst-case On-therapy Increase From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Change from Baseline in heart rate is categorized as decrease to <60 beats per minute (bpm), change to normal or no change, and increase to >100 bpm relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant's heart rate value decreased to <60 bpm and increased to >100 bpm post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Heart Rate

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Change from Baseline in temperature is categorized as a decrease to <=35 degrees celsius (C), change to normal or no change as 35-38 degrees C, and increase to >=38 degrees C relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant temperature value decreased to <=35 degrees C and increased to >=38 degrees C post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Temperature

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Oxygen saturation measures the capacity of blood to transport oxygen to other parts of the body. Oxygen binds to hemoglobin in red blood cells when moving through the lungs. A pulse oximeter uses two frequencies of light (red and infrared) to determine the percentage of hemoglobin in the blood that is saturated with oxygen,that is called as blood oxygen saturation or SpO2. Change from Baseline was calculated as the individual post-Baseline value (Days 8,15; Weeks 3 to 136 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase I: Change From Baseline in Oxygen Saturation (SpO2) Measured Via Pulse Oxymetry at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Mean change in body weight from Baseline was determined. Change from Baseline was calculated as the individual post-Baseline value (Weeks 3 to 136 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase I: Change From Baseline in Weight at the Indicated Time Points

Time: From Baseline until the post-treatment Visit ( average of 1.38 year)

Description: Single twelve (12)-lead ECGs were perfomred at Baseline, Weeks 3 to 132 and post-treatment Visit. ECG findings were categorized as: normal, abnormal - clinically significant (CS), or abnormal - not clinically significant (NCS), as determined by the investigator.

Measure: Phase I: Number of Participants With the Indicated Electrocardiogram (ECG) Findings at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Absolute change from Baseline in LVEF were summarized at each scheduled assessment time and in the worst-case post Baseline. Only the post Baseline assessments that used the same method (ECHO or Multi Gated Acquisition Scan [MUGA]) as the Baseline assessments were used to derive the change from Baseline. The change from Baseline was categorized as: any increase; no change; 0-<10 Decrease, 10-19 Decrease, >=20 Decrease, >=10 Decrease and >= lower limit of normal (LLN), >=10 Decrease and below LLN, >=20 Decrease and >=LLN and >=20 Decrease and below LLN. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram (ECHO)

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Confirmed overall response (ORR) is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). ORR was assessed by investigator and blinded independent central review (BICR).

Measure: Phase II: Number of Participant With Confirmed Overall Response

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Secondary Outcomes

Description: Blood samples were collected from each par. at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr post-dose on Day 21 (repeat dose) for PK analysis. GSK2118436 metabolites included GSK2285403, GSK2298683, and GSK2167542. AUC from time zero to last quantifiable concentration (concn) (AUC[0-t]) was determined using the linear trapezoidal rule for increasing concn and the logarithmic trapezoidal rule for decreasing. The AUC from time zero extrapolated to infinity (AUC[0-inf] was calculated, where data permit, as the sum of AUC(0-t) and Ct/z, where Ct is the observed plasma concn obtained from the log-linear regression analysis of the last quantifiable time-point and z is the terminal phase rate constant. Area under the concentration-time curve over 12 hr and 24 hr dosing interval is called AUC[0-12] and AUC[0-24]. AUC(0-inf) was calculated only at Day 1.

Measure: Phase I: Area Under the Plasma Concentration Versus Time Curve (AUC) of GSK2118436 and Metabolites, and GSK1120212 After Single and Repeat Dose

Time: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)

Description: Blood samples were collected from each participant at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr post-dose on Day 21 (repeat dose) for PK analysis. GSK2118436 metabolites included GSK2285403, GSK2298683 and GSK2167542. Cmax was determined from the raw concentration-time data.

Measure: Phase I: Maximum Plasma Concentration (Cmax) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose

Time: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)

Description: Trough concentration is the lowest level that a drug is present in the body. Pre-dose (trough) blood samples were collected on Day 8, Day 15, Weeks 3, 8, 16 and 24 for estimating plasma trough concentration. GSK2118436 metabolites included GSK2285403, GSK2298683, and GSK2167542. Ctau was determined from the raw concentration-time data.

Measure: Phase I: Plasma Trough Concentration (Ctau) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose

Time: At pre-dose on Day 8, Day 15, Weeks 3, 8, 16 and 24

Description: Blood samples were collected from each participant at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr post-dose on Day 21 (repeat dose) for PK analysis. GSK2118436 metabolites included GSK2285403, GSK2298683, and GSK2167542. Tmax is defined as the time of occurrence of Cmax. Tmax was determined directly from the raw concentration-time data. The apparent terminal elimination half-life (t1/2) obtained as the ratio of ln2/lamdaz, where lamdaz is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. . T1/2 was calculated only at Day 1.

Measure: Phase I: Time of Occurrence of Cmax (Tmax) and Terminal Phase Half Life (t1/2) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose

Time: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)

Description: Confirmed ORR is defined as the percentage of participants with a confirmed CR or PR according to RECIST, version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). ORR was assessed by investigator and BICR.

Measure: Phase I: Number of Participants With Confirmed Overall Response Rate

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Description: ORR is defined as the percentage of participants with an unconfirmed CR or PR according to RECIST version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). Unconfirmed ORR was assessed by investigator and BICR.

Measure: Phase I: Number of Participants With Unconfirmed Overall Response Rate

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Description: PFS is defined as the time from the first dose of study treatment to the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or disease progression minus the date of first dose plus one day. The date of documented disease progression is defined as the date of disease progression based on radiologic evidence. Participants with documented date of disease progresssion or death and who had not received subsequent anticancer treatment prior to the date of documented disease progression or death were included in the analysis of PFS. PFS was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase I: Progression Free Survival (PFS)

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: Duration of response is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause among participants with confirmed CR or PR. The participant who showed a CR or PR was included in the analysis of duration of response. Duration of response was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase I: Duration of Response

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: ORR is defined as the percentage of participants with an unconfirmed CR or PR according to RECIST version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). Unconfirmed ORR was assessed by investigator and BICR.

Measure: Phase II: Number of Participants With Unconfirmed Overall Response

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Description: PFS is defined as the time from the first dose of study treatment to the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or disease progression minus the date of first dose plus one day. The date of documented disease progression is defined as the date of disease progression based on radiologic evidence. Participants with documented date of disease progresssion or death and who had not received subsequent anticancer treatment prior to the date of documented disease progression or death were included in the analysis of PFS. PFS was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase II: Progression Free Survival (PFS)

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: Duration of response is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause among participants with confirmed CR or PR. The participant who showed a CR or PR was included in the analysis of duration of response. Duration of response was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase II: Duration of Response

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: An AE is defined as any untoward MO in a part. temporally associated with the use of a MP, whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. SAE is defined as any untoward MO that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect and protocol-specific SAEs:ALT>=3xULN and bilirubin>=2xULN(>35% direct) (or ALT>=3xULN, international normalized ratio>1.5), any new primary cancers, treatment emergent malignancies except basal cell carcinoma, symptomatic or asymptomatic LVEF decrease, retinal pigment epithelial detachment or retinal vein occlusion, pyrexia with hypotension,or dehydration or renal insufficiency,or severe (>=G3) rigor/chills.

Measure: Phase II: Number of Participants With Any Adverse Event and Any Serious Adverse Event

Time: From the start of study treatment until 30 days after study treatment discontinuation (average of 1.38 years)

Description: CCPs were graded according to NCI CTCAE garde version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 from Baseline grade occurred. CCPs that were not graded according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those parameters for which the category decreased to Low or increased to High relative to the Baseline category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. CCPs included: albumin, alkaline phosphatase, ALT, AST, total bilirubin, calcium, creatinine, glucose, potassium, magnesium, sodium, inorganic phosphorus, chloride, LDH, total protein, urea/BUN and uric acid.

Measure: Phase II: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Clinical Chemistry Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Hematology parameters were summarized according to NCI CTCAE G, version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 from Baseline G occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those parameters for which the category decreased to Low or increased to High relative to the Baseline category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Hematology parameters included: hemoglobin, lymphocytes, total neutrophils, platelet count, WBC counts, basophils, eosinophils, hematocrit, MCHC, MCH, MCV, monocytes and RBC count.

Measure: Phase II: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Hematology Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Urine samples were collected for urine dipstick analysis at Baseline and at the post-treatment Visit. The number of participants with negative (absence) and positive (presence: trace, 1+, 2+, 3+, 4+ or 5+) results for UOB, UGLU, UKET, UP and UUBIL were summarized. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase II: Number of Participants With the Indicated Urinalysis Results

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: The ECOG pef status 5-point scale is used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the par. and to determine appropriate treatment and prognosis: G0, fully active, able to carry on all pre-disease pef without restriction. G1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, example, light house work, office work. G2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about >50% of waking hrs. G3, capable of only limited selfcare; confined to bed or chair >50% of waking hrs. G4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. G5, dead. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Number of par. who improved, had no change, or deteriorated in pef status from BL is summarized.

Measure: Phase II: Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in ECOG Perormance Status

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: SBP and DBP values were graded using (NCI CTCAE version 4.0). SBP was categorized as: G1 (Increase to >=120 to 140 mmHg), G2 (Increase to >=140 to <160 mmHg), and G3 (Increase to >=160 mmHg). DBP was categorized as: G1 (Increase to >=80 to <90 mmHg), G2 (Increase to >=90 to <100 mmHg), and G3 (Increase to >=100 mmHg). The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of G0.

Measure: Phase II: Number of Participants With Worst-case On-therapy Increase From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Change from Baseline in heart rate is categorized as decrease to <60 bpm, change to normal or no change, and increase to >100 bpm relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant's heart rate value decreased to <60 bpm and increased to >100 bpm post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Heart Rate

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Change from Baseline in temperature is categorized as a decrease to <=35 degrees C, change to normal or no change as 35-38 degrees C, and increase to >=38 degrees C relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant temperature value decreased to <=35 degrees C and increased to >=38 degrees C post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Temperature

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Oxygen saturation measures the capacity of blood to transport oxygen to other parts of the body. Oxygen binds to hemoglobin in red blood cells when moving through the lungs. A pulse oximeter uses two frequencies of light (red and infrared) to determine the percentage of hemoglobin in the blood that is saturated with oxygen, that is called as blood oxygen saturation, or SpO2. Change from Baseline was calculated as the individual post-Baseline value (Days 8 and 15; Weeks 3 to 132 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase II: Change From Baseline in Oxygen Saturation Measured Via Pulse Oxymetry at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Mean change in body weight from baseline was determined. Change from Baseline was calculated as the individual post-Baseline value (Weeks 3 to 132 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase II: Change From Baseline in Weight at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Single 12-lead ECGs were performed at Baseline, Weeks 3 to 132 and post-treatment Visit. ECG findings were categorized as: normal, abnormal - CS, or abnormal - NCS, as determined by the investigator.

Measure: Phase II: Number of Participants With the Indicated Electrocardiogram Findings at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Absolute change from Baseline in LVEF were summarized at each scheduled assessment time and in the worst-case post Baseline. Only the post Baseline assessments that used the same method (ECHO or MUGA) as the Baseline assessments were used to derive the change from Baseline. The change from Baseline was categorized as: any increase; no change; 0-<10 Decrease, 10-19 Decrease, >=20 Decrease, >=10 Decrease and >= LLN, >=10 Decrease and below LLN, >=20 Decrease and >=LLN and >=20 Decrease and below LLN. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction as Assessed by Echocardiogram

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

104 A Multi-center Phase II Study of AUY922 in Patients With Stage IV Non-small Cell Lung Cancer (NSCLC) With Driver Molecular Alterations Other Than Sensitive EGFR Mutation, Who Have Progressed After One Line of Systemic Therapy

This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC.

NCT01922583
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: AUY922
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

V600E) or in exon 11; point mutation (e.g. --- V600E ---

Primary Outcomes

Description: To define the by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC

Measure: Objective response rate

Time: Patients will be followed up for 2 years(post disease progression)

Secondary Outcomes

Description: Patients will be followed for progression-free survival (PFS) and overall survival (OS) which will be analyzed by using a Kaplan-Meier curve. Patients will be followed up for PFS and OS for 2 years.

Measure: Efficacy, progression-free survival (PFS)

Time: Patients will be followed up for PFS and OS for 2 years.(post disease progression)

Description: Patients will be followed for overall survival (OS)

Measure: overall survival (OS)

Time: Patients will be followed up for OS for 2 years.(post disease progression)

105 Phase II Study of Pembrolizumab in Combination With Binimetinib and Bevacizumab in Patients With Refractory Colorectal Cancer

This is an open-label, single-center, single-arm phase II clinical trial evaluating the combination of pembrolizumab, binimetinib, and bevacizumab in patients with metastatic colorectal adenocarcinoma who have not responded to prior therapy.

NCT03475004
Conditions
  1. Colorectal Cancer
  2. Metastatic Cancer
Interventions
  1. Drug: Pembrolizumab, Bevacizumab, and Binimetinib
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

- Patients with BRAF V600E mutations are not elgible for the study. --- V600E ---

Primary Outcomes

Description: Overall Response Rate based on CT imaging and how it compares to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1)

Measure: Determine the effectiveness pembrolizumab, binimetinib, and bevacizumab on the response rate of colorectal cancer

Time: Study beginning to study end; 12 months

Secondary Outcomes

Description: Kaplan-Meier product-limit method will be used to summarize the time to event results

Measure: Determine the effectiveness of pembrolizumab, binimetinib, and bevacizumab on progression free survival of colorectal cancer

Time: Study start date to first sign of disease progression or death, whichever comes first, assessed up to 100 weeks

Description: Kaplan-Meier product-limit method will be used to summarize the time to event results

Measure: Determine the effectiveness of pembrolizumab, binimetinib, and bevacizumab on overall survival of colorectal cancer

Time: Study start to first sign of disease progression or death. whichever comes first, assessed up to 100 weeks

Description: Grade 1, 2, 3, or 4 toxicities as defined by CTCAE v4 will be evaluated

Measure: Evaluation of the safety and tolerability of pembrolizumab, binimetinib, and bevacizumab when given together

Time: Study beginning to study end, 12 months

106 A Phase II Study of Rucaparib in Patients With Genomic LOH High and/or Deleterious BRCA1/2 Mutation Stage IV or Recurrent Non-Small Cell Lung Cancer (LUNG-MAP Sub-Study)

This phase II Lung-MAP trial studies how well rucaparib works in treating patients with genomic loss of heterozygosity (LOH) high and/or deleterious BRCA1/2 mutation stage IV non-small cell lung cancer or that has come back. Rucaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03845296
Conditions
  1. Deleterious BRCA1 Gene Mutation
  2. Deleterious BRCA2 Gene Mutation
  3. Loss of Heterozygosity
  4. Lung Non-Small Cell Squamous Carcinoma
  5. Recurrent Large Cell Lung Carcinoma
  6. Recurrent Lung Adenocarcinoma
  7. Recurrent Lung Non-Small Cell Carcinoma
  8. Recurrent Non-Squamous Non-Small Cell Lung Carcinoma
  9. Stage IV Lung Cancer AJCC v8
  10. Stage IVA Lung Cancer AJCC v8
  11. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Rucaparib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma of Lung Carcinoma, Squamous Cell
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Squamous cell carcinoma

- Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy. --- T790M --- --- V600E ---

Primary Outcomes

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times.

Measure: Investigator assessed progression free survival (PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Response will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. Response rates and associated confidence intervals will be calculated. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times. Response rates can be estimated within 16% with 95% confidence.

Measure: Duration of response (DoR)

Time: From date of first documentation of response (complete response [CR] or partial response [PR]) to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times.

Measure: Overall survival

Time: From date of sub-study registration to date of death due to any cause, assessed up to 3 years

Measure: Time to death

Time: From date of sub-study registration to date of death due to any cause, assessed up to 3 years

Description: Toxicity will be evaluated among all patients enrolled on the study (combining the squamous and non-squamous cohorts). Toxicity can be estimated to within 11% with 95% confidence.

Measure: Incidence of adverse events

Time: Up to 3 years

107 A Phase Ib/II, Open-Label Study of M7824 in Combination With Chemotherapy in Participants With Stage IV Non-small Cell Lung Cancer

The main purpose of the study is to evaluate the safety and tolerability of M7824 in combination with chemotherapy.

NCT03840915
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Cisplatin
  2. Drug: Carboplatin
  3. Drug: Pemetrexed
  4. Drug: Nab-paclitaxel
  5. Drug: Gemcitabine
  6. Drug: Docetaxel
  7. Drug: M7824
  8. Drug: Carboplatin
  9. Drug: Carboplatin
  10. Drug: M7824
  11. Drug: Paclitaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Fresh biopsies should be collected if archived tumor material is not available - Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study entry and date of first dose Exclusion Criteria: - The participant's tumor harbors an epidermal growth factor receptor (EGFR) sensitizing (activating) mutation,ROS1 rearrangement, or BRAF V600E mutation or anaplastic lymphoma kinase (ALK) positive, if targeted therapy is locally approved - Mixed small cell with NSCLC cancer histology - Has received major surgery within 4 weeks prior to the first dose of study intervention; received thoracic radiation therapy (RT) of > 30 gray (Gy) within 6 months prior to the first dose of study intervention - Previous malignant disease (other than the target malignancy to be investigated in this study) within the last 3 years - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. --- V600E ---

Primary Outcomes

Measure: Incidence of Dose Limiting Toxicities (DLTs)

Time: Day 1 to Day 21 (Cycle 1)

Measure: Incidence of Treatment Emergent Adverse Events (TEAEs) and Treatment Related Adverse Events

Time: Up to 3 years

Secondary Outcomes

Measure: Confirmed Objective Response as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Time: Up to 3 years

Measure: Progression-Free Survival (PFS) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Time: Up to 3 years

Measure: Overall Survival (OS)

Time: Up to 3 years

Measure: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Time: Up to 3 years

Measure: Concentration of M7824 Observed Immediately at the End of Infusion (Ceoi)

Time: Up to 3 years

Measure: Concentration of M7824 Observed Immediately Before Next Dosing (Ctrough)

Time: Up to 3 years

Measure: Area Under the Serum Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of M7824

Time: Up to 3 years

Measure: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of M7824

Time: Up to 3 years

Measure: Maximum Observed Serum Concentration (Cmax) of M7824

Time: Up to 3 years

Measure: Time to Reach Maximum Serum Concentration (Tmax) of M7824

Time: Up to 3 years

Measure: Apparent Terminal Half-life (t1/2) of M7824

Time: Up to 3 years

Measure: Immunogenicity of M7824, as Assessed by Anti-drug Anti-body (ADA) Assay

Time: Up to 3 years

108 BRAF-/MEK-Inhibition With Dabrafenib and Trametinib in Melanoma Patients in the Adjuvant Setting: a Non-interventional Observatory Study

Adjuvant therapy with dabrafenib plus trametinib in melanoma was approved in 2018 by the EMA (EUropean Medicines Agency). The purpose of this non-interventional study is to assess the usage of adjuvant dabrafenib and trametinib in clinical practice, where the patient population may differ from study population.

NCT03944356
Conditions
  1. Melanoma
Interventions
  1. Drug: Dabrafenib and Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- V600E/K mutation-positive cutaneous melanoma - Adjuvant treatment with combination therapy of Dabrafenib (Tafinlar®) and Trametinib (Mekinist®) as indicated in the SmPC (Summary of Product Characteristics) and by prescription, that has been started no longer that 4 weeks before inclusion of the patient into the study or which will be initiated directly after inclusion - Age ≥ 18 years - Signed written informed consent Exclusion Criteria: - Lack of basic demographics and staging information - Current or planned participation within a clinical trial. --- V600E ---

Treatment with the BRAF inhibitor dabrafenib plus the MEK (Mitogen-activated protein kinase kinase) inhibitor trametinib showed improved overall survival in patients with unresectable or metastatic BRAF V600E/K-mutant melanoma (COMBI-d and COMBI-v studies). --- V600E ---

Primary Outcomes

Description: Median time on adjuvant dabrafenib + trametinib treatment defined as the interval between start of treatment and permanent discontinuation of treatment.

Measure: Median time on treatment

Time: Date of first dose up to 12 months

Secondary Outcomes

Description: Rate of permanent study drug discontinuation due to any reason.

Measure: Permanent study drug discontinuation due to any reason

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Rate of permanent study drug discontinuation due to adverse drug reactions (ADRs).

Measure: Permanent study drug discontinuation due to adverse drug reactions

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Occurrence of pyrexia and related symptoms, listing the grade, number of episodes, and time to resolution.

Measure: Pyrexia and related symptoms

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Type of adverse drug reaction (ADR) management applied for pyrexia and correlation with occurrence/persistence of pyrexia.

Measure: Adverse drug reaction management: pyrexia

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: ADRs persisting/emerging up to 3 months post-treatment.

Measure: Adverse drug reactions in Follow-up

Time: From date of first treatment until the date of treatment end plus 3 months of follow-up, assessed up to 15 months

Description: Assessment of health-related quality of life (HRQoL), measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30). The EORTC QLQ-C30 consists of the folowing scales, with each dimension specifying five levels of severity [not at all (level 1), a little (level 2), quite a bit (level 3), very much (level 4)]: functional scales (Physical, Role, Cognitive, Emotional, Social Functioning) symptom scales (Fatigue, Pain and Nausea/Vomiting) single item scales (Dyspnoea, Insomnia, Appetite Loss, Constipation, Diarrhoea and Financial Difficulties). Additionally the Global Health Status and QoL scales are incorporated, specifying on a scale from 1 (very poor) to 7 (excellent).

Measure: Health-related quality of life

Time: Over the course of treatment plus 3 months safety follow up, assessed up to 15 months

Description: Relapse free survival (RFS) time and rate

Measure: Relapse free survival

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Distant metastasis free survival (DMFS) time.

Measure: Distant metastasis free survival time

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Distant metastasis free survival (DMFS) rate.

Measure: Distant metastasis free survival rate

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Overall survival (OS) time.

Measure: Overall survival time

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Overall survival (OS) rate.

Measure: Overall survival rate

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Correlation between time on treatment and efficacy endpoints (RFS, DMFS, OS).

Measure: Time on treatment and efficacy endpoints

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

109 Early Identification and Treatment of Occult Metastatic Disease in Stage III Colon Cancer

This research study is comparing two standard of care treatment options based on blood test results for participants who have metastatic colorectal cancer. The names of the potential treatments involved in this study are: - Active surveillance - FOLFIRI treatment - Nivolumab treatment - Encorafenib/Binimetinib/Cetuximab treatment

NCT03803553
Conditions
  1. Metastatic Colorectal Cancer
  2. Stage III Colorectal Cancer
Interventions
  1. Drug: FOLFIRI Protocol
  2. Other: ACTIVE SURVEILLANCE
  3. Drug: Nivolumab Protocol
  4. Drug: Encorafenib/Binimetinib/Cetuximab Protocol
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort.. Disease-free survival (DFS) of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment. --- V600E ---

Determine the disease-free survival DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort.. ctDNA clearance as Marker. --- V600E ---

- Patients who are MSI-high or have a BRAF V600E mutation are excluded from Arm 1 (FOLFIRI) and Arm 2 (Active Surveillance). --- V600E ---

- Participants must have normal organ, marrow, and hematologic function as defined below: - Hemoglobin ≥9 g/dL (5.58 mmol/L) - Total bilirubin ≤ 1.5 (25.65 μmol/L) - Platelets ≥100,000/μL Encorafenib, binimetinib, and cetuximab Specific Exclusion Criteria for BRAF V600E mutant Cohort: - Patients with a BRAFV600E mutation and who are MSI-H are excluded from Arm 5 (ENCO/BINI/CETUX) - Prior therapy with a BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib). --- V600E ---

- Encorafenib in combination with binimetinib and cetuximab is one of the first effective regimens to target the BRAF V600E-mutation in colorectal cancer. --- V600E ---

Primary Outcomes

Description: Disease-free survival (DFS) between ctDNA-positive patients treated with additional treatment of FOLFIRI and ctDNA-positive patients who are untreated

Measure: Disease-free survival (DFS)

Time: 5 years

Description: Compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional treatment of FOLFIRI and those who are untreated

Measure: Clearance rate of ctDNA

Time: 7 Months

Secondary Outcomes

Description: Overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy (Arm 1) and ctDNA-positive patients who are untreated (Arm 2)

Measure: Overall Survival (OS) Rate

Time: 5 years

Description: Determine clearance rate of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort

Measure: Clearance rate of ctDNA of Arm 4: Nivolumab Treatment

Time: 13 months

Description: Determine the disease-free survival (DFS) of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort

Measure: Disease-free survival (DFS) of Arm 4: Nivolumab Treatment

Time: 5 years

Description: Determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort.

Measure: Clearance rate of ctDNA of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment

Time: 7 months

Description: Determine the disease-free survival DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort.

Measure: Disease-free survival (DFS) of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment

Time: 5 years

Description: Examine the correlation of ctDNA clearance as a surrogate marker for disease burden

Measure: ctDNA clearance as Marker

Time: 13 Months

Description: Compare lead time to recurrence and sensitivity of predicting recurrence between ctDNA and tumor markers

Measure: Lead time to recurrence

Time: 5 years

110 A Retrospective Non Interventional Study on First Line Treatment for Patients With BRAFV600E Mutant Metastatic Colorectal Cancer (mCRC)

The presence of a BRAFV600E mutation is considered a marker of poor prognosis in patients with mCRC, and findings from clinical trials have largely remained inconclusive regarding the efficacy of first line treatments for BRAF-mutant mCRC patients. In the absence of targeted/specific treatment for BRAF-mutant mCRC, treatment practices can vary based on local practices and guidelines. There is, therefore, an unmet need to document the current practices for first-line treatment of BRAF-mutant mCRC, and their effectiveness and safety in a real-world setting. This real-world, multicenter non-interventional study (NIS) will describe the treatment patterns, effectiveness and safety of current treatment regimens in BRAFV600E mutant mCRC patients in Europe, with the aim to put the clinical study findings of the ongoing Phase 2, single-arm, open label trial (ANCHOR) into context of the current treatment landscape excluding investigational therapies. Additionally, the NIS output may be used to support future health technology assessment submissions and publications.

NCT04317599
Conditions
  1. BRAF V600E Mutation Positive
  2. Metastatic Colorectal Cancer
Interventions
  1. Other: Non Interventional study
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

BRAF V600E Mutation Positive Metastatic Colorectal Cancer Colorectal Neoplasms This retrospective, multi-center longitudinal study on BRAFV600E mutant mCRC patients will be conducted in Europe to characterize the first-line treatment patterns. --- V600E ---

Primary Outcomes

Description: Agent or combination of agents received, Duration of treatment, Maintenance therapy (if any)

Measure: First-line Systemic anticancer therapy (SACT) treatment patterns in BRAFV600E mutant mCRC patients

Time: time of treatment initiation (for mCRC) until the time of first documented disease progression, treatment discontinuation or switch, whichever is earlier or end of study observation period up to 31 December 2020

Secondary Outcomes

Description: Description of the demographic and clinical profile of patients at the time of treatment initiation (for mCRC)

Measure: Demographic and clinical characteristics

Time: from the date of the start of first-line treatment for mCRC until the end of the observation period (date of death or last day of study observation period for patients alive at the time of data abstraction) up to 31 December 2020

Description: the length of time between initiation of first-line treatment for mCRC and the first documented disease progression

Measure: Progression-free Survival (PFS)

Time: from the date of the start of first-line treatment for mCRC until the end of the observation period (date of death or last day of study observation period for patients alive at the time of data abstraction) up to 31 December 2020

Description: length of time between first-line treatment initiation (for mCRC) and death (due to any cause)

Measure: Overall Survival (OS)

Time: from the date of the start of first-line treatment for mCRC until the end of the observation period (date of death or last day of study observation period for patients alive at the time of data abstraction) up to 31 December 2020

Description: number of complete response (CR) or partial response (PR)

Measure: Overall Response rate (ORR)

Time: from the date of the start of first-line treatment for mCRC until the end of first-line treatment up to 31 December 2020

Description: the length of time between initiation of first-line treatment for mCRC and documented disease progression (or start of subsequent Line Of Treatment (LOT), if disease progression is not well documented in patient medical record), treatment discontinuation or switch to another treatment (defined as change from one treatment regimen to another treatment regimen, e.g., change from FOLFOX-based regimen to FOLFIRI or irinotecan-based regimen)

Measure: Time to treatment cessation

Time: from the date of the start of first-line treatment for mCRC until the documented disease progression up to 31 December 2020

111 Altering Adjuvant Therapy Based on Pathologic Response to Neoadjuvant Dabrafenib and Trametinib (ALTER-PATH NeoDT)

This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. Patients who achieve a pathologic complete response after 8 weeks of neoadjuvant dabrafenib and trametinib will receive adjuvant dabrafenib and trametinib. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as spartalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving dabrafenib, trametinib, and spartalizumab may help to control melanoma.

NCT04310397
Conditions
  1. Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  2. Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  3. Pathologic Stage IIID Cutaneous Melanoma AJCC v8
Interventions
  1. Drug: Dabrafenib
  2. Biological: Spartalizumab
  3. Procedure: Therapeutic Conventional Surgery
  4. Drug: Trametinib
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Dabrafenib, Trametinib, and Spartalizumab for the Treatment of BRAF V600E or V600K Mutation Positive Stage IIIB/C/D Melanoma This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. --- V600E ---

Dabrafenib, Trametinib, and Spartalizumab for the Treatment of BRAF V600E or V600K Mutation Positive Stage IIIB/C/D Melanoma This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. --- V600E --- --- V600K --- --- V600E ---

Only cases where a complete surgical resection with tumor- free margins can safely be achieved are defined as resectable - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Act (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Patients who have been previously treated in the adjuvant setting with ipilimumab or interferon alpha or investigational vaccines for melanoma will be eligible for treatment after a 28 day wash-out period - Patients who have previously received anti PD-1 in the adjuvant setting will be allowed if it has been six months or longer since previous drug exposure - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Women of childbearing potential, defined as all women physiologically capable of becoming pregnant will be required to use highly effective methods of contraception during dosing and for 150-days after stopping treatment with spartalizumab. --- V600E ---

Primary Outcomes

Description: Will be estimated with a 95% confidence interval by using the Kaplan-Meier method. Cox proportional hazards regression models will be fit to assess the association between various clinical, demographic, and disease covariates and RFS separately by pathologic response group.

Measure: Relapse-free survival (RFS) rate

Time: From the time of surgery to any recurrence event, assessed up to 12 months

Secondary Outcomes

Description: The rate of grade 3+ adverse events will be tabulated and presented by group.

Measure: Incidence of adverse events

Time: Up to 2 years

Description: Will be reported with 95% confidence intervals, and Cox regression models will be used to assess the association between similar covariates.

Measure: Overall survival

Time: From treatment initiation to death, assessed up to 2 years

Description: Will be reported with 95% confidence intervals, and Cox regression models will be used to assess the association between similar covariates.

Measure: Distant metastasis-free survival

Time: From treatment initiation to development of documented distant metastatic disease outside the loco-regional site of the primary tumor or lymph node metastasis, assessed up to 2 years

Other Outcomes

Description: Will be assessed quantitatively. Kruskal-Wallis tests will be used to compare these parameters at each time point between responders (pathological complete response [pCR]) and non-responders (no pCR). Changes in each parameter from baseline to surgery will also be compared between responders and non-responders.

Measure: Immune and molecular features of response and resistance

Time: At baseline and at surgical resection

Description: Markers and changes in markers over time will be compared between responders and non-responders by using Kruskal-Wallis tests. In addition, generalized linear mixed models may be used to model these markers over time.

Measure: Association between circulating blood markers and treatment response and relapse

Time: At baseline, and assessed up to 2 years

Description: A survey will be provided to surgeons regarding the difficulty of surgery. These data will be subjective and will be summarized graphically as numbers permit.

Measure: Surgical resectability

Time: Up to 2 years

112 A Phase 1, Open Label, Dose Escalation Study of RLY-1971 in Subjects With Advanced or Metastatic Solid Tumors

This study is a multi-center, open-label, dose escalation study of RLY-1971 in subjects with advanced or metastatic solid tumors.

NCT04252339
Conditions
  1. Solid Tumor, Unspecified, Adult
Interventions
  1. Drug: RLY-1971
MeSH:Neoplasms
HPO:Neoplasm

Male and female subjects of child-bearing potential are willing to use medically acceptable methods of birth control from the screening visit through 30 days after the last dose of study medication Exclusion Criteria: 1. Subjects with documented history of tumor mutations that may not be amenable to treatment with RLY-1971, including 1. KRAS mutations: G12D, G12V, G13X, and Q61X 2. BRAF V600E mutation 3. MEK mutations 2. Subjects with prior antineoplastic therapy within 3 weeks of Study Day 1, or 5 half-lives, whichever is shorter 3. Subjects with prior palliative radiotherapy within 1 week of Study Day 1 4. Subjects who have had major surgery or trauma, or incomplete recovery from surgery or trauma, within 4 weeks of Study Day 1 5. Subjects with known central nervous system (CNS) primary tumor, uncontrolled CNS metastases, or carcinomatous meningitis. --- G12D --- --- G12V --- --- V600E ---

Primary Outcomes

Measure: Maximum Tolerated Dose (MTD)

Time: Escalation Phase - 18 month Enrollment

Measure: Recommended Phase 2 Dose (RP2D)

Time: Escalation Phase - 18 month Enrollment

Secondary Outcomes

Description: Blood samples may be taken at pre-dose, 0.5, 1, 2, 4, 6, and 8hrs on Cycle I Day 1 and 15, 24 hrs post dose on Cycle 1 Day 2, 48hrs post dose on Cycle 1 Day 3, and post dose on Cycle 2 Day 1

Measure: Plasma concentration levels of RLY-1971

Time: At the beginning of Cycle 1 & Cycle 2 (Each Cycle is 21 days)

Description: Evaluation by RECIST 1.1; ORR is defined as the proportion of subjects in the response evaluable population who achieve the best overall response (BOR) of CR or PR

Measure: Objective Response Rate (ORR)

Time: Through study completion (an average of one year)

Description: DCR is defined as the percentage of response evaluable subjects who achieve a BOR of CR, PR or SD for at least 3 months

Measure: Disease Control Rate (DCR)

Time: Through study completion (an average of one year)

Other Outcomes

Description: Blood will be collected at pre-dose at baseline on Cycle 1, Day 1 (C1D1) and at 3 time points (pre-dose, 2 hours post-dose, and 4 hours post-dose) on Cycle 1, Day 15 (C1D15) to assess the extent of target engagement.

Measure: Changes in phospho-ERK levels

Time: At the beginning of Cycle 1 Day 1 post and pre

Description: Blood will be collected at screening and at End of Treatment on all patients

Measure: Tumor mutations by sequencing circulating tumor DNA (ctDNA)

Time: At the beginning of Cycle 1 Day 1

Description: DOR is defined as the time from the participant's initial objective response (CR or PR) to RLY-1971, to disease progression or death due to any cause, whichever occurs first

Measure: Duration of Response (DOR)

Time: Through study completion (an average of one year)

Description: TTR is defined as the period of time from the date of first the dose of RLY-1971 administration until the first objective documentation of response.

Measure: Time to Response (TTR)

Time: Through study completion (an average of one year)

Description: TTP is defined as the interval between the first dose of RLY-1971 until disease progression

Measure: Time to Progression (TTP)

Time: Through study completion (an average of one year)

Description: PFS is defined as the time from the start of study treatment to the first documented disease progression per RECIST v1.1, or death due to any cause, whichever occurs first

Measure: Progression-free Survival (PFS).

Time: Through study completion (an average of one year)

113 Phase I Study of Intra-Tumoral Injections of Autologous Ex Vivo Expanded Natural Killer Cells in Children With Recurrent High Grade Glioma

Patients will receive 3 cycles of NK cell infusions over 12 weeks. Each cycle will consist of 1 infusion per week for 3 weeks, followed by a rest week (week 4). Dose will be escalated in an inter-patient stepwise fashion consisting of 4 dose levels.

NCT04254419
Conditions
  1. High Grade Glioma
Interventions
  1. Biological: NK cells
MeSH:Glioma
HPO:Glioma

To determine the o6-methylguanine-DNA-methyltransferase (MGMT) methylation and mutation status of BRAF V600E, ACVR1, ATRX, TP53, H3.3 G34, H3.3/ H3.1 K27 and IDH1, along with the presence or absence of 9p21 (CDKN2A) homozygous deletion as well as PDGFR amplification. --- V600E ---

Primary Outcomes

Description: To identify the incidence of adverse events from autologous natural killer cells that have been propagated ex vivo with genetically-modified feeder cells and administered intra-tumoral via Ommaya reservoir in patients with recurrent high-grade glioma. This will be evaluated using the CTCAE version 5

Measure: Incidence of adverse events from NK cells

Time: 36 months

Description: To establish the maximum tolerated dose (MTD) of autologous natural killer cells that have been propagated ex vivo with genetically-modified feeder cells and administered intra-tumoral via Ommaya reservoir in patients with recurrent high-grade glioma. MTD will be the maximum dose at which fewer than one-third of patients experience a dose-limiting toxicity during cycle 1 of therapy

Measure: Maximum tolerated dose

Time: 36 months

Secondary Outcomes

Description: To determine the overall survival, defined as the percentage of patients in the study who are alive at 6 months following start of treatment

Measure: Overall survival

Time: 6 months

Other Outcomes

Description: To assess the antitumor activity based on imaging and cytology of autologous NK cell administration directly into the tumor or the resection cavity.

Measure: NK cell antitumor activity

Time: 36 months

Description: NK cell phenotypes will be measured by mass cytometry (unit of measure= % of nucleated cells)

Measure: Assessment of the immuno-phenotype of expanded NK cells for high-grade glioma patients

Time: 36 months

Description: NK cell functional potency will be measured as cytotoxicity by calcien- AM cytotoxicity assays (unit of measure= % of patietns with complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), or progressive disease (PD) with calculated 95% confidence intervals)

Measure: Assessment of function of expanded NK cells for high-grade glioma patients

Time: 36 months

Description: To determine the immune signature-based profile of each patient's tumor as assayed by the NanoString PanCancer IO360 panel

Measure: Assessment of the immune signature based profile

Time: 36 months

Description: To determine the o6-methylguanine-DNA-methyltransferase (MGMT) methylation and mutation status of BRAF V600E, ACVR1, ATRX, TP53, H3.3 G34, H3.3/ H3.1 K27 and IDH1, along with the presence or absence of 9p21 (CDKN2A) homozygous deletion as well as PDGFR amplification

Measure: Determination of genetic changes on high-grade gliomas

Time: 36 months

Description: To determine changes in the TCR repertoire diversity using a Nanostring custom reagent that evaluates the VDJ sequences present before and after NK cell treatment.

Measure: Changes of the T-cell Receptor Repertoires

Time: 36 months

114 A Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Advanced NSCLC Patients

This phase I/Ib trial studies the side effects and best dose of CB-839 HCl when given together with sapanisertib in treating patients with non-small cell lung cancer that has spread to other places in the body (advanced). CB-839 HCl and sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT04250545
Conditions
  1. Leptomeningeal Neoplasm
  2. Metastatic Lung Non-Small Cell Carcinoma
  3. Metastatic Malignant Neoplasm in the Brain
  4. Recurrent Lung Non-Small Cell Carcinoma
  5. Stage IV Lung Cancer AJCC v8
  6. Stage IVA Lung Cancer AJCC v8
  7. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Sapanisertib
  2. Drug: Telaglenastat Hydrochloride
MeSH:Carcinoma Lung Neoplasms Neoplasms Carcinoma, Non-Small-Cell Lung Meningeal Neoplasms
HPO:Carcinoma Neoplasm Neoplasm of the lung Non-small cell lung carcinoma

Patients with autoimmune or other conditions where PD-(L)1 checkpoint inhibitors are contraindicated are eligible with progression on or after platinum-based chemotherapy or immunotherapy - Dose escalation: patients with NSCLC known to harbor EGFR, ALK, ROS1, BRAF V600E/K activating mutations must have also progressed on appropriate Food and Drug Administration (FDA)-approved targeted therapies to be eligible for dose escalation - Dose expansion: patients must have stage IV or recurrent/metastatic NSCLC harboring 1) NFE2L2 mutations (LSCC); 2) KEAP1 mutations (LSCC); KRAS/KEAP1 or KRAS/NFE2L2 co-mutations (non-squamous NSCLC); or 3) LSCC WT for NFE2L2 or KEAP1 who have progressed on or after platinum-based chemotherapy and/or PD (L)1 immune checkpoint inhibitors or immunotherapy. --- V600E ---

Primary Outcomes

Description: Will be evaluated according to dose-limiting toxicities during cycle 1 graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Measure: Maximum tolerated dose/recommended phase II dose of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in combination (dose-escalation)

Time: Up to 28 days

Description: Response rate will be calculated for each cohort along with an exact 95% confidence interval.

Measure: Response rate (dose-expansion)

Time: Up to 27 months

Description: Median PFS will be determined using the Kaplan-Meier method individual for each cohort and for all patients as well.

Measure: Median progression free survival (PFS) (dose-expansion)

Time: Up to 27 months

Secondary Outcomes

Description: ORR will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

Measure: Objective response rate (ORR)

Time: Up to 27 months

Description: Will be evaluated by Kaplan-Meier estimates.

Measure: PFS

Time: Up to 27 months

Description: DCR will be assessed by RECIST 1.1 criteria.

Measure: Disease control rate (DCR)

Time: Up to 27 months

Description: Change in tumor uptake of radio-labelled glutamine on PET from baseline to cycle 1 day 8 will be quantified by the standardized uptake value maximum (SUVmax) (a standard PET parameter) in the largest measurable lesion. The before and after 18F-Gln PET values will be compared using log(after/before) as a measure of relative change.

Measure: Metabolic response (18Glutamine [GLN]-positron emission tomography [PET]/computed tomography [CT]; 18Fluorodeoxyglucose [FDG]-PET/CT)

Time: Up to 27 months

Other Outcomes

Description: Genomic and metabolic signatures will be correlated with responses. Changes in glutamine, glutamate, aspartate, and asparagine will be measured, and responders will be compared to non-responders using a two-sample t-test or Wilcoxon test.

Measure: Genomic and metabolic signatures

Time: Up to 27 months

115 A Phase I, First-In-Human, Multicenter, Open-Label Study of ABM-1310, Administered Orally in Adult Patients With Advanced Solid Tumors

This is a Phase I, First-In-Human, open label, dose escalation study to evaluate the safety, tolerability, and pharmacokinetics of ABM-1310. A "3+3" design will be used to determine MTD and RP2D.

NCT04190628
Conditions
  1. Advanced Solid Tumor
  2. BRAF V600 Mutation
Interventions
  1. Drug: ABM-1310
MeSH:Neoplasms
HPO:Neoplasm

- Documentation of positive BRAF V600E mutation, or any other B-Raf V600 mutation is required for enrollment. --- V600E ---

Primary Outcomes

Measure: Determine Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dose (RP2D)

Time: End of Cycle 1 (each cycle is 28 days) or up to treatment discontinuation (an average of 6 months)

Secondary Outcomes

Description: Safety and tolerability of ABM-1310 as a single agent

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time: Up to 30 days from treatment discontinuation

Description: Safety and tolerability of ABM-1310 as a single agent

Measure: Number of participants with abnormal laboratory values

Time: Up to 30 days from treatment discontinuation

Description: Pharmacokinetic (PK) profile of ABM-1310 as a single agent

Measure: Area under the concentration time curve (AUC)

Time: Up to Day 1 of Cycle 2 (each cycle is 28 days)

Description: Pharmacokinetic (PK) profile of ABM-1310 as a single agent

Measure: Maximum plasma concentration (Cmax)

Time: Up to Day 1 of Cycle 2 (each cycle is 28 days)

Description: Pharmacokinetic (PK) profile of ABM-1310 as a single agent

Measure: Steady-state concentration (Css)

Time: Up to Day 1 of Cycle 2 (each cycle is 28 days)

Description: Pharmacokinetic (PK) profile of ABM-1310 as a single agent

Measure: Time to maximum plasma concentration (Tmax)

Time: Up to Day 1 of Cycle 2 (each cycle is 28 days)

Description: Pharmacokinetic (PK) profile of ABM-1310 as a single agent

Measure: Half-life (T1/2)

Time: Up to Day 1 of Cycle 2 (each cycle is 28 days)

Description: Preliminary efficacy of ABM-1310 as a single agent

Measure: Objective Response Rate (ORR)

Time: Up to study discontinuation (an average of 1 year)

Description: Preliminary efficacy of ABM-1310 as a single agent

Measure: Disease Control Rate (DCR)

Time: Up to study discontinuation (an average of 1 year)

Description: Preliminary efficacy of ABM-1310 as a single agent

Measure: Duration of Response (DOR)

Time: Up to study discontinuation (an average of 1 year)

Other Outcomes

Description: Preliminary efficacy of ABM-1310 as a single agent

Measure: Exploratory preliminary efficacy in patients by types of BRAF V600 mutation

Time: Up to study discontinuation (an average of 1 year)

Description: Preliminary efficacy of ABM-1310 as a single agent

Measure: Exploratory progression free survival (PFS)

Time: Up to study discontinuation (an average of 1 year)

116 Association Of Prognosis And BRAF V600E Mutations In Papillary Thyroid Carcinoma

The purpose of this study is to determine whether BRAF V600E mutation in our patients with papillary thyroid cancer has an association with poor prognosis.

NCT01417442
Conditions
  1. Papillary Thyroid Carcinoma
Interventions
  1. Genetic: BRAF V600E POSITIVITY
MeSH:Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases
HPO:Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Association Of Prognosis And BRAF V600E Mutations In Papillary Thyroid Carcinoma. --- V600E ---

BRAF V600E Mutations In Papillary Thyroid Carcinoma The purpose of this study is to determine whether BRAF V600E mutation in our patients with papillary thyroid cancer has an association with poor prognosis. --- V600E ---

BRAF V600E Mutations In Papillary Thyroid Carcinoma The purpose of this study is to determine whether BRAF V600E mutation in our patients with papillary thyroid cancer has an association with poor prognosis. --- V600E --- --- V600E ---

BRAF V600E MUTATION. --- V600E ---

Inclusion Criteria: - Patients with papillary thyroid cancer Exclusion Criteria: - Patients who do not want to be a part of this study Inclusion Criteria: - Patients with papillary thyroid cancer Exclusion Criteria: - Patients who do not want to be a part of this study Papillary Thyroid Carcinoma Carcinoma Thyroid Neoplasms Thyroid Cancer, Papillary Thyroid Diseases Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy and BRAF V600E mutation is the most common genetic alteration identified in PTC, ranging from 25 to 80%, with the average rate about 45%. --- V600E ---

Various studies demonstrated a relationship between BRAF V600E mutation and aggressive characteristics of the cancer, including the worse patient prognosis. --- V600E ---

So the investigators will examine BRAF V600E mutation in our patients with PTC and try to assess the role of this mutation in prognosis and further management of the patients. --- V600E ---

Primary Outcomes

Measure: BRAF V600E MUTATION

Time: 2 years

117 Clinical and Pathophysiological Investigations Into Erdheim-Chester Disease

Background: - Erdheim Chester Disease (ECD) is a very rare disease in which abnormal white blood cells start growing and affect the bones, kidneys, skin, and brain. ECD can cause severe lung disease, kidney failure, heart disease, and other complications that lead to death. Because ECD is a rare disease, found mostly in men over 40 years of age, there is no standard treatment for it. More information is needed to find out what genes can cause ECD and how best to treat it. Objectives: - To collect study samples and medical information on people with Erdheim Chester Disease. Eligibility: - Individuals 2 to 80 year of age who have been diagnosed with Erdheim Chester Disease. Design: - Participants will be screened with a physical exam and medical history. - Participants will have a study visit to provide samples for study, including blood, urine, and skin tissue samples. Participants will also have lung, heart, and muscle function tests; imaging studies of the brain, chest, and whole body; a treadmill running stress test; an eye exam; and other tests as needed by the study doctors. - Participants will be asked to return for a similar set of tests every 2 years, and to remain in contact for possible treatment options.

NCT01417520
Conditions
  1. Myelofibrosis
  2. Gaucher Diseas
  3. Gaucher Disease
  4. Pulmonary Fibrosis
  5. Hermansky-Pudlak Syndrome (HPS)
  6. Cancer
MeSH:Pulmonary Fibrosis Gaucher Disease Hermanski-Pudlak Syndrome Primary Myelofibrosis Erdheim-Chester Disease
HPO:Pulmonary fibrosis

We will analyze the data with the assistance of an NIH statistician using parametric and non-parametric methods to assess overall trends in survival, and to look for patterns in organ involvement, patterns in response to various therapeutic regimens, and, lastly, to look for an association between the BRAF V600E mutation and disease severity. --- V600E ---

Primary Outcomes

Description: To comprehensively describe the natural history of ECD, including genetic and epidemiological aspects, its associated complications, and responses to various treatments.

Measure: To comprehensively describe the natural history of ECD, including genetic and epidemiological aspects, its associated complications, and responses to various treatments.

Time: 1 day

Description: To identify molecular markers important for diagnosis and treatment.

Measure: To identify molecular markers important for diagnosis and treatment.

Time: 1 day

118 Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)

This is a single arm phase II trial focused on how dabrafenib and trametinib before and after surgery works in treating patients with stage IIIB-C melanoma that has a specific mutation in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib and trametinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving dabrafenib and trametinib after surgery may kill any remaining tumor cells.

NCT02231775
Conditions
  1. BRAF V600E Mutation Present
  2. BRAF V600K Mutation Present
  3. Stage IIIB Cutaneous Melanoma AJCC v7
  4. Stage IIIC Cutaneous Melanoma AJCC v7
Interventions
  1. Drug: Dabrafenib
  2. Other: Laboratory Biomarker Analysis
  3. Procedure: Therapeutic Conventional Surgery
  4. Drug: Trametinib
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.. Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E ---

uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E ---

uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency BRAF V600E Mutation Present BRAF V600K Mutation Present Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Study enrollment was stopped in April 2016 due to a substantial improvement in RFS in Arm B vs Arm A treated patients. --- V600E ---

Primary Outcomes

Description: RFS will be compared between patients with a pathologic complete response (pCR) and patients without a pCR using a two-sided log-rank test.

Measure: Relapse-free survival (RFS)

Time: Up to 12 months

Secondary Outcomes

Description: The association between RFS and OS and covariates of interest will be assessed using Cox proportional hazards regression analysis.

Measure: Overall survival (OS)

Time: Up to 1 year

Description: Logistic regression will be used to assess the association between the probability of complete pathologic response and clinical and disease covariates of interest.

Measure: Complete pathologic response

Time: Up to 1 year

Description: Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.

Measure: Incidence of adverse events

Time: Up to 1 year

119 A Pilot Study of Dabrafenib and Trametinib for Patients With BRAF Mutated Ameloblastoma

This pilot clinical trial studies dabrafenib and trametinib in treating patients with ameloblastoma and a specific mutation (change) in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02367859
Conditions
  1. Ameloblastoma
  2. BRAF Gene Mutation
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Ameloblastoma Adamantinoma

The outcome will be expressed as the mean, with standard deviation.. Inclusion Criteria: - Histological diagnosis of ameloblastoma; all stages are eligible; patients must have evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria - B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E or other known dabrafenib sensitive BRAF mutation in tumor by any Clinical Laboratory Improvement Amendments (CLIA) certified lab; may include, for example, Sanger sequencing, SNaPshot platform, immunohistochemistry, Foundation One tests, etc.) - Life expectancy > 3 months - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Absolute neutrophil count (ANC) > 1.5 x10^9/L - Platelet (PLT) > 99 x 10^9/L - Hemoglobin > 8 g/dL - Total bilirubin (Tbili) < 1.6 x upper limit of normal (ULN) - Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.6 x ULN - Alkaline phosphatase (alk phos) < 2.6 x ULN - Serum creatinine < 1.6 x ULN or creatinine clearance > 50 ml/min - Ability to understand and the willingness to sign a written informed consent document - Patients of childbearing potential must agree to use effective contraception until at least 6 months after treatment with dabrafenib - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Left ventricular ejection fraction equal to or greater than normal Exclusion Criteria: - No prior treatment with agents targeting BRAF mutant tyrosine kinases or radiation of target lesions - Invasive malignancy other than ameloblastoma within 3 years, excluding curatively treated basal cell carcinoma, and other highly curable cancers such as early stage cutaneous squamous cell carcinoma (T1 NO) cervical carcinoma in situ (CIS), early stage prostate cancer, thyroid cancer or breast cancer - Uncontrolled hypertension, chronic heart failure (CHF), or other major medical illness - Prior allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib - Concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) - Concomitant use of proton pump inhibitors, H2-receptor antagonists, antacids - Known glucose-6-phosphate dehydrogenase (G6PD) deficiency - Pregnant or nursing patients; women of childbearing potential must have a negative pregnancy test within 14 days of enrollment - Electrocardiogram (EKG) with QTcB (Bazett's formula) > 480 ms done within 14 days of enrollment - Interstitial lung disease or pneumonitis - A history of retinal vein occlusion (RVO) - Congestive heart failure NYHA class III or worse (Marked limitation of physical activity. --- V600E ---

Less than ordinary activity causes fatigue, palpitation, or dyspnea.) - A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months Inclusion Criteria: - Histological diagnosis of ameloblastoma; all stages are eligible; patients must have evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria - B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E or other known dabrafenib sensitive BRAF mutation in tumor by any Clinical Laboratory Improvement Amendments (CLIA) certified lab; may include, for example, Sanger sequencing, SNaPshot platform, immunohistochemistry, Foundation One tests, etc.) - Life expectancy > 3 months - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Absolute neutrophil count (ANC) > 1.5 x10^9/L - Platelet (PLT) > 99 x 10^9/L - Hemoglobin > 8 g/dL - Total bilirubin (Tbili) < 1.6 x upper limit of normal (ULN) - Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.6 x ULN - Alkaline phosphatase (alk phos) < 2.6 x ULN - Serum creatinine < 1.6 x ULN or creatinine clearance > 50 ml/min - Ability to understand and the willingness to sign a written informed consent document - Patients of childbearing potential must agree to use effective contraception until at least 6 months after treatment with dabrafenib - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Left ventricular ejection fraction equal to or greater than normal Exclusion Criteria: - No prior treatment with agents targeting BRAF mutant tyrosine kinases or radiation of target lesions - Invasive malignancy other than ameloblastoma within 3 years, excluding curatively treated basal cell carcinoma, and other highly curable cancers such as early stage cutaneous squamous cell carcinoma (T1 NO) cervical carcinoma in situ (CIS), early stage prostate cancer, thyroid cancer or breast cancer - Uncontrolled hypertension, chronic heart failure (CHF), or other major medical illness - Prior allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib - Concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) - Concomitant use of proton pump inhibitors, H2-receptor antagonists, antacids - Known glucose-6-phosphate dehydrogenase (G6PD) deficiency - Pregnant or nursing patients; women of childbearing potential must have a negative pregnancy test within 14 days of enrollment - Electrocardiogram (EKG) with QTcB (Bazett's formula) > 480 ms done within 14 days of enrollment - Interstitial lung disease or pneumonitis - A history of retinal vein occlusion (RVO) - Congestive heart failure NYHA class III or worse (Marked limitation of physical activity. --- V600E ---

Primary Outcomes

Description: Tumor response was assessed per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Overall tumor response was assessed as the number of participants achieving either a complete response (CR) or a partial response (PR). The criteria are: CR = Disappearance of all target lesions PR = ≥ 30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome is reported as the number of participants achieving the different levels of tumor response per RECIST, a number without dispersion.

Measure: Tumor Response

Time: 6 weeks

Secondary Outcomes

Description: Percent of tumor necrosis at the time of endpoint biopsy or surgical resection will be assessed. The tumor specimen from resection will be examined and the volume of the necrosis compared to the volume of the total tumor determined by central pathology. Percent tumor necrosis, in increments of 10%, will be determined. The outcome will be reported as the mean percent tumor necrosis, with standard deviation.

Measure: Percent Tumor Necrosis

Time: 6 weeks

Description: An immunohistochemical laboratory analysis to assess proliferation will be performed on the initial pre-treatment biopsy (baseline) vs either the endpoint tumor biopsy or the tumor specimen from the resection. Ki-67 immunohistochemistry will be scored by at least 2 pathologists using percentage positive cells as the primary metric. Proliferation will be assessed as the difference from baseline in Ki-67 labeling to the end of treatment (tumor biopsy or the tumor specimen). The outcome will be expressed as the mean, with standard deviation.

Measure: Change in Proliferation

Time: 6 weeks

Description: An immunohistochemical laboratory analysis to assess phosphorylation of the tumor markers MEK and ERK on the initial pre-treatment biopsy (baseline) vs either the endpoint tumor biopsy or the tumor specimen from the resection. Immunohistochemistry will be scored by at least 2 pathologists using percentage positive cells and intensity of staining as the primary metrics. Phosphorylation of MEK and ERK will be assessed as the observed difference in phosphorylated MEK and ERK labeling from baseline to the end of treatment (tumor biopsy or the tumor specimen). The outcome will be expressed as the mean, with standard deviation.

Measure: Phosphorylation of Tumor Markers MEK and ERK

Time: 6 weeks

120 COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection

This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]) combination therapy or two placebos for 12 months.

NCT01682083
Conditions
  1. Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
  3. Drug: Placebos
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. --- V600E ---

In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.. Key Inclusion Criteria: - Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. --- V600E ---

- History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) Key Inclusion Criteria: - Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. --- V600E ---

Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. --- V600E ---

Primary Outcomes

Description: Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.

Measure: Relapse-free Survival (RFS)

Time: Approximately 3.5 years

Secondary Outcomes

Description: Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo

Measure: Overall Survival

Time: approximately 3.5 years

Description: Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.

Measure: Distant Metastasis-free Survival

Time: approximately 3.5 years

Description: Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.

Measure: Freedom From Relapse

Time: approximately 3.5 years

121 A Phase I Trial of Vemurafenib and Ipilimumab in Subjects With V600 BRAF Mutation-positive Metastatic Melanoma

Treatment of subjects who have metastatic melanoma that expresses an activated mutant form of the BRAF oncogene (V600E) with a combination of the specific BRAF inhibitor, Vemurafenib, and the Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) inhibitor mAb Ipilimumab will be safe and feasible and will show preliminary evidence of anti-tumor efficacy and survival in comparison to historical results following treatment with either agent alone.

NCT01400451
Conditions
  1. Melanoma
Interventions
  1. Drug: Ipilimumab (BMS-734016)
  2. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Ph I Ipilimumab Vemurafenib Combo in Patients With v-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) Treatment of subjects who have metastatic melanoma that expresses an activated mutant form of the BRAF oncogene (V600E) with a combination of the specific BRAF inhibitor, Vemurafenib, and the Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) inhibitor mAb Ipilimumab will be safe and feasible and will show preliminary evidence of anti-tumor efficacy and survival in comparison to historical results following treatment with either agent alone. --- V600E ---

Primary Outcomes

Description: AEs graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Lead In Period: between the first vemurafenib dose and the day prior to the first ipilimumab dose.

Measure: During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone

Time: From first vemurafenib dose to day prior to first ipilimumab dose (28 days); Patients who never progressed from Lead-in to combination treatment (720 mg Alone): first dose to last dose + 90 days (approximately 2 years)

Description: AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. AEs: onset on or after ipilimumab start and within 90 days of last dose. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Day 1=first dose of ipilimumab.

Measure: During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib

Time: Combination drugs: Day 1 to last dose of drug + 90 days (approximately 2 years)

Description: DLT defined as a >= Grade 3 drug-related AE during induction with ipilimumab in combination with vemurafenib excluding: Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of known or suspected tumor); Grade 3 cutaneous squamous cell carcinoma; Grade 3 photosensitivity that resolved to a Grade 1 or baseline within 15 days; Grade 3 immune-mediated events of the skin (rash, pruritis) or endocrine systems (hypothyroidism, hyperthyroidism, hypopituitarism, adrenal insufficiency, hypogonadism and cushingoid) that resolved to a Grade 1 or baseline within 28 days; a transient (resolving within 6 hours of onset) Grade 3 infusion-related AE. Hepatic=elevated aspartate aminotransferase and alanine aminotransferase. Maximum tolerable dose (MTD) was defined as the maximum dose of combination treatment that could be given to 6 subjects such that no more than 2 subjects experience DLT. Day 1=first day of concurrent therapy with ipilimumab and vemurafenib.

Measure: Number of Participants With Hepatic Dose Limiting Toxicities (DLT) in Participants Treated With Concurrent Ipilimumab and Vemurafenib

Time: Day 1 to last dose of drug + 90 (approximately 2 years)

122 A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF V600 - Dependent Advanced Solid Tumors

This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and the triple combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to assess the clinical efficacy and to further assess the safety of the combinations in selected patient populations. Oral LGX818 and MEK162 will be administered on a continuous schedule. Oral LEE011 will be administered once daily on a three weeks on, one week off schedule. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. A cycle is defined as 28 days. The dose escalation parts of the trial will be conducted in adult patients with BRAF V600-dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. The dose escalation will be guided by a Bayesian logistic regression model (BLRM). Following MTD/RP2D declaration, patients will be enrolled in three Phase II arms for the dual combination and one Phase II arm for the triple combination. All patients will be followed for 30 days for safety assessments after study drugs discontinuation. All patients enrolled in the Phase II part of the study will be followed for survival.

NCT01543698
Conditions
  1. Solid Tumors Harboring a BRAF V600 Mutation
Interventions
  1. Drug: LGX818
  2. Drug: MEK162
  3. Drug: LEE011
MeSH:Neoplasms
HPO:Neoplasm

Inclusion Criteria: Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available - Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation - Evidence of measurable disease as determined by RECIST v1.1 - World Health Organization (WHO) Performance Status ≤ 2 - Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential Exclusion Criteria: Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors - Symptomatic or untreated leptomeningeal disease - Symptomatic brain metastases. --- V600E ---

Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available - Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation - Evidence of measurable disease as determined by RECIST v1.1 - World Health Organization (WHO) Performance Status ≤ 2 - Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential Exclusion Criteria: Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors - Symptomatic or untreated leptomeningeal disease - Symptomatic brain metastases. --- V600E ---

Primary Outcomes

Description: To estimate the MTD(s) and/or recommended phase 2 dose(s) (RP2D(s)) of oral LGX818 in combination with oral MEK162, and of oral LGX818 in combination with oral MEK162 and oral LEE011 in patients with BRAF V600-dependent advanced solid tumors by measuring the incidence of DLTs as defined by the protocol.

Measure: Phase Ib: Estimation of Maximum Tolerated Dose (MTD) by measuring incidence of dose limiting toxicities (DLT)

Time: up to 8 months

Description: Assess clinical efficacy of the LGX818 and MEK162 dual combination and LGX818 and MEK162 and LEE011 triple combination in the Phase II populations by evaluating the disease control rate (DCR) and objective response rate (ORR) as per RECIST 1.1

Measure: Phase II: Clinical efficacy

Time: up to 14 months

Secondary Outcomes

Description: To characterize the safety and tolerability of LGX818 and MEK162 in combination, and LGX818 and MEK162 and LEE011 in combination by evaluating the incidence and severity (as per CTCAE grading) of AEs in all patients enrolled in the study.

Measure: Safety and tolerability of LGX818 and MEK162 dual combination, and LGX818 and MEK162 and LEE011 triple combination by evaluating the incidence and severity of adverse events (AE).

Time: up to 17 months

Description: To determine the single and multiple dose PK profile of the LGX818 and MEK162 combination and LGX818 and MEK162 and LEE011 combination, by measuring plasma concentrations of MEK162 and LGX818 and LEE011 resp. at different timepoints prior and post study drug combination dosing on several days within cycle 1 and subsequent cycles.

Measure: Determination of single and multiple dose of Pharmacokinetics (PK) profile by measuring plasma concentrations versus time after study drug combination dosing (Phase Ib)

Time: up to 8 months

Description: To assess preliminary anti-tumor activity of the LGX818 and MEK162 combination, and the LGX818 and MEK162 and LEE011 combination by evaluating the ORR as per RECIST 1.1. Safety Issue?: (FDAAA) No

Measure: Preliminary clinical anti-tumor activity by evaluating the objective response rate (Phase Ib)

Time: up to 8 months

Description: To further assess clinical efficacy of the LGX818 and MEK162 combination and the LGX818 and MEK162 and LEE011 combination in the Phase II populations by measuring progression free survival (PFS) as per RECIST 1.1

Measure: Further clinical efficacy (phase II)

Time: up to 14 months

123 cKIT, BRAF/NRAS Mutations in Advanced Melanoma : Clinical Outcome in Response to Tyrosine-kinase Inhibitors - KitMel Project

Background: Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients. Until now, available therapies were few and unreliable, but recent understanding of melanomas' molecular pathways has improve their classification and new clinical strategies have been proposed. Initial studies showed that B-Raf/N-Ras mutations (respectively V600E and Q61) are the most frequent alteration being present in 70 to 80% of melanomas, characterizing non Chronic Sun-induced Damage skins (CSD). These include Superficial Spreading Melanomas (SSM) and Nodular Melanomas (NM). Other studies showed that c-Kit mutations are presently the predominant activating mutation (20 - 40 %) in Acro-Lentiginous Melanomas (ALM), Mucous Melanomas (MM) and in melanomas arising on CSD skin. c-Kit mutation pattern is more complex with four exons being affected leading to different mutations, which incidence and biological impact are less documented. BRAF/NRAS genetics alterations drive constantly cell growth, being thus attractive targets. Spectacular results have indeed been obtained with the BRAF inhibitor that targets the V600E BRAF-mutated form. Data from GIST disease revealed that the different c-Kit mutations modulate differently c-Kit function and the response to targeted therapies. Because c-Kit targeted therapy is a critical clinical issue, the investigators aimed to identify the most frequent mutations present in our population to propose appropriate screening test and adapt the therapy. Methods: 250 melanoma samples corresponding to an homogeneous white-Caucasian population (Brittany, France) will be screened. c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible). c-Kit copy number will be quantified by q-PCR and level of c-Kit determined by immunohistochemistry (IHC, CD117). Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing). Expected Results: Taken together, the investigators anticipate that the present genetic analysis of the tumours from patients with advanced melanoma will first document the type and frequency of cKit mutations, will confirm or not that BRAF, NRAS and cKit mutations are mutually exclusive and document their repartition in the melanomas sub-types. Finally this study will clue researchers in to how well patients will respond to a therapy that targets the growth-promoting proteins BRAF/NRAS and cKIT.

NCT01543113
Conditions
  1. Melanoma
Interventions
  1. Other: sequencing
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Initial studies showed that B-Raf/N-Ras mutations (respectively V600E and Q61) are the most frequent alteration being present in 70 to 80% of melanomas, characterizing non Chronic Sun-induced Damage skins (CSD). --- V600E ---

Spectacular results have indeed been obtained with the BRAF inhibitor that targets the V600E BRAF-mutated form. --- V600E ---

Primary Outcomes

Description: c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible)

Measure: c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible)

Time: Day 1

Secondary Outcomes

Description: level of c-Kit determined by immunohistochemistry

Measure: level of c-Kit determined by immunohistochemistry

Time: Day 1

Description: Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing).

Measure: Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing).

Time: Day 1

124 An Open-Label, Multicentre, Corollary Study of Pre-Operative Therapy With Dabrafenib and the Combination of Dabrafenib With Trametinib in Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.

NCT01978236
Conditions
  1. Melanoma and Brain Metastases
Interventions
  1. Drug: Dabrafenib 150 mg
  2. Drug: Trametinib 2.0 mg
MeSH:Melanoma Neoplasm Metastasis
HPO:Cutaneous melanoma Melanoma

Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. --- V600E ---

The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. --- V600E ---

It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. --- V600E ---

Inclusion Criteria: - Signed written informed consent - Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. --- V600E ---

multiple sclerosis) - A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection - Current acute infection requiring intravenous antibiotics - A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency - The history or evidence of following cardiac abnormalities: - Corrected QT (QTc) interval using Bazett's Formula; (QTcB) >= 480 msecs - A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - Coronary angioplasty or stenting within the past 12 weeks - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Abnormal cardiac valve morphology (>= Grade 2) documented by echocardiogram (ECHO) - History of or evidence of clinically significant uncontrolled cardiac arrhythmias - Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy - Subjects with intra-cardiac defibrillators or permanent pacemakers - Pregnant, lactating or breastfeeding females - Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2118436 or excipients that contraindicate their participation Inclusion Criteria: - Signed written informed consent - Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. --- V600E ---

Primary Outcomes

Description: Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib were collected on day of surgical resection of the brain metastasis(es), Two samples were collected before surgery and 2 samples after surgery with one hour gap in between. Upon collection blood was placed on wet ice. Plasma was isolated within 60 minutes of collection and frozen at -20 degree celsius.

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma)

Time: Pre-surgery and post-surgery on Day 15

Description: Concentrations of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib, and possibly other drug-related species were quantified in the pharmacokinetic tissue sample by an investigative Liquid chromatography- mass spectrometry (LC-MS)/MS method. The spatial distribution of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib and possibly other drug-related species in the tissue samples were determined using an investigative matrix assisted laser desorption ionization (MALDI) analysis method. Parenchymal brain metastases and extracranial metastases using MALDI imaging was not determined for all participants (completed by GSK for the first two participants enrolled)

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Parenchymal Brain Metastases

Time: Day 15

Description: Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib and trametinib (as appropriate), were planned but not collected.

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) and Trametinib (Cohort B Only) in CSF Samples.

Time: Pre-surgery and post-surgery on Day 15

Secondary Outcomes

Description: Concentrations of dabrafenib, its metabolites hydroxy-, carboxy- and desmethyl-dabrafenib) and trametinib in CSF (in participants who agree for optional collection of CSF at the time of brain tumor resection). Optional collection of CSF was obtained in the operating room on the day of brain metastasis resection. CSF samples for only one participant were collected and analyzed.

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) in Cerebrospinal Fluid (CSF) Samples

Time: Day 15

Description: Changes in MAPK pathway markers in paired extracranial biopsies taken pre-treatment, during craniotomy, and at disease progression, and changes in markers between post-operative intracranial and extracranial biopsies was planned but not performed as the study was terminated due to low enrollment.

Measure: Number of Participants With Changes in Mitogen-activated Protein Kinase (MAPK) Pathway Markers

Time: Up to Day 15

Description: Changes in the radiographic characteristics of the tumors were planned to be compared to (1) levels of dabrafenib, its metabolites and trametinib (where appropriate) in the brain metastases, plasma, and CSF, and (2) MAPK pathway activation status in tumors at the time of surgery. Results were planned to be compared to the analysis of early clinical responses in extracranial metastases, as determined by the Positron emission tomography (PET-CT) imaging. This analysis was planned but not performed as the study was terminated due to low enrollment

Measure: Number of Participants With Changes in Radiographic Tumors

Time: Up to 2 years

Description: The change from Baseline to the pre-surgery intracranial disease assessment in the SLD of intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

Measure: Percent Change From Baseline to Pre-surgery in the Sum of the Longest Diameters (SLD) of Intracranial Target Lesions

Time: Up to 2 years

Description: The maximum change from Baseline in the SLD of unresected intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

Measure: Maximum Percent Change From Baseline in the SLD of Unresected Intracranial Target Lesions

Time: Up to 2 years

Description: Overall Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime as per modified Response Evaluation Criteria in Solid Tumors (RECIST). The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence and is determined programmatically based on the investigator's assessment of response at each time point. Overall Extracranial Response Rate was planned but not analyzed as the study was terminated due to low enrollment.

Measure: Percentage of Participants With Overall Extracranial Response Rate in Unresected Lesions

Time: Approximately 2 years or death whichever occurs first

Description: Overall survival, defined as the time from first dose of study treatment to death for any reason, was planned to summarize using Kaplan-Meier quartile estimates along with two sided 95% confidence intervals. But were not performed as the study was terminated due to low enrollment.

Measure: Percentage of Participants With Overall Survival

Time: Approximately 2 years or death whichever occurs first

Description: Vital sign measurements including temperature, respiratory rate, systolic and diastolic blood pressure, and pulse rate were planned to be performed but were neither summarized nor listed as the study was terminated.

Measure: Number of Participants With Abnormal Vital Signs

Time: Up to 2 years

Description: A complete physical examination was planned which included assessments of the head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and extremities. Height and weight was also planned to be measured and recorded. A complete physical exam including a thorough genitourinary examination for female participants, inspection of the head and neck region, and digital rectal examination for both male and female participants was planned to be performed at Screening, and Month 12 or at discontinuation if discontinuation occurs prior to Month 12. If the participants had a genitourinary and rectal exam within 6 months of screening, these assessments need not to be repeated at screening. But data for physical examinations were not summarized and listed as the study was terminated.

Measure: Number of Participants With Abnormal Physical Examinations

Time: Up to 2 years

Description: 112-lead ECGs were planned to be obtained at screening during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. At each assessment a 12-lead ECG was planned to be performed by qualified personnel at the site after at least a five-minute rest with the participants in a semi-recumbent or supine position. But data for 12-lead ECGs were not summarized and listed as the study was terminated.

Measure: Number of Participants With Abnormal 12-lead Electrocardiograms (ECG)

Time: Screening

Description: ECHO include an evaluation for Left ventricular ejection fraction (LVEF) and both right- and left-sided valvular lesions. ECHO was planned to be performed at screening, Week 8 and every 16 weeks till discontinuation. data for ECHO was not summarized and listed as the study was terminated.

Measure: Number of Participants With Abnormal Echocardiogram (ECHO)

Time: Up to 2 years

Description: Laboratory assessments included parameters like Hematology, Standard Chemistry, Coagulation, Serum Pregnancy. Assessment of these parameters were planned to be performed by the central laboratory on screening, Day prior to surgery, Every 4 weeks after restart and Discontinuation, but were not analyzed as the study was terminated due to low enrollment.

Measure: Number of Participants With Abnormal Clinical Laboratory Assessments

Time: Up to 2 years

Description: AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE were collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy using Medical Dictionary for Regulatory Activities (MedDRA)

Measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

Time: Up to 2 years

125 Phase II Study of Durvalumab (MEDI4736) (Anti-PD-L1) and Trametinib (MEKi) in MSS Metastatic Colon Cancer

The goal of this clinical research study is to learn if durvalumab and trametinib can help to control microsatellite stable (MSS) colorectal cancer. The safety of these drugs will also be studied. This is an investigational study. Durvalumab is FDA approved and commercially available for the treatment of previously treated advanced bladder cancer. Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K. It is investigational to use durvalumab and trametinib to treat MSS colorectal cancer. Up to 56 participants will be enrolled in this study. All will take part at MD Anderson.

NCT03428126
Conditions
  1. Malignant Neoplasms of Digestive Organs
  2. Colorectal Cancer
  3. Colon Cancer
Interventions
  1. Drug: Durvalumab
  2. Drug: Trametinib
MeSH:Neoplasms Colorectal Neoplasms Colonic Neoplasms
HPO:Colon cancer Neoplasm Neoplasm of the colon Neoplasm of the large intestine

Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K. --- V600E ---

Primary Outcomes

Description: MTD defined as highest dose level with less than 2 patients with dose limiting toxicity (DLT) out of at least six patients in the cohort. DLT defined as any adverse event (AE) of severity grade 3 or 4 (including serious or life-threatening) considered possibly, probably or definitely related to the combination of Durvalumab and Trametinib determined by NCI CTCAEv4.03.

Measure: Maximum Tolerated Dose (MTD) of Durvalumab and Trametinib in MSS Metastatic Colon Cancer

Time: 28 days

Measure: Best Overall Response (CR+PR) Determined by Immune Response Criteria

Time: Baseline up to 2 months

126 With or withoutA140 + mFOLFOX6 Treat 1st Line mCRC in RAS Wide Type, Multicenter, Double-blind, Randomized, Controlled Phase III Trial

The study is an double blind, randomized, multicenter phase 3 trial. The efficacy analyses are based on 570 Chinese patients with RAS wt mCRC treated with mFOLFOX-6 ± cetuximab. Study treatment continues until disease progression or unacceptable toxicity (ie, not for a fixed number of courses). The primary endpoint of the study is progression-free survival (PFS) time according to RECIST 1.0; key secondary endpoints include overall survival (OS) time, overall response rate (ORR), and safety/tolerability.

NCT03426371
Conditions
  1. Metastatic
  2. Metastatic Colorectal Cancer
Interventions
  1. Drug: KL-140
  2. Drug: Placebo
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Quality of life score is defined of questionnaire EORTC QLQ-C30.. Inclusion Criteria: - Signed written informed consent - Male or female subjects, 18-75 years of age - Medically accepted effective contraception if procreative potential exists - Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum - RAS wild-type and BRAF-V600E wild-type status in tumor tissue - At least one measurable lesion by computer tomography (CT) or magnetic resonance imaging (MRI) according to RECIST - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - Life expectancy of at least 12 weeks - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - White blood cell count >= 3 × 10x9/L with neutrophils >= 1.5 × 10x9/L, platelet count >=75 × 10x9/L and hemoglobin >= 8 g/dL; Total bilirubin <= 1.5 × upper limit of reference range, Aspartate transaminase (AST) and alanine transaminase (ALT) <= 2.5 × upper limit of reference range or <= 5 × upper reference range in subjects with liver metastasis;Serum creatinine <= 1.5 × upper limit of reference range Exclusion Criteria: - Known hypersensitivity or allergic reactions against any of the components of the trial treatments - Radiotherapy or surgery (excluding prior diagnostic biopsy) in the 28 days before trial treatment - Known brain metastasis and/or leptomeningeal disease. --- V600E ---

cardiac failure of New York Heart Association classes III-IV, uncontrolled coronary artery disease, cardiomyopathy, uncontrolled arrhythmia, uncontrolled hypertension, or history of myocardial infarction in the last 5 years, or left ventricular ejection fraction below the institutional range of normal on a baseline multiple gated acquisition scan or echocardiogram - Renal replacement therapy - Peripheral neuropathy > grade 1 - History of organ allograft, autologous stem cell transplantation, or allogeneic stem cell transplantation - Previous malignancy other than CRC in the last 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix - Known and declared history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C - Known severe coagulation disorders - Previous chemotherapy for CRC except adjuvant treatment if terminated > 12 months (oxaliplatin-based chemotherapy) or > 6 months (non-oxaliplatin-based chemotherapy) before the start of treatment in this trial - Previous treatment with anti-EGFR monoclonal antibody therapy - Other non-permitted concomitant anticancer therapies, chronic systemic immune therapy or hormone therapy - Granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) within 3 weeks of trial entry,blood transfusion,or blood components transfusion - Pregnancy (absence to be confirmed by serum β-human chorionic gonadotropin test) or breastfeeding - Ongoing alcohol or drug abuse - Known neurological or psychiatric diseases - Participation in another clinical trial within the past 4 weeks - Legal incapacity or limited legal capacity - Other significant disease that in the investigator's opinion should exclude the subject from the trial Inclusion Criteria: - Signed written informed consent - Male or female subjects, 18-75 years of age - Medically accepted effective contraception if procreative potential exists - Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum - RAS wild-type and BRAF-V600E wild-type status in tumor tissue - At least one measurable lesion by computer tomography (CT) or magnetic resonance imaging (MRI) according to RECIST - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - Life expectancy of at least 12 weeks - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - White blood cell count >= 3 × 10x9/L with neutrophils >= 1.5 × 10x9/L, platelet count >=75 × 10x9/L and hemoglobin >= 8 g/dL; Total bilirubin <= 1.5 × upper limit of reference range, Aspartate transaminase (AST) and alanine transaminase (ALT) <= 2.5 × upper limit of reference range or <= 5 × upper reference range in subjects with liver metastasis;Serum creatinine <= 1.5 × upper limit of reference range Exclusion Criteria: - Known hypersensitivity or allergic reactions against any of the components of the trial treatments - Radiotherapy or surgery (excluding prior diagnostic biopsy) in the 28 days before trial treatment - Known brain metastasis and/or leptomeningeal disease. --- V600E ---

Primary Outcomes

Description: PFS was defined as the duration (in months) from randomization until the first progressive disease (PD) observation as assessed by the investigators according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.0, or death due to any cause when death occurred within 90 days of randomization or the last tumor assessment, whichever was later. PD was defined as at least a 20% increase in the sum of longest diameter (LD) of the target lesions, taking as references the smallest sum LD since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.

Measure: Progression Free Survival (PFS) Time

Time: Time Frame: Baseline up to 128 weeks

Secondary Outcomes

Description: OS was defined as the time (in months) from randomization to death. For subjects who were still alive at the analysis data cut-off date or who lost to follow-up, survival was censored at the last recorded date that the subject was known to be alive.

Measure: Overall Survival (OS) Time

Time: Time Frame: Baseline up to 258 weeks

Description: The Best ORR was defined as the percentage of subjects having achieved complete response (CR) or partial response (PR) according to RECIST version 1.0 as determined by the IRC. CR: defined as disappearance of all target and all non-target lesions and no new lesions. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters, no progression of non-target lesions and no new lesions. The Best ORR was defined as the percentage of subjects having achieved complete response (CR) or partial response (PR) according to RECIST version 1.0 as determined by the investigators. CR: defined as disappearance of all target and all non-target lesions and no new lesions. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters, no progression of non-target lesions and no new lesions.

Measure: Best Overall Response Rate (ORR)

Time: Time Frame: Baseline up to 128 weeks

Description: TTF was defined as time from randomization to date of the first occurrence of radiologically confirmed PD. Clinical PD according to the Investigator's assessment , discontinuation of treatment due to progression or adverse event, start of new anticancer therapy, withdrawal of consent, or death within 90 days of last tumor assessment or randomization. Subjects without event were censored on the date of last tumor assessment.

Measure: Time to Treatment Failure (TTF)

Time: Time Frame: Baseline up to 128 weeks

Description: Quality of life score is defined of questionnaire EORTC QLQ-C30.

Measure: quality of life score

Time: Time Frame: Baseline up to 258 weeks

127 A Prospective, Open-lable, Multicenter, Randomized, Controlled Phase II Clinical Trial to Evaluate the Efficacy of Irinotecan Versus Oxaliplatin in the First-line Treatment of Refractory Metastatic Colorectal Cancer

This is a prospective, open-lable, multicenter, randomized, controlled, phase II clinical study. The aim is to evaluate the efficacy of Irinotecan versus Oxaliplatin in the first-line treatment of refractory metastatic colorectal cancer.

NCT03567629
Conditions
  1. mCRC
Interventions
  1. Drug: Irinotecan
  2. Drug: Oxaliplatin
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

3. Subjects with BRAF V600E mutation. --- V600E ---

Primary Outcomes

Description: Evaluation of the Progression-free Survival of Irinotecan-based regimen versus Oxaliplatin-based regimen in refractory metastatic colorectal cancer patients.

Measure: Progression-free Survival: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first.

Time: assessed up to 10 months

Secondary Outcomes

Description: Evaluation of the Overall Survival of Irinotecan-based regimen versus Oxaliplatin-based regimen in refractory metastatic colorectal cancer patients.

Measure: Overall Survival : From date of enrollment until the date of death.

Time: 2 years

Description: flurouracil drugs:fluorouracil、S1、Capecitabine

Measure: Evaluation of PFS in patients with different fluorouracil drugs and different genotyping subgroups.

Time: 10months

Description: flurouracil drugs:fluorouracil、S1、Capecitabine

Measure: Evaluation of OS in patients with different fluorouracil drugs and different genotyping subgroups.

Time: 2 years

Description: Adverse reactions evaluation is based on the National Cancer Institute adverse event General terminology Standard [CTCAE] 4.0 version

Measure: The incidence of treatment related emergent adverse events(Safety and Tolerance)

Time: Until 28 days after the deadline of enrollment

128 Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations

This is a single-centre, open-label Phase II study of the investigational drugs binimetinib and encorafenib that will be taken my mouth (orally) daily in adult patient with advanced and/or metastatic solid tumors for which no other standard therapy is available. The main purpose is to evaluate the objective response rate (ORR) of the study drugs in the growth of the cancer in patients with class 2 and 3 BRAF mutations.

NCT03839342
Conditions
  1. Solid Tumor
Interventions
  1. Drug: Binimetinib
  2. Drug: Encorafenib
MeSH:Neoplasms
HPO:Neoplasm

Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations. --- V600E ---

Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations This is a single-centre, open-label Phase II study of the investigational drugs binimetinib and encorafenib that will be taken my mouth (orally) daily in adult patient with advanced and/or metastatic solid tumors for which no other standard therapy is available. --- V600E ---

Number of identified molecular mechanisms of acquired resistance to binimetinib and encorafenib in tumors with non-V600E BRAF mutations, measured by analysis of molecular profiles and validated with PDX models in vitro and in vivo.. null. --- V600E ---

Any patient with a tumor expressing a BRAF V600E mutation 2. Any patient with melanoma whose tumor expresses a BRAF V600K mutation 3. Prior therapy with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or any MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib). --- V600E ---

This study will look at participants in these classes (non-V600E BRAF mutations). --- V600E ---

Primary Outcomes

Measure: Objective response rate defined as per RECIST v1.1.

Time: 2.5 years

Secondary Outcomes

Measure: Number of participants with toxicities as per NCI CTCAE v5.0.

Time: 2.5 years

Measure: Disease progression defined as per RECIST v1.1 and monitored throughout the study period. Progression Free Survival defined as time from study registration to disease progression or death from any cause.

Time: 2.5 years

Measure: Disease Control Rate defined in accordance with RECIST v1.1, as the percentage of patients who achieve a complete response, partial response or stable disease after 24 weeks of treatment.

Time: 2.5 years

Measure: Overall survival measured as the length of time from the first day of treatment to the day of death. Median OS will be reported.

Time: 2.5 years

Measure: Change in circulating tumor DNA (ctDNA) profiles measured by serial analysis of ctDNA profiles at baseline, mid-cycle 1, with each subsequent cycle, and at progression, validated by comparison to molecular profiles of corresponding fresh tumor biopsies

Time: 2.5 years

Measure: Number of fresh tumor biopsies collected, frozen, and stored for subsequent development of patient derived xenografts.

Time: 2.5 years

Measure: Number of identified molecular mechanisms of acquired resistance to binimetinib and encorafenib in tumors with non-V600E BRAF mutations, measured by analysis of molecular profiles and validated with PDX models in vitro and in vivo.

Time: 2.5 years

129 A Phase I Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic Thyroid Cancer

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

NCT03975231
Conditions
  1. BRAF NP_004324.2:p.V600E
  2. BRAF V600K Mutation Present
  3. Thyroid Gland Anaplastic Carcinoma
Interventions
  1. Drug: Dabrafenib
  2. Radiation: Intensity-Modulated Radiation Therapy
  3. Drug: Trametinib
MeSH:Thyroid Neoplasms Thyroid Carcinoma, Anaplastic Carcinoma Thyroid Diseases
HPO:Abnormality of the thyroid gland Anaplastic thyroid carcinoma Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

- Presence of BRAF mutation (V600E or V600K) in tumor tissue. --- V600E ---

Primary Outcomes

Measure: Maximum tolerated dose of combination therapy of dabrafenib and trametinib administered concurrently with intensity-modulated radiation therapy (IMRT)

Time: 1 year

Secondary Outcomes

Description: Will be defined as the proportion of patients who have a partial response (PR), or complete response (CR) within the first 4 weeks of IMRT. Complete response (CR) and partial response (PR) will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be calculated with the exact binomial 95% confidence intervals.

Measure: Objective response rate

Time: 1 year

Description: Will be evaluated by RECIST criteria for disease limited to the radiation field (neck) following the first set of scans after completion of IMRT. Estimated by Kaplan-Meier method.

Measure: Time to progression for local disease recurrence

Time: 1 year

Description: Estimated by Kaplan-Meier method.

Measure: Overall survival

Time: From the start date of the treatment to the date of death, assessed up to 1 year

Description: Estimated by Kaplan-Meier method.

Measure: Progression free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

130 A Phase II Study of Binimetinib in Combination With Encorafenib in Adults With Recurrent BRAF V600-Mutated High-Grade Astrocytoma or Other Primary Brain Tumor

The goal of this study is to estimate the efficacy of encorafenib and binimetinib as measured by radiographic response in recurrent high-grade primary brain tumors.

NCT03973918
Conditions
  1. High Grade Glioma
  2. BRAF V600E
  3. BRAF V600K
  4. Anaplastic Astrocytoma
  5. Anaplastic Pleomorphic Xanthoastrocytoma
  6. Gliosarcoma
  7. Glioblastoma
Interventions
  1. Drug: Encorafenib
  2. Drug: Binimetinib
  3. Biological: Research Bloods
  4. Biological: Tumor Tissue
MeSH:Glioblastoma Astrocytoma Gliosarcoma
HPO:Astrocytoma Glioblastoma multiforme Subependymal giant-cell astrocytoma

High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Glioblastoma Astrocytoma Gliosarcoma Primary Objective Estimate the efficacy of combination treatment with encorafenib and binimetinib, as measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs). --- V600E ---

High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Glioblastoma Astrocytoma Gliosarcoma Primary Objective Estimate the efficacy of combination treatment with encorafenib and binimetinib, as measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs). --- V600E --- --- V600K --- --- V600E ---

Secondary Objectives 1. Estimate efficacy as measured by progression-free survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug. 2. Evaluate duration of response in subjects who have a partial or complete response. --- V600E ---

4. Estimate efficacy as measured by overall survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug. 5. Characterize the toxicity profile of the combination of encorafenib and binimetinib in this patient population. --- V600E ---

Primary Outcomes

Description: Number of participants from each treatment cohort with response as defined by Response Assessment in Neuro-oncology (RANO) criteria: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Measure: Tumor radiographic response per RANO for 3 treatment cohorts

Time: 1 year

Secondary Outcomes

Description: Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status

Measure: Progression free survival for 3 treatment cohorts

Time: up to 1 year

Description: median overall survival

Measure: Overall Survival

Time: up to 2 years

Description: Time from response to progression. Response is defined by RANO: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Measure: Duration of response

Time: up to 1 year

Measure: Number of participants with adverse events as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0)

Time: 1 year

131 A Phase II Randomized Study of Ramucirumab Plus MK3475 (Pembrolizumab) Versus Standard of Care for Patients Previously Treated With Immunotherapy for Stage IV or Recurrent Non-Small Cell Lung Cancer (Lung-MAP Non-Matched Sub-Study)

This phase II Lung-MAP non-Match treatment trial studies how well ramucirumab and pembrolizumab work versus standard of care in treating patients with non-small cell lung cancer that is stage IV or has come back. Immunotherapy with monoclonal antibodies, such as ramucirumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in standard of care chemotherapy for non-small cell lung cancer, such as docetaxel, gemcitabine hydrochloride, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ramucirumab and pembrolizumab together may work better in treating patients with non-small lung cancer compared to standard of care.

NCT03971474
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Cancer AJCC v8
  3. Stage IVA Lung Cancer AJCC v8
  4. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Docetaxel
  2. Drug: Gemcitabine
  3. Drug: Gemcitabine Hydrochloride
  4. Biological: Pembrolizumab
  5. Drug: Pemetrexed
  6. Drug: Pemetrexed Disodium
  7. Biological: Ramucirumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients who were screened under S1400 (legacy screening/pre-screening study) must have had prior PD-L1 testing by the Dako 22C3 PharmDx immunohistochemistry (IHC) assay, and must have results available for stratification purposes - Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy - Patients must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). --- T790M --- --- V600E ---

Primary Outcomes

Description: Will be compared between patients previously treated with platinum-based chemotherapy and immunotherapy for stage IV or recurrent non-small cell lung cancer randomized to ramucirumab and MK-3475 (pembrolizumab) versus standard of care (SoC). Will be estimated using the method of Kaplan-Meier.

Measure: Overall survival (OS)

Time: Up to 3 years

Secondary Outcomes

Description: Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average hazard ratio (HR) will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.

Measure: Investigator assessed-progression-free survival (IA-PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average HR will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.

Measure: Duration of response (DOR)

Time: From date of first documentation of response (CR or PR), or death due to any cause among patients who achieve a response (CR or PR), assessed up to 3 years

Description: Binary proportions will be summarized with associated confidence intervals. Will be compared with toxicities using a chi-squared test at the 1-sided 0.05 level.

Measure: Response rates (RR)

Time: Up to 3 years

Description: Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Binary proportions will be summarized with associated confidence intervals. Will be compared with RR using a chi-squared test at the 1-sided 0.05 level.

Measure: Incidence of adverse events

Time: Up to 3 years

132 A Randomized Phase II Study of TAK228 (MLN0128, Sapanisertib) Plus Docetaxel Versus Standard of Care in Patients With Previously - Treated NFE2L2 or KEAP1-Positive Stage IV or Recurrent Squamous Cell Lung Cancer (ECOG-ACRIN LUNG-MAP Sub-Study)

This phase II LUNG-MAP treatment trial studies how well sapanisertib and docetaxel work for the treatment for squamous cell lung cancer that is stage IV or has come back (recurrent). Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sapanisertib and docetaxel may work better in treating patients with squamous cell lung cancer compared to standard chemotherapy.

NCT04267913
Conditions
  1. Lung Squamous Cell Carcinoma
  2. Recurrent Lung Carcinoma
  3. Stage IV Lung Cancer AJCC v8
  4. Stage IVA Lung Cancer AJCC v8
  5. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Dexamethasone
  2. Drug: Docetaxel
  3. Biological: Ramucirumab
  4. Drug: Sapanisertib
MeSH:Carcinoma Lung Neoplasms
HPO:Carcinoma Neoplasm of the lung

These cases should be discussed with a study chair prior to enrollment - Patients must agree to have blood specimens submitted for circulating tumor DNA (ctDNA) - Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - Patients with impaired decision-making capacity are eligible as long as their neurological or psychological condition does not preclude their safe participation in the study (e.g., tracking pill consumption and reporting adverse events to the investigator) Exclusion Criteria: - Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy - Patient must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days following treatment, and prior to sub-study randomization, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 14 days prior to sub-study randomization. --- T790M --- --- V600E ---

Primary Outcomes

Description: IA-PFS will be compared between the arms using a stratified log-rank test.

Measure: Investigator-assessed progression-free survival (IA-PFS)

Time: Up to 3 years

Secondary Outcomes

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Measure: Overall response rate (ORR)

Time: Up to 3 years

Description: Will be estimated using the Kaplan-Meier method. The Brookmeyer-Crowley method will be used to estimate 95% confidence intervals for the median. For point estimates at landmark times, the associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model adjusting for the stratification factors.

Measure: Duration of response

Time: Up to 3 years

Description: Will be estimated using the Kaplan-Meier method. The Brookmeyer-Crowley method will be used to estimate 95% confidence intervals for the median. For point estimates at landmark times, the associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model adjusting for the stratification factors.

Measure: Progression free survival

Time: Up to 3 years

Description: Will be estimated using the Kaplan-Meier method. The Brookmeyer-Crowley method will be used to estimate 95% confidence intervals for the median. For point estimates at landmark times, the associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model adjusting for the stratification factors.

Measure: Overall survival

Time: Up to 3 years

133 A Phase II Study of LOXO-292 in Patients With RET Fusion-Positive Stage IV or Recurrent Non-Small Cell Lung Cancer (LUNG-MAP Sub-Study)

This phase II LUNG-MAP treatment trial studies how well selpercatinib works in treating patients with RET fusion-positive non-small cell lung cancer that is stage IV or has come back (recurrent). Selpercatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT04268550
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Cancer AJCC v8
  3. Stage IVA Lung Cancer AJCC v8
  4. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Selpercatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

This includes EGFR sensitizing mutations, EGFR T790M, ALK gene fusion, ROS1 gene fusion, KRAS activating mutation, BRAF V600E mutation and MET exon 14 skipping mutation or high-level amplification and expression - Note: EGFR, ALK, ROS, KRAS, and BRAF testing is performed as part of the LUNGMAP screening/pre-screening FoundationOne test. --- T790M --- --- V600E ---

Primary Outcomes

Description: A response will be confirmed by a complete response (CR) or partial response (PR). Proportions and associated confidence intervals will be calculated.

Measure: Response rate by blinded independent centralized review (BICR)

Time: Up to 3 years from date of sub-study registration

Secondary Outcomes

Description: Will be assessed using Common Terminology Criteria for Adverse Event version 5.0.

Measure: Incidence of adverse events

Time: Up to 3 years from date of sub-study registration

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: BICR-progression-free survival (PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by BICR or symptomatic deterioration, or death due to any cause, assessed up to 3 years from date of sub-study registration

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Investigator-assessed (IA) PFS

Time: From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years from date of sub-study registration

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Overall survival

Time: Up to 3 years from date of sub-study registration

Description: Will be evaluated among patients who achieve a confirmed response. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times. The median DOR and percentage with DOR at landmark times at 6 and 12 months after documentation of confirmed response will be estimated.

Measure: BICR-duration of response (DOR)

Time: From date of first documentation of confirmed response (CR or PR) to date of first documentation of progression assessed by BICR or symptomatic deterioration, or death due to any cause among patients who achieve, assessed at 6 and 12 months

Description: Will be assessed among patients with brain metastases. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Central nervous system (CNS) response rate

Time: Baseline

Description: Will be assessed among patients with brain metastases. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Duration of intracranial response among patients with a CNS response

Time: Baseline

134 Phase 2 Trial for Binimetinib for Patients With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

Background: Most people with hairy cell leukemia have a BRAF gene mutation. They can be treated with BRAF inhibitors, drugs that target this mutation. For people who do not have this mutation, BRAF inhibitors are not a treatment option. We found that in hairy cell leukemia, when BRAF is not mutated, the MEK gene frequently is. Binimetinib is a MEK inhibitor which targets MEK. It is important to determine if this drug can be a good treatment option in those who cannot benefit treatment with BRAF inhibitors. Objective: To see if binimetinib is an effective treatment for hairy cell leukemia that does not have a BRAF mutation. Eligibility: People ages 18 and older with hairy cell leukemia without a mutation in the BRAF gene and whose disease either did not respond to treatment or came back after treatment Design: Participants will be screened with: - Medical history - Physical exam - Blood and urine tests - Lung and heart tests - Eye exam - Bone marrow biopsy: A needle will be injected through the participant s skin into the bone to remove a sample of marrow. - CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They might receive a contrast agent by vein. Before they start treatment, participants will have an abdominal ultrasound, pulmonary function tests, and exercise stress tests. Participants will take binimetinib by mouth twice daily in 28-day cycles. They will keep a medication diary. Participants will have at least one visit before every cycle. Visits will include repeats of some screening tests. Participants may continue treatment as long as their disease does not get worse and they do not have bad side effects. About a month after their last dose of treatment, participants will have a follow-up visit. They will then have visits once a year. ...

NCT04322383
Conditions
  1. Hairy Cell Leukemia
Interventions
  1. Drug: binimetinib
MeSH:Leukemia Leukemia, Hairy Cell
HPO:Leukemia

Hairy Cell Leukemia Leukemia Leukemia, Hairy Cell Background: - Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 1900 new cases per year in the US. - BRAF V600E mutation is very common in classic HCL. - HCL variant (HCLv) is wild type for BRAF and is more aggressive compared to classic HCL due to its lower response and shorter duration of response to standard purine analog chemotherapy. --- V600E ---

- While BRAF and MEK combination inhibition is making an impact in the treatment of BRAF V600E mutated HCL, this treatment is not applicable for patients with BRAF-WT HCL/HCLv. --- V600E ---

Primary Outcomes

Description: Percentage of patients with the best overall response of CR or PR to therapy

Measure: overall response rate

Time: every year

Secondary Outcomes

Description: the time criteria are met for CR or PR (whichever is recorded first) until the first date that patient no longer qualifies as a PR

Measure: CR rate

Time: every year

Description: duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

Measure: Progression free survival

Time: every year

Description: the time from the start of the treatment until time of death from any cause

Measure: Overall survival

Time: every year

Description: duration of time from the start of the binimetinib to next line of treatment

Measure: time to next treatment

Time: every year

Description: The fraction of patients with toxicity noted will be reported by grade and type of toxicity identified.

Measure: safety

Time: every 4 weeks

Description: determine whether the response to binimetinib is different in patients with and without MAP2K1 (MEK mutations), in patients for which MEK status is known

Measure: different response relative to MAP2K1 mutations

Time: every year

135 Phase 2 Trial of Encorafenib Plus Binimetinib for Patients With BRAF V600E Mutated Relapsed/Refractory HCL

Background: Hairy cell leukemia (HCL) does not usually respond to chemotherapy. Most people with HCL have a BRAF gene mutation. This can increase the growth of cancer cells. Vemurafenib has been tested to treat these people. However, researchers think a combination of drugs might work better. Objective: To test if treatment with a combination of encorafenib and binimetinib in BRAF mutant HCL is more effective than treatment with vemurafenib. Eligibility: People ages 18 and older with BRAF mutant HCL that did not respond to or came back after treatment Design: Participants will be screened with: Medical history Physical exam Bone marrow biopsy: A needle will be injected through the participant s skin and into a bone to remove liquid. Blood and urine tests Heart and lung function tests CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They may have a contrast agent injected into a vein. Eye exam Participants will take the study drugs by mouth in 28-day cycles. They will take encorafenib daily. They will take binimetinib twice daily. They will keep a pill diary. Participants will take their temperature daily. Participants will have at least 1 visit before each cycle. Visits will include repeats of some screening tests. They will also include abdominal ultrasounds, exercise stress tests, and skin evaluations. Participants may continue treatment as long as their disease does not get worse and they do not have bad side effects. About a month after their last dose of treatment, participants will have a follow-up visit. Then they will have annual follow-ups....

NCT04324112
Conditions
  1. Hairy Cell Leukemia
Interventions
  1. Drug: binimetinib
  2. Drug: Encorafenib
MeSH:Leukemia, Hairy Cell

Phase 2 Trial of Encorafenib Plus Binimetinib for Patients With BRAF V600E Mutated Relapsed/Refractory HCL. --- V600E ---

Encorafenib Plus Binimetinib for People With BRAF V600E Mutated Relapsed/Refractory HCL Background: Hairy cell leukemia (HCL) does not usually respond to chemotherapy. --- V600E ---

2. Patients must have BRAF V600E mutation as confirmed from fresh bone marrow aspirate, peripheral blood sample, or lymph node/mass by the Laboratory of Pathology, NCI 3. Patients who are ineligible for, unable to obtain in a timely manner, cannot access, unwilling to undergo or have failed Moxetumomab Pasudotox trial at NCI 4. Refractory or relapsed disease- defined as either: - Refractory- no response or disease progression in <=1 year following first-line treatment with a purine analog, or - Relapsed- having relapsed following treatment with at least 1 prior purine-analog treatment 5. Age >=18 years 6. --- V600E ---

- About 90% of classic HCL patients have the BRAF V600E mutation, which leads to Rasindependent activation of the MAPK pathway, causing increased phosphorylation (hyperactivation) of MEK, followed by ERK, therefore promoting the proliferation and survival of HCL cells. --- V600E ---

Eligibility: - BRAF V600E mutant HCL with at least 1 prior purine analog treatment - Need for treatment, as evidenced by any one of the following: ANC <1 x10(3)/mcL, Hgb <10g/dL, Platelet count <100 x10(3)/mcL, leukemia cell count >5 x10(3)/mcL, symptomatic splenomegaly, enlarging HCL mass > 2cm in short axis - Greater than or equal to 18 years of age - No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment. --- V600E ---

Primary Outcomes

Description: determine if treatment with combination encorafenib and binimetinib in BRAF V600E+HCL is associated with a CR rate which exceeds that of vemurafenib

Measure: CR rate

Time: every year

Secondary Outcomes

Description: Fraction of patients who achieve MRD negative CR after treatment with encorafenib and binimetinib

Measure: MRD negative CR

Time: every year

Description: duration of time from the start of the study drugs to next line of treatment

Measure: time to next treatment

Time: every year

Description: the time from the start of the treatment until time of death from any cause

Measure: overall survival

Time: every year

Description: the time from study enrollment to the first occurrence of progression, relapse after response, or death from any cause

Measure: event free survival

Time: every year

Description: the time criteria are met for CR or PR (whichever is recorded first) until the first date that patient no longer qualifies as a PR

Measure: duration of response

Time: every year

Description: duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

Measure: progression free-survival

Time: every year

Description: fraction of patients that have pyrexia at any time while on study

Measure: rate of pyrexia

Time: every year

136 An Open-label, Multicenter, Phase II Study of Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation

This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib and trametinib in stage IV disease to subjects with BRAF V600E mutant advanced non-small cell lung cancer. Subjects will receive dabrafenib 150 mg bid and trametinib 2 mg once daily in combination therapy and continue on treatment until disease progression, death, or unacceptable adverse event.

NCT03543306
Conditions
  1. Cancer
  2. Lung Cancer Metastatic
  3. BRAF V600E
Interventions
  1. Drug: daborafenib plus trametinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

An Open-label, Multicenter, Phase II Study of Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation. --- V600E ---

Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib and trametinib in stage IV disease to subjects with BRAF V600E mutant advanced non-small cell lung cancer. --- V600E ---

Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib and trametinib in stage IV disease to subjects with BRAF V600E mutant advanced non-small cell lung cancer. --- V600E --- --- V600E ---

Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed Cancer Lung Cancer Metastatic BRAF V600E Lung Neoplasms null --- V600E ---

Primary Outcomes

Description: ORR is a proportion of patients with a best overall response defined as complete response or partial response by RECIST1.1

Measure: Objective response rate

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Secondary Outcomes

Description: DOR is calculated as the time from the date of the first document of complete remission (CR) or partial remission (PR) to the first documented preogressive disease (PD) or death due to any cause for patients with PR or CR.

Measure: Duration of response

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: . PFS is defined as time from the first dose of investigational products (IPs) to progression or death due to any cause. OS is defined as time from the first dose of IPs to death due to any cause.

Measure: Progression-free survival

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Measure: Overall survival

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: DCR is calculated as the proportion of patients with best response of CR, PR and SD.

Measure: Disease control rate

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

137 A Phase 1, Open-Label, Multicenter, Multi-Dose Escalation Study of CM-24 (MK-6018) as Monotherapy and In Combination With Pembrolizumab (MK-3475) in Subjects With Selected Advanced or Recurrent Malignancies

The purpose of this study is to evaluate the safety and tolerability of humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 (CM-24 [MK-6018]), administered intravenously as monotherapy and in combination with Pembrolizumab (MK-3475), in participants with selected advanced or recurrent malignancies. Escalating multiple doses will be evaluated to determine the recommended dose for Phase 2 clinical studies.

NCT02346955
Conditions
  1. Non-small Cell Lung Carcinoma (NSCLC)
  2. Melanoma
  3. Bladder Cancer
  4. Colorectal Cancer
  5. Gastric Cancer
  6. Ovarian Cancer
Interventions
  1. Biological: CM-24 (MK-6018)
  2. Biological: Pembrolizumab (MK-3475)
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Participants in the Monotherapy Expansion Cohort must have one of the following advanced or recurrent malignancies: cutaneous melanoma showing primary progression following treatment with an anti-programmed cell death (PD) or anti-PDL1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Participants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Melanoma with BRAF V600E or V600K mutation-positive melanoma must have progressed on, or were intolerant to, prior BRAF- or MEK-inhibitor therapy - Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with progressing or new tumors since last antitumor therapy - Must have adequate hematologic, renal, and liver function - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Females must not be pregnant (negative human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) or breastfeeding - Women of childbearing potential and male participants must agree to use adequate contraception throughout the study and for up to 180 days after study treatment - An estimated life expectancy of at least 3 months - Must consent to provide an archival tumor biopsy sample at any time point from screening to study exit - Must consent to allow the acquisition of new tissue biopsy samples during the study Exclusion Criteria: - History of severe hypersensitivity reactions or immune related adverse events to other monoclonal antibodies - History of other active malignancy within the prior 2 years - History of insulin-dependent or uncontrolled Diabetes Mellitus - History of inflammatory bowel disease - Autoimmune disorders - Known HIV and/or Hepatitis B or C infections - Known systemic bleeding or platelet disorder - Receipt of live vaccines with 4 weeks (28 days) of study - History or evidence of non-infectious pneumonitis that required steroids or current pneumonitis Inclusion Criteria: - Males and females ≥18 years of age - Participants in the Dose Escalation portion must have one of the following advanced or recurrent malignancies: gastrointestinal (colorectal or gastric); ovarian; melanoma; non-small cell lung adenocarcinoma; or bladder. --- V600E ---

- Participants in the Monotherapy Expansion Cohort must have one of the following advanced or recurrent malignancies: cutaneous melanoma showing primary progression following treatment with an anti-programmed cell death (PD) or anti-PDL1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Participants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Melanoma with BRAF V600E or V600K mutation-positive melanoma must have progressed on, or were intolerant to, prior BRAF- or MEK-inhibitor therapy - Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with progressing or new tumors since last antitumor therapy - Must have adequate hematologic, renal, and liver function - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Females must not be pregnant (negative human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) or breastfeeding - Women of childbearing potential and male participants must agree to use adequate contraception throughout the study and for up to 180 days after study treatment - An estimated life expectancy of at least 3 months - Must consent to provide an archival tumor biopsy sample at any time point from screening to study exit - Must consent to allow the acquisition of new tissue biopsy samples during the study Exclusion Criteria: - History of severe hypersensitivity reactions or immune related adverse events to other monoclonal antibodies - History of other active malignancy within the prior 2 years - History of insulin-dependent or uncontrolled Diabetes Mellitus - History of inflammatory bowel disease - Autoimmune disorders - Known HIV and/or Hepatitis B or C infections - Known systemic bleeding or platelet disorder - Receipt of live vaccines with 4 weeks (28 days) of study - History or evidence of non-infectious pneumonitis that required steroids or current pneumonitis Non-small Cell Lung Carcinoma (NSCLC) Melanoma Bladder Cancer Colorectal Cancer Gastric Cancer Ovarian Cancer Carcinoma, Non-Small-Cell Lung null --- V600E ---

Primary Outcomes

Measure: Number of participants with Adverse Events (AEs)

Time: From time of first dose until the end of follow-up (up to 123 weeks)

Measure: Number of participants discontinuing study drug due to AEs

Time: From time of first dose until the end of follow-up (up to 105 weeks)

Measure: Number of participants with a Dose Limiting Toxicity (DLT)

Time: From time of first dose until the end of follow-up (up to 12 weeks)

Secondary Outcomes

Measure: Maximum drug concentration in serum/plasma (Cmax)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Time to reach Cmax in serum/plasma (Tmax)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Terminal-phase elimination half-life in serum/plasma (t1/2)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Area under the plasma/serum concentration versus time curve from time zero to the last measured time (AUC 0-T)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Area under the plasma/serum concentration versus time curve from time zero to infinity (AUC 0-∞)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Objective Response Rate (ORR) defined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

Time: From time of screening until the end of follow-up (up to 123 weeks)

Measure: Time from ORR to disease progression or death (DOR)

Time: From time of screening until the end of follow-up (up to 123 weeks)

138 A Phase I/II Study of Concurrent Ipilimumab and Dabrafenib in Unresectable Stage III or Stage IV Melanoma

Phase I/II study of ipilimumab concurrent ipilimumab and dabrafenib as first line treatment in Stage III or IV melanoma. Assessing safety of Ipilimumab and dabrafenib in combination. Also, assessing disease control rates.

NCT02200562
Conditions
  1. Stage III or IV Melanoma
Interventions
  1. Drug: ipilimumab and dabrafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Severity of the AEs will be graded according to the CTCAE version 4.0.. Inclusion Criteria: - For Phase I: Locally advanced or metastatic BRAF V600E/K/R positive melanoma that is either treatment-naïve or treatment-experienced. --- V600E ---

- For phase II: Histological diagnosis of BRAF V600E/K melanoma, unresectable stage III or stage IV, according to the AJCC Staging Manual, 7th Edition, 2011. --- V600E ---

- The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications - Pregnancy or breast feeding - A history of a severe hypersensitivity reaction to ipilimumab or dabrafenib - Any reason why, in the opinion of the investigator, the patient should not participate Inclusion Criteria: - For Phase I: Locally advanced or metastatic BRAF V600E/K/R positive melanoma that is either treatment-naïve or treatment-experienced. --- V600E ---

Primary Outcomes

Description: All patients who receive any study treatment will be included in the final summaries and listings of safety data. Detailed information collected for each AE will include a description of the event, duration, severity, relatedness to study drugs, action taken, and clinical outcome. Severity of the AEs will be graded according to the CTCAE version 4.0.

Measure: Safety of ipilimumab and dabrafenib in combination

Time: Safety analysis will be measured based on frequency and severity of adverse events experienced by patients during the study treatment period which is expected to last about 24 weeks.

139 An Open Label Multicenter, Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma With BRAFv600 Mutated and CDKN2A Loss and Expression of Rb and Treated by Vemurafenib

An open label multicentre, phase I-II study with tumour molecular pharmacodynamics (MPD) evaluation and pharmacokinetics of PD-0332991 added to vemurafenib in patients suffering metastatic melanoma with BR. The main objective is to establish the Maximum Tolerated Dose (MTD) of PD-0332991 when added to standard vemurafenib therapy (960 mg BID). The estimated MTD is defined as the dose of PD-0332991 combined with vemurafenib that will be associated with a prespecified proportion of patients experiencing a Dose-Limiting Toxicity (DLT), ie, 1/3.

NCT02202200
Conditions
  1. Melanoma BRAF V600E/K Mutated
  2. CDNKN2A Loss Defined
Interventions
  1. Drug: PD- 0332991
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Changes from baseline of ANC and platelet levels Efficiency on the cell-cycle machinery and proliferation (tumor sample) Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology) Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).. Inclusion Criteria: - Age > 18 years - Stage IV or un-resectable stage III melanoma - Presence of BRAF V600E/K mutation and CDNKN2A loss and expression of Rb using immunohistochemistry in a recent metastatic sample (< 6 months) - A previous exposure to BRAF inhibitor or combination of BRAF and MEK inhibitors therapy is allowed unless it has been stopped more than 3 months before study enrolment(This will defined the two strata of the trial) - No previous therapy by MEK inhibitor unless associated with BRAF inhibitors - No previous therapy with the AKT/PI3K pathway inhibitor - Patients should have a tumour available for repeated biopsies for pharmacodynamics evaluation - Life expectancy of > 3 months - ECOG performance status <2 - Signed informed consent - Patient with health insurance coverage - No patient under guardianship or curators Exclusion Criteria: - Inadequate hepatic function defined as serum bilirubin>25 μmol/l, transaminases > 3.0 times the upper limit of normal (ULN) or 5ULN in cases of liver metastases; - Inadequate bone marrow function defined as absolute neutrophil count<1500/mcl, platelets<150000/mcl and haemoglobin<8g/dL - Inadequate renal function with serum creatinine>2.0mg/dl) --- V600E ---

- Chemotherapy, immunotherapy within 4 weeks - Drugs interfering with PD-0332991 and vemurafenib metabolism - Malabsorption syndrome or other condition that would interfere with enteral absorption - Congenital long QT syndrome or screening QTc > 470 msec - Need for chronic corticosteroid therapy of ≥10 mg of prednisone per day Inclusion Criteria: - Age > 18 years - Stage IV or un-resectable stage III melanoma - Presence of BRAF V600E/K mutation and CDNKN2A loss and expression of Rb using immunohistochemistry in a recent metastatic sample (< 6 months) - A previous exposure to BRAF inhibitor or combination of BRAF and MEK inhibitors therapy is allowed unless it has been stopped more than 3 months before study enrolment(This will defined the two strata of the trial) - No previous therapy by MEK inhibitor unless associated with BRAF inhibitors - No previous therapy with the AKT/PI3K pathway inhibitor - Patients should have a tumour available for repeated biopsies for pharmacodynamics evaluation - Life expectancy of > 3 months - ECOG performance status <2 - Signed informed consent - Patient with health insurance coverage - No patient under guardianship or curators Exclusion Criteria: - Inadequate hepatic function defined as serum bilirubin>25 μmol/l, transaminases > 3.0 times the upper limit of normal (ULN) or 5ULN in cases of liver metastases; - Inadequate bone marrow function defined as absolute neutrophil count<1500/mcl, platelets<150000/mcl and haemoglobin<8g/dL - Inadequate renal function with serum creatinine>2.0mg/dl) --- V600E ---

- Chemotherapy, immunotherapy within 4 weeks - Drugs interfering with PD-0332991 and vemurafenib metabolism - Malabsorption syndrome or other condition that would interfere with enteral absorption - Congenital long QT syndrome or screening QTc > 470 msec - Need for chronic corticosteroid therapy of ≥10 mg of prednisone per day Melanoma BRAF V600E/K Mutated CDNKN2A Loss Defined Melanoma null --- V600E ---

Primary Outcomes

Description: DLTs, serious adverse events and adverse events leading to treatment discontinuations will be determined as follows: Any grade 3 or more non-haematological toxicity excluding: Grade 3 asymptomatic increase in liver function tests (AST, ALT, ALP) reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement. Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. 5HT3 antagonists and corticosteroids). Grade 3 diarrhoeas if encountered despite adequate and optimal anti diarrhoea therapy. Confirmed grade 3 QTc prolongation (QTc >500 msec) that persists after correction of other possible causes such as electrolyte imbalance Grade 4 hyperlipidemia if it is encountered despite adequate and optimal therapy. Any grade 4 neutropenia of > 5 days duration, or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia > 1 day, or grade 3 with bleeding.

Measure: Occurrence within the first 2 cycles of treatment of a DLT

Time: 42 Days

Secondary Outcomes

Description: Occurrence of clinical benefit (defined as Complete Response (CR), Partial Response (PR) or stable disease (SD)) and progressive disease based on the best overall response which depends on the tumour evaluations assessed using RECIST at the end of each 2 cycles.

Measure: Efficacy

Time: 42 Days

Description: survival

Measure: 1 year survival rate

Time: 1 year

Description: Occurrence of clinically significant changes in a laboratory parameter and/or vital signs judged to be related to the trial medication within the first 6 months.

Measure: Tolerance

Time: 6 months

Other Outcomes

Description: Changes from baseline of ANC and platelet levels Efficiency on the cell-cycle machinery and proliferation (tumor sample) Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology) Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).

Measure: Pharmacodynamic

Time: 42 days

140 Phase I Study of AT13387 in Combination With Dabrafenib and Trametinib in Patients With BRAF-Mutant Melanoma and Other Solid Tumors

This phase I trial studies the side effects and best dose of onalespib when given together with dabrafenib and trametinib in treating patients with BRAF-mutant melanoma or solid tumors that have spread to another place in the body (metastatic) or cannot be removed by surgery. Onalespib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02097225
Conditions
  1. BRAF V600E Mutation Present
  2. BRAF V600K Mutation Present
  3. Metastatic Malignant Solid Neoplasm
  4. Metastatic Melanoma
  5. Stage III Cutaneous Melanoma AJCC v7
  6. Stage IIIA Cutaneous Melanoma AJCC v7
  7. Stage IIIB Cutaneous Melanoma AJCC v7
  8. Stage IIIC Cutaneous Melanoma AJCC v7
  9. Stage IV Cutaneous Melanoma AJCC v6 and v7
  10. Unresectable Solid Neoplasm
Interventions
  1. Drug: Dabrafenib
  2. Other: Laboratory Biomarker Analysis
  3. Drug: Onalespib
  4. Other: Pharmacological Study
  5. Drug: Trametinib
MeSH:Neoplasms Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm Neoplasm of the skin

Will be performed to assess how changes in the expression of the key signaling proteins relate to patient response.. Inclusion Criteria: - Patients must have histologically confirmed, BRAF-mutant (V600E/K) solid tumor (molecularly confirmed using Cobas assay or a comparable Food and Drug Administration [FDA]-approved assay) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF targeted therapy, and for which standard curative measures do not exist or are no longer effective - If test at Clinical Laboratory Improvement Act (CLIA)-certified laboratory (lab) used a non-FDA approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; patients may have received any number of prior lines of therapy, including treatment with a BRAF and/or MEK inhibitor - All prior anti-cancer treatment-related toxicities must be less than or equal to grade 1 according to the Common Terminology Criteria for Adverse Events version 5 (CTCAE version 5.0; National Cancer Institute [NCI], 2017) at the time of enrollment; a notable exception are endocrinopathies caused by immune checkpoint inhibitors that are appropriately treated with medical management (e.g. --- V600E ---

m^2 - Potassium > 3 and < 5.5 mEq/L - Magnesium > 1.2 and < 2.5 mEq - Left ventricular >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) ejection fraction - Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) from 14 days prior to randomization, throughout the treatment period, and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Ability to understand and the willingness to sign a written informed consent document - Able to swallow and retain oral medication, and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Exclusion Criteria: - Patients who received prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to day 1 of cycle 1; patients are permitted to be on dabrafenib and trametinib standard of care at start of therapy without wash-out period prior to day 1 of cycle 1; dosing will change to protocol determined dose levels on day 1 of cycle 1 - Patients must not have received prior HSP90 inhibitor therapy - Patients who are receiving any other investigational agents; patients who have taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization - Patients with history of activating RAS mutation positive tumors regardless of interval from current study; however, patients may have concurrent BRAFV600 and RAS mutations in the tumor to be treated with protocol therapy - Patients must have no clinical evidence of leptomeningeal or brain metastasis causing spinal cord compression that are symptomatic or untreated or not stable for >= 4 weeks (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History of known immediate or delayed hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to AT13387, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO) - Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the mother being treated with the study drugs - Patients known to be human immunodeficiency virus (HIV)-positive patients and on combination antiretroviral therapy are ineligible - History of another malignancy other than the study indication under this trial within 5 years of study enrollment; does not apply to subjects who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, in situ breast cancer, or other in situ cancers - Exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History of interstitial lung disease or pneumonitis - History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): - History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm mercury (Hg) - History or evidence of cardiovascular risk including any of the following: - An average of the three most recent QT intervals corrected for heart rate using the Bazett's formula QTcB >= 460 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - Prior placement of an implantable defibrillator - History of or identification on screening imaging of intracardiac metastases - No known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV); patients with chronic or cleared HBV infection and HCV infection are eligible - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded Inclusion Criteria: - Patients must have histologically confirmed, BRAF-mutant (V600E/K) solid tumor (molecularly confirmed using Cobas assay or a comparable Food and Drug Administration [FDA]-approved assay) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF targeted therapy, and for which standard curative measures do not exist or are no longer effective - If test at Clinical Laboratory Improvement Act (CLIA)-certified laboratory (lab) used a non-FDA approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; patients may have received any number of prior lines of therapy, including treatment with a BRAF and/or MEK inhibitor - All prior anti-cancer treatment-related toxicities must be less than or equal to grade 1 according to the Common Terminology Criteria for Adverse Events version 5 (CTCAE version 5.0; National Cancer Institute [NCI], 2017) at the time of enrollment; a notable exception are endocrinopathies caused by immune checkpoint inhibitors that are appropriately treated with medical management (e.g. --- V600E ---

m^2 - Potassium > 3 and < 5.5 mEq/L - Magnesium > 1.2 and < 2.5 mEq - Left ventricular >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) ejection fraction - Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) from 14 days prior to randomization, throughout the treatment period, and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Ability to understand and the willingness to sign a written informed consent document - Able to swallow and retain oral medication, and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Exclusion Criteria: - Patients who received prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to day 1 of cycle 1; patients are permitted to be on dabrafenib and trametinib standard of care at start of therapy without wash-out period prior to day 1 of cycle 1; dosing will change to protocol determined dose levels on day 1 of cycle 1 - Patients must not have received prior HSP90 inhibitor therapy - Patients who are receiving any other investigational agents; patients who have taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization - Patients with history of activating RAS mutation positive tumors regardless of interval from current study; however, patients may have concurrent BRAFV600 and RAS mutations in the tumor to be treated with protocol therapy - Patients must have no clinical evidence of leptomeningeal or brain metastasis causing spinal cord compression that are symptomatic or untreated or not stable for >= 4 weeks (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History of known immediate or delayed hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to AT13387, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO) - Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the mother being treated with the study drugs - Patients known to be human immunodeficiency virus (HIV)-positive patients and on combination antiretroviral therapy are ineligible - History of another malignancy other than the study indication under this trial within 5 years of study enrollment; does not apply to subjects who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, in situ breast cancer, or other in situ cancers - Exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History of interstitial lung disease or pneumonitis - History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): - History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm mercury (Hg) - History or evidence of cardiovascular risk including any of the following: - An average of the three most recent QT intervals corrected for heart rate using the Bazett's formula QTcB >= 460 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - Prior placement of an implantable defibrillator - History of or identification on screening imaging of intracardiac metastases - No known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV); patients with chronic or cleared HBV infection and HCV infection are eligible - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Malignant Solid Neoplasm Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Solid Neoplasm Neoplasms Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of onalespib (AT13387) given weekly in combination with dabrafenib and trametinib in patients with BRAF-mutant metastatic or unresectable solid tumors. --- V600E ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0. Toxicity rates will be summarized with a 90% exact binomial confidence interval.

Measure: Maximum tolerated dose of onalespib in combination with dabrafenib and trametinib, defined as the highest dose level at which 0 or 1 of six patients has experienced a dose limiting toxicity

Time: 28 days

Secondary Outcomes

Description: The response rate will be presented as a point estimate with a 90% exact binomial confidence interval.

Measure: Objective response rate, defined as the proportion of patients with complete or partial response as their best response to therapy assessed according to Response Evaluation Criteria in Solid Tumors version 1.1

Time: The date of first dose of trial therapy and the date of objectively documented disease progression or cessation of trial therapy, whichever occurs first, assessed up to 28 days after end of treatment

Description: The distribution of progression-free survival will be summarized using the product-limit method of Kaplan-Meier.

Measure: Progression-free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 28 days after end of treatment

Description: Median times for each endpoint will be presented with two-sided, 90% confidence intervals estimated using log(-log[survival]) methodology. Kaplan-Meier estimates of 6-month progression-free survival will also be presented with two-sided, 90% confidence intervals.

Measure: Progression-free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months

Description: The distribution of overall survival will be summarized using the product-limit method of Kaplan-Meier. Kaplan-Meier estimates of 1-year overall survival will also be presented with two-sided, 90% confidence intervals.

Measure: Overall survival

Time: 1 year

Description: The one-year disease-free survival after treatment will be estimated using the product-limit methods of Kaplan-Meier, and presented with 90% confidence intervals.

Measure: Disease-free survival

Time: 1 year

Other Outcomes

Description: Descriptive statistics including mean, standard deviation, coefficient of variation, geometric mean, median, minimum and maximum will be computed for each pharmacokinetic variable; descriptive statistics for natural-log transformed pharmacokinetic variables will also be provided.

Measure: Pharmacokinetic parameters (maximal plasma or serum concentration, area under the curve to the last collection point, area under the curve for dose interval, and time of maximal concentration)

Time: Course 1, days 1 and 15 (pre-dose, 1, 2, 4, 6, 8, 24 hour post-dose) and day 1 in courses 2, 4, 8, and 12 (pre-dose)

Description: Will be performed to assess how changes in the expression of the key signaling proteins relate to patient response.

Measure: Changes in the expression of the key signaling proteins

Time: Baseline to 7 days (1 week)

141 A Phase I Study of the Anti-PD-1 Antibody Nivolumab in Combination With Dabrafenib and/or Trametinib in Patients With BRAF or NRAS-mutated Metastatic Melanoma

This study evaluates nivolumab in combination drug treatments involving 1) nivolumab and dabrafenib 2) nivolumab and trametinib and 3) nivolumab, dabrafenib and trametinib in patients with BRAF or NRAS-mutated metastatic melanoma.

NCT02357732
Conditions
  1. Metastatic Melanoma
Interventions
  1. Drug: Nivolumab
  2. Drug: Trametinib
  3. Drug: Dabrafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.. Inclusion Criteria: - Histologically confirmed metastatic melanoma (Stage IV) or unresectable Stage III melanoma with BRAF V600E/K or NRAS mutations. --- V600E ---

Inclusion Criteria: - Histologically confirmed metastatic melanoma (Stage IV) or unresectable Stage III melanoma with BRAF V600E/K or NRAS mutations. --- V600E ---

Primary Outcomes

Description: It is planned to determine the maximum tolerable dose with a modified version of the standard "up and down" (3+3) dose-finding method using cohorts of 3 patients. At the start of the trial, three patients will be placed on dose level 1. The decision rules based on the observed dose limiting toxicities (DLTs) in this and subsequent cohorts are given. Only DLTs observed in a patient during the first cycle (28 days) will be used for the dose escalation decisions. Patients will be considered evaluable for toxicity if they receive 1 complete cycle of therapy, or if they experience DLT; in-evaluable patients will be replaced.

Measure: To determine the Maximally Tolerated Dose and/or Recommended Phase II Dose (RP2D) of nivolumab in combination with dabrafenib and/or trametinib in patients with BRAF- or NRAS-mutated metastatic melanoma

Time: The first four weeks of dosing

Secondary Outcomes

Description: Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and by the Immune Related Response Criteria. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.

Measure: Antitumor Effects and Immune Related Response

Time: Every twelve weeks for three years while on study drug

142 Study of Circulating Tumor Cells Before and After Treatment in Patients With Metastatic Melanoma.

Circulating tumor cells (CTC) are the subject of increasing interest in clinical oncology as a prognostic factor and predictor of therapeutic response. The detection of CTC by immunomagnetic method has proved its reliability and its usefulness for monitoring breast cancer, colon and prostate in the metastatic and immunomagnetic detection system (CellSearch, Veridex LLC) was approved by the FDA in these indications. However, to date there is no reliable method to detect CTCs in melanoma (CMC). Studies based on PCR amplification of mRNA by reverse specific melanoma is disappointing. Recently, a new detection system of CMC immunomagnetic was presented (CellSearch, Veridex LLC, United States). This system has the advantage of combining immunomagnetic selection step and a step of identifying by immunofluorescence. A preclinical study on serial dilutions of melanoma cells has shown encouraging results. The investigators propose a prospective study of the CellSearch system in patients with melanoma. Primary objective: To determine the effect of treatment on the number of circulating melanoma cells in patients with metastatic melanoma. Secondary objectives: - determine the percentage of patients with metastatic melanoma with melanoma cells circulating - seek a relationship between the number of circulating melanoma cells and prognosis in patients with metastatic melanoma - seek a relationship between the change in the number of circulating melanoma cells before / after treatment and tumor response in patients with metastatic melanoma

NCT01573494
Conditions
  1. Melanoma
Interventions
  1. Other: Sampling of blood
MeSH:Melanoma Neoplastic Cells, Circulating
HPO:Cutaneous melanoma Melanoma

Difference in tumor response between patients according to the variation of circulating melanoma cells/ml before and after treatment.. Inclusion Criteria: - Patients > or = 18 years - Patients with advanced melanoma stage IIIC (unresectable) or stage IV - Patient not treated or not responding to chemotherapy with chemotherapy session last> 1 month - Patients who signed informed consent - Patients presenting no socio-economic, psychological, familial or geographical allow proper understanding of the information leaflet of the protocol or the regular monitoring in the department of dermatology - Patients with a life expectancy greater than 3 months - Patients with melanoma measurable by RECIST version 1.1 - Patients with venous good for venipuncture Exclusion Criteria: - Patients with contraindication for treatment with chemotherapy or V600E BRAF inhibitor or ipilimumab or have conditions concomitant heavy may interfere with the treatment of metastatic melanoma - Pregnant women or nursing - People vulnerable detainees, adults under guardianship or curatorship, minors. --- V600E ---

Inclusion Criteria: - Patients > or = 18 years - Patients with advanced melanoma stage IIIC (unresectable) or stage IV - Patient not treated or not responding to chemotherapy with chemotherapy session last> 1 month - Patients who signed informed consent - Patients presenting no socio-economic, psychological, familial or geographical allow proper understanding of the information leaflet of the protocol or the regular monitoring in the department of dermatology - Patients with a life expectancy greater than 3 months - Patients with melanoma measurable by RECIST version 1.1 - Patients with venous good for venipuncture Exclusion Criteria: - Patients with contraindication for treatment with chemotherapy or V600E BRAF inhibitor or ipilimumab or have conditions concomitant heavy may interfere with the treatment of metastatic melanoma - Pregnant women or nursing - People vulnerable detainees, adults under guardianship or curatorship, minors. --- V600E ---

Primary Outcomes

Description: Measuring the number of circulating melanoma cells/ml in the peripheral blood by the test before and after treatment CellSearch.

Measure: Measuring the number of circulating melanoma cells/ml in blood

Time: baseline and 3 months

Secondary Outcomes

Description: Calculating the number of patients who test positive detection of circulating melanoma cells measured in peripheral blood with the CellSearch test before and after treatment.

Measure: number of patients who test positive detection of circulating melanoma cells measured in peripheral blood with the CellSearch test

Time: 3 months

Description: Difference in survival between patients depending on the number of circulating melanoma cells/ml before treatment, according to Kaplan-Meier method.

Measure: Difference in survival

Time: baseline and 6 months

Description: Difference in tumor response between patients according to the variation of circulating melanoma cells/ml before and after treatment.

Measure: Difference in tumor response

Time: 6 months

143 FOLFOXIRI Plus Bevacizumab as First-line Treatment for BRAF V600E Mutant Metastatic Colorectal Cancer: a Prospective Evaluation

The purpose of this study is to prospectively verify if FOLFOXIRI plus bevacizumab as first-line treatment could be considered a promising approach to improve the outcome of BRAF mutant metastatic colorectal cancer patients

NCT01437618
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: FOLFOXIRI plus bevacizumab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

FOLFOXIRI Plus Bevacizumab as First-line Treatment for BRAF V600E Mutant Metastatic Colorectal Cancer: a Prospective Evaluation. --- V600E ---

Inclusion Criteria: - Histologically confirmed colorectal adenocarcinoma; - Availability of formalin-fixed paraffin embedded tumor block from primary and/or metastasis; - BRAF V600E mutant status of primary colorectal cancer and/or related metastasis; - Unresectable and measurable metastatic disease according to RECIST criteria; - Male or female, aged > 18 years and < 75 years; - ECOG PS < 2 if aged < 71 years; - ECOG PS = 0 if aged 71-75 years; - Life expectancy of more than 3 months; - Adequate haematological function: ANC ≥ 1.5 x 10^9/L; platelets ≥ 100 x 10^9/L, Hb ≥ 9 g/dL; - Adequate liver function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases ≤ 5 x ULN); - Serum creatinine ≤ 1.5 x ULN; - Previous adjuvant chemotherapy is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse; - At least 6 weeks from prior extended radiotherapy and 4 weeks from surgery; - Written informed consent to experimental treatment and molecular analyses. --- V600E ---

Primary Outcomes

Measure: Progression-Free Survival

Time: About 24-30 months (From treatment initiation to evidence of progression or death from any cause)

144 A Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LGX818 in Adult Patients With Locally Advanced or Metastatic BRAF Mutant Melanoma

CLGX818X2101 is a first-time in-human, phase I study to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of daily administered LGX818 (daily, twice daily and/or every-other-day), a RAF kinase inhibitor. Patients with locally advanced or metastatic melanoma harboring the BRAF V600 mutation (during dose escalation phase and expansion phase) and patients with metastatic colorectal cancer harboring the BRAF V600 mutation (during the expansion phase) will be enrolled. The study consists of a dose escalation part were cohorts of patients will receive escalating oral doses of LGX818, followed by a safety dose expansion part were patients will be treated with oral dose of LGX818 given at the MTD or RP2D.

NCT01436656
Conditions
  1. Melanoma and Metastatic Colorectal Cancer
Interventions
  1. Drug: LGX818
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

2. Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation. --- V600E ---

Primary Outcomes

Measure: Incidence of Dose Limiting Toxicities

Time: Approximately every 8 weeks (up to 2 years)

Secondary Outcomes

Measure: Number and nature of Adverse events and clinical activity

Time: Approximately 3 years

Description: LGX818 Plasma concentration

Measure: Pharmacokinetic profile of LGX818

Time: Approximately 2 years

Description: This includes duration of response, time to response, progression free survival and overall survival.

Measure: Tumor response per RECIST

Time: Approximately 3 years

Description: Baseline molecular status (mutation/ amplification/ expression) in tumor tissue of potential predictive markers

Measure: Baseline molecular status

Time: Approximately 3 years

145 Dose-seeking and Efficacy Study of the Combination of the BRAF Inhibitor Vemurafenib and High-dose Interferon Alfa-2b for Therapy of Advanced Melanoma

This is a dose-seeking and efficacy study of combined BRAF Inhibitor Vemurafenib and High-dose Interferon alfa-2b for therapy of advanced melanoma.

NCT01943422
Conditions
  1. Melanoma
Interventions
  1. Drug: High-dose Interferon alfa-2b
  2. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- BRAF V600E and V600K mutated - Cutaneous squamous cell carcinomas (SCC) lesions identified at baseline must be excised. --- V600E ---

Primary Outcomes

Description: At each dose level, the number of patients experiencing Adverse Events over their course of treatment will be characterized by type of Adverse Event and grade using NCI CTCAE (v4.0), and by time of onset in relation to the first day of therapy.

Measure: Number of Participants with Adverse Events to determine Ph II dose

Time: 12-24 months from study start

Secondary Outcomes

Description: •Progression Free Survival will be evaluated at 6 months using the Kaplan-Meier method. Overall Survival will be measured from the initial date of treatment to the recorded date of death, and analyzed similarly to Progression Free Survival. Overall Survival will also be analyzed with the Kaplan-Meier method. The complete response rate and partial response rate will be estimated by the proportion of patients with a best response respectively by RECIST criteria.

Measure: Progression Free and overall survival (Efficacy)

Time: 48 months

Other Outcomes

Description: Melanoma metastases removed from patients pretreatment, post-BRAFI alone and Post B-RAF+ will be analyzed for expression of IFNAR1 and immunologically relevant molecules such as HLA antigens, APM components and MA; these results will be correlated with T cell infiltration. In addition the metastases will be tested for extent of melanoma cell proliferation and apoptosis.

Measure: Improve tumor STAT signaling

Time: 48 months

146 A Phase 1 Study of Dabrafenib in Combination With Lapatinib in BRAF Mutant Thyroid Cancer

This phase I trial studies the side effects and best dose of lapatinib when given together with dabrafenib in treating patients with thyroid cancer that cannot be removed by surgery and has not responded to previous treatment (refractory). Dabrafenib and lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01947023
Conditions
  1. Metastatic Thyroid Gland Carcinoma
  2. Unresectable Thyroid Gland Carcinoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Dabrafenib Mesylate
  3. Drug: Lapatinib
  4. Drug: Lapatinib Ditosylate
MeSH:Carcinoma Thyroid Neoplasms Thyroid Diseases
HPO:Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Mean percentage change is calculated and compared with respect to each genotype.. Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - The effects of dabrafenib on the developing human fetus are unknown; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed due to drug-drug interactions which can render hormonal contraceptives ineffective) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be decreased - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8, since concentrations of dabrafenib may be increased - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dabrafenib, breastfeeding should be discontinued if the mother is treated with dabrafenib; these potential risks may also apply to other agents used in this study Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E ---

Primary Outcomes

Description: Will be defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity MTD is defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity.

Measure: Maximum tolerated dose (MTD) of lapatinib, in combination with the established dose of dabrafenib

Time: First 42 days of treatment

Secondary Outcomes

Description: Tissues such as phosphorylated mitogen-activated protein kinase 1 (ERK), human epidermal growth factor receptor (HER) 2, HER3, epidermal growth factor receptor (EGFR), platelet derived growth factor (PDGF), or protein kinase B (AKT) will be examined. Mean percent change will be calculated and compared.

Measure: Mean percent change in the post-treatment tissues relative to pre-treatment tissues for the phosphorylated protein targets examined

Time: Baseline to day 7 of cycle 1

Description: Genes including sodium/iodide symporter (NIS), dual-specificity phosphatase 5 (DUSP5), and plasminogen activator (PLAT) will be examined. Mean percentage change is calculated and compared with respect to each genotype.

Measure: Mean percentage change in transcript levels in the post-treatment tissues relative to pre-treatment tissues for several genes analyzed by reverse-transcriptase-polymerase chain reaction

Time: Baseline to day 7 of cycle 1

147 The Effect of BRAF Inhibition With Vemurafenib On The Innate and Adaptive Immune Systems in Patients With Unresectable Stage III or Stage IV Melanoma Expressing a V600 BRAF Mutation

Approximately 40-60 % of cutaneous melanomas select for a mutation in a protein called BRAF which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK) pathway. When BRAF is mutated the MAPK pathway remains active allowing for melanoma to grow. Vemurafenib is an oral treatment which blocks the activity of BRAF which leads to decreasing the activity of the MAPK pathway. When patients with melanoma expressing specific mutation in BRAF are treated with vemurafenib approximately 50% will develop a response to treatment with shrinkage of tumor. When compared to a standard chemotherapy called dacarbazine used to treat melanoma, treatment with vemurafenib leads to a statistically significant overall survival or living longer benefit. Because of this survival benefit vemurafenib was Food and Drug Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF mutation called V600E BRAF. There is increasing evidence that the immune system can also be important in affecting melanoma growth and survival and there are immune treatments FDA approved for the treatment of metastatic melanoma. There is some limited evidence that blocking BRAF with vemurafenib may affect the activity of components of the immune system. It is important to better characterize and understand the effects of vemurafenib treatment on various components of the immune system. The purpose of this study is to systematically evaluate the effects of vemurafenib treatment (at FDA approved dosing regimen) on parts of the immune systems called the innate and adaptive immune systems. The hypothesis is that vemurafenib treatment will affect the immune system.

NCT01942993
Conditions
  1. Melanoma
Interventions
  1. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Because of this survival benefit vemurafenib was Food and Drug Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF mutation called V600E BRAF. --- V600E ---

Over 90% of mutations in BRAF occur at position V600 with the most common being a V600E mutation. --- V600E ---

The response rate to treatment with vemurafenib in patients with stage IV melanoma expressing a V600E BRAF mutation is approximately 50%. --- V600E ---

Based on this survival benefit vemurafenib was FDA approved for treatment of stage IV melanoma expressing a V600E BRAF mutation. --- V600E ---

Primary Outcomes

Description: Immuno-fluorescence and flow cytometry will be performed on blood specimens obtained to determine changes in the immune cell signature in the blood on day 8 and day 57 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the Immune Cellular Signature in the Blood Circulation

Time: baseline, day 8, and day 57

Secondary Outcomes

Description: Immuno-fluorescence and flow cytometry will be performed on tumor specimens obtained to determine changes in the immune cell signature in the tumor on day 8-10 and day 57 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the Immune Cellular Signature in the Tumor

Time: baseline, day 8-10, and day 57

Description: Global changes in the blood transcriptome in response to vemurafenib therapy will be performed using gene expression arrays. Change in the blood transcriptosome on day 8 and day 57 as compared to baseline.

Measure: Changes in Transcriptional Profile in the Blood

Time: baseline, day 8, and day 57

Description: Global changes in the transcriptosome of tumor associated immune cells in response to therapy will be performed using gene expression arrays. The transcriptosome in tumor will be compared on purified tumor immune cells obtained from a pretreatment tumor biopsy performed at baseline and a second biopsy obtained after starting treatment and obtained between days 8-10.

Measure: Change in Transcriptional Profile in Tumor

Time: baseline and day 8-10

Description: change in dendritic cell function at day 8 and day 57 as compared to baseline

Measure: Changes in Dendritic Cell Function in Blood

Time: baseline day 8, and day 57

Description: Changes in dendritic cell function in tumor on day 8-10 as compared to baseline

Measure: Changes in Dendritic Cell Function in Tumor

Time: baseline and day 8-10

Description: Changes in macrophage function in blood at day 8 and day 57 as compared to baseline

Measure: Changes in Macrophage Function in Blood

Time: baseline, day 8, and day 57

Description: changes in macrophage function in tumor on day 8-10 as compared to baseline

Measure: Changes in Macrophage Function in Tumor

Time: baseline and day 8-10

Description: changes in global T cell function in blood on day 8 and day 57 as compared to baseline

Measure: Changes in Global T Cell Function in Blood

Time: baseline, day 8, and day 57

Description: Changes in Global T cell function in Tumor on day 8 as compared to baseline

Measure: Changes in Global T Cell Function in Tumor

Time: baseline and day 8-10

Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 8, day 15 and day 126 as compared to baseline

Measure: Changes in Tumor Antigen Specific T Cell Function in Blood

Time: baseline, day 8, day 15 and day 126

Description: Changes in Histocytometry of tumor on day 8-10 as compared to baseline. Histocytometry is a novel microscopic analytical method (Gerner et al. 2012) which combines the advantages of flow cytometry and Microscopic techniques. This techniques allows for the visualization and quantification of phenotypically complex cellular subsets and provides spatial and cell-cell interactions.

Measure: Changes in Histocytometry of Tumor

Time: baseline and day 8-10

Description: Response to vemurafenib treatment based on changes in tumor burden using CT or MRI imaging studies. Response are categorized as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD),

Measure: Response to Vemurafenib Treatment

Time: up to 57 days

Description: Number of participants who developed cutaneous squamous cell carcinomas while on the study

Measure: Number of Participants Who Developed of Cutaneous Squamous Cell Carcinomas

Time: up to 5 months

148 A Sequential Safety and Biomarker Study of BRAF-MEK Inhibition on the Immune Response in the Context of Combined CTLA-4 Blockade and PD-1 Blockade for BRAF Mutant Melanoma

This randomized phase I trial studies the side effects and best way to give ipilimumab with or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating melanoma.

NCT01940809
Conditions
  1. BRAF V600E Mutation Present
  2. BRAF V600K Mutation Present
  3. Metastatic Melanoma
  4. Stage III Cutaneous Melanoma AJCC v7
  5. Stage IIIA Cutaneous Melanoma AJCC v7
  6. Stage IIIB Cutaneous Melanoma AJCC v7
  7. Stage IIIC Cutaneous Melanoma AJCC v7
  8. Stage IV Cutaneous Melanoma AJCC v6 and v7
Interventions
  1. Drug: Dabrafenib
  2. Biological: Ipilimumab
  3. Other: Laboratory Biomarker Analysis
  4. Biological: Nivolumab
  5. Drug: Trametinib
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.. Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma. --- V600E ---

Primary Outcomes

Description: Presented with 90% confidence intervals calculated using exact binomial methods.

Measure: Incidence of grade 3 or higher immune-related adverse events (irAEs), graded according to the National Cancer Institute (NCI) CTCAE v4.0

Time: Up to 3 weeks after end of ipilimumab induction

Secondary Outcomes

Description: Presented with 90% confidence intervals calculated using exact binomial methods by randomized treatment arm.

Measure: Proportion of patients receiving dabrafenib and trametinib with grade 3 or higher irAEs after disease progression on ipilimumab, according to the NCI CTCAE v4.0

Time: Up to 4 weeks after completion of study treatment

Description: Summarized by treatment arm and presented with 90% exact binomial confidence intervals. Fisher's exact test will be used.

Measure: Response rate for the total treatment period according to Response Evaluation Criteria in Solid Tumors v1.1

Time: Up to 4 weeks after completion of study treatment

Description: Summarized by treatment arm and presented with 90% exact binomial confidence intervals. Fisher's exact test will be used.

Measure: Disease-control rate

Time: Up to 4 weeks after completion of study treatment

Other Outcomes

Description: The relationship between pre-treatment marker levels and response will be assessed according to expression cut-off between positive and negative. Fisher's exact test will be used to detect an increase in response rate and a secondary, sensitivity analysis will use a stratified Fisher's exact test.

Measure: Biomarker expression levels

Time: Baseline

Description: Biomarkers measured on a continuous scale will be summarized and compared across response categories using the Wilcoxon rank-sum test. For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.

Measure: Fold-changes in biomarkers

Time: Baseline to 3 weeks after fourth ipilimumab dose

Description: Biomarkers measured on a continuous scale will be summarized and compared across response categories using the Wilcoxon rank-sum test. For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.

Measure: Change in immune activation, measured by changes in biomarker levels

Time: Baseline to 3 weeks after fourth ipilimumab dose

149 A Phase II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Regorafenib in Patients With Metastatic Colorectal Cancer Who Have Failed First-line Therapy

In recent years, anti-angiogenic agents have been incorporated into clinical practice for the treatment of metastatic CRC, leading to improvements in progression-free survival and overall survival. Regorafenib is an oral multi-kinase inhibitor that targets angiogenic and oncogenic kinases. Although structurally similar to another multi-kinase inhibitor, sorafenib, it appears to be pharmacologically more potent and possesses broader antiangiogenic properties. Both sorafenib and regorafenib target BRAF wild-type and BRAF V600E mutant but the inhibition of p38 MAP kinase is a peculiar characteristic of regorafenib. A Phase I study of regorafenib as a single agent in patients with heavily pretreated CRC showed promising clinical activity with a disease control rate (PR + SD) of 59% in evaluable patients. In the Phase III trial (CORRECT), which was a randomized double-blind, placebo-controlled study comparing either regorafenib plus best supportive care (BSC) or placebo plus BSC, it was shown that regorafenib significantly increased overall survival (OS), progression-free survival (PFS) and disease control rate (DCR), independently of KRAS status. A major interest, given the data presented in the CORRECT trial, is to determine predictive biomarkers to indicate patients likely to benefit, or to be resistant to this anti-angiogenic compound. This study aims to determine the efficacy of regorafenib as single-agent treatment for the treatment of second-line metastatic colorectal cancer and to identify predictive biomarkers in the actual metastatic tumors to be treated. In the case of metastatic CRC patients, liver lesions are frequently the most common site of metastatic deposit and these lesions can be biopsied to assess putative biomarkers. Patients will be asked to undergo a biopsy of a metastatic lesion prior to treatment, and an optional liver biopsy at the time of relapse. Using several high-throughput discovery platforms, biomarkers will be identified in the metastatic tumor specimens and in blood samples collected throughout the treatment. This will allow us to evaluate putative biomarkers and monitor tumor biomarker dynamics using serial blood collection. The objectives of this trial are to help identify the patient subgroup most likely to be responsive or resistant to regorafenib, so that future treatment with regorafenib can be directed to the more responsive but as yet identified patient population.

NCT01949194
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: Regorafenib
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Both sorafenib and regorafenib target BRAF wild-type and BRAF V600E mutant but the inhibition of p38 MAP kinase is a peculiar characteristic of regorafenib. --- V600E ---

Primary Outcomes

Description: A biopsy from a liver metastasis will be taken at baseline for discovery of biomarkers that correlate with response to regorafenib. Genomic material (DNA and RNA) will be isolated from all biopsies. Those that pass quality control (high quality DNA, RNA and >60% tumor content) will be considered evaluable. Batched analysis will be performed at the end of the study with the evaluable samples for multiplex biomarker discovery. Patient's biomarker status at baseline will be correlated with treatment effect on PFS and response (including response rate and disease control rate) to explore which biological targets may be particularly important in defining the appropriate treatment population for regorafenib.

Measure: A biomarker (in blood or tissue) that may be predictive of level of response to regorafenib

Time: 4 years

Secondary Outcomes

Description: Assessment of safety profile of regorafenib in treated patients : report of Adverse Events according to the The NCI's Common Toxicity Criteria version 4.0

Measure: Number of participants with adverse events

Time: Up to 3 years

Description: The time from the date of registration until the date of radiological disease progression assessed by RECIST 1.1 or until death due to any cause, even in the absence of radiological progression.

Measure: Progression free survival (PFS) time

Time: Time from registration to progressive disease (up to 3 years)

Description: Determination of the objective response rate (ORR: CR (complete response) +PR (partial response) +SD (stable disease)) of treated patients according to RECIST 1.1 criteria.

Measure: Objective Response Rate (RR)

Time: Up to 3 years

150 Screening Protocol to Detect BRAF V600 Mutation-Positive Patients for Enrollment Into Clinical Research Studies of Vemurafenib

This is a screening study to detect BRAF V600 mutation-positive patients for enrollment into clinical research studies of Zelboraf (vemurafenib). Tumor samples will be collected and analyzed from eligible patients with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma. All institutions with identified patients as defined by this screening protocol will have potential access to the separate vemurafenib protocol MO28072.

NCT01804140
Conditions
  1. Multiple Myeloma, Neoplasms
MeSH:Multiple Myeloma
HPO:Multiple myeloma

V600E, V600K, V600D, and V600R are the different types of BRAF V600 mutations.. Inclusion Criteria: - Histologically confirmed solid tumors (excluding melanoma and papillary thyroid cancer) or multiple myeloma refractory to standard therapy or for which standard or curative therapy does not exist or is not considered appropriate by the investigator - Patients with multiple myeloma must have received at least one line of prior systemic therapy for the treatment of multiple myeloma Exclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status > 2 - Uncontrolled concurrent malignancy - Active or untreated CNS metastases - History of known carcinomatous meningitis - Prior treatment with a BRAF or MEK inhibitor (prior sorafenib is allowed) - Uncontrolled, severe medical illness or condition as defined in protocol MO28072 Inclusion Criteria: - Histologically confirmed solid tumors (excluding melanoma and papillary thyroid cancer) or multiple myeloma refractory to standard therapy or for which standard or curative therapy does not exist or is not considered appropriate by the investigator - Patients with multiple myeloma must have received at least one line of prior systemic therapy for the treatment of multiple myeloma Exclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status > 2 - Uncontrolled concurrent malignancy - Active or untreated CNS metastases - History of known carcinomatous meningitis - Prior treatment with a BRAF or MEK inhibitor (prior sorafenib is allowed) - Uncontrolled, severe medical illness or condition as defined in protocol MO28072 Multiple Myeloma, Neoplasms Multiple Myeloma null --- V600E ---

Primary Outcomes

Description: Formalin-fixed paraffin-embedded (FFPEs) tumor samples (at least 5 serially-cut, unstained, 5 micrometer [μm] sections) were collected from eligible participants who consented to participate in the study. FFPE tumor samples were either from archived sections (from the initial diagnosis of cancer) or from fresh biopsies that were performed according to local standards. Tumor samples were then sent to a central laboratory to identify activating BRAF V600 mutations. Identification of mutations was done using bidirectional direct Sanger sequencing procedure.

Measure: Percentage of Participants With BRAF V600 Mutation Positivity in Tumor Samples by Cancer Type

Time: Up to 1 year

Description: FFPEs tumor samples (at least 5 serially-cut, unstained, 5 μm sections) were collected from eligible participants who consented to participate in the study. FFPE tumor samples were either from archived sections (from the initial diagnosis of cancer) or from fresh biopsies that were performed according to local standards. Tumor samples were then sent to a central laboratory to identify activating BRAF V600 mutations. Identification of mutations was done using bidirectional direct Sanger sequencing procedure. V600E, V600K, V600D, and V600R are the different types of BRAF V600 mutations.

Measure: Number of Participants Classified Based on Different Types of BRAF V600 Mutation Patterns in Tumor Samples

Time: Up to 1 year

151 Phase II, Open-label, Single Arm, Multicenter Study of Encorafenib, Binimetinib Plus Cetuximab in Subjects With Previously Untreated BRAF V600E -Mutant Metastatic Colorectal Cancer

The purpose of this study is to evaluate the efficacy and safety of the combination of study drugs encorafenib, binimetinib and cetuximab in patients who have BRAF V600 mutant metastatic colorectal cancer and have not received any prior treatment for their metastatic disease.

NCT03693170
Conditions
  1. BRAF V600E-mutant Metastatic Colorectal Cancer
Interventions
  1. Drug: encorafenib
  2. Drug: Binimetinib
  3. Drug: Cetuximab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Phase II, Open-label, Single Arm, Multicenter Study of Encorafenib, Binimetinib Plus Cetuximab in Subjects With Previously Untreated BRAF V600E -Mutant Metastatic Colorectal Cancer. --- V600E ---

Change in the Quality of Life Questionnaire for Cancer subjects.. Inclusion Criteria: - Male or female ≥ 18 years of age - Histologically or cytologically confirmed CRC that is metastatic - Presence of BRAF V600E in tumor tissue determined by local assay at any time prior to screening and confirmed by central laboratory - Evidence of measurable disease as per RECIST, v1.1 - Subject able to receive cetuximab as per approved label with regards to RAS status - ECOG Status 0 or 1 - Adequate renal, hepatic, cardiac and bone marrow functions and adequate electrolytes as per protocol - Subject able to take oral medications Exclusion Criteria: - Prior systemic therapy for metastatic disease - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other anti-EGFR inhibitors - Symptomatic brain metastasis or Leptomeningeal disease - History or current evidence of Retinal Vein Occlusion (RVO) or current risk factors for RVO - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to first dose. --- V600E ---

- Impaired cardiovascular function or clinically significant cardiovascular diseases: history of myocardial infarction or coronary disorders within 6 months prior to start of study treatment, symptomatic congestive heart failure (grade 2 or higher), past or current clinically significant arrhythmia and/or conduction disorder within 6 months prior to study treatment start - History of thromboembolic or cerebrovascular events within 6 months prior to start of study treatment - Concurrent neuromuscular disorder that is associated with potential elevation of Creatine Kinase - Known contraindication to cetuximab administration as per SPC/approved label Inclusion Criteria: - Male or female ≥ 18 years of age - Histologically or cytologically confirmed CRC that is metastatic - Presence of BRAF V600E in tumor tissue determined by local assay at any time prior to screening and confirmed by central laboratory - Evidence of measurable disease as per RECIST, v1.1 - Subject able to receive cetuximab as per approved label with regards to RAS status - ECOG Status 0 or 1 - Adequate renal, hepatic, cardiac and bone marrow functions and adequate electrolytes as per protocol - Subject able to take oral medications Exclusion Criteria: - Prior systemic therapy for metastatic disease - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other anti-EGFR inhibitors - Symptomatic brain metastasis or Leptomeningeal disease - History or current evidence of Retinal Vein Occlusion (RVO) or current risk factors for RVO - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to first dose. --- V600E ---

- Impaired cardiovascular function or clinically significant cardiovascular diseases: history of myocardial infarction or coronary disorders within 6 months prior to start of study treatment, symptomatic congestive heart failure (grade 2 or higher), past or current clinically significant arrhythmia and/or conduction disorder within 6 months prior to study treatment start - History of thromboembolic or cerebrovascular events within 6 months prior to start of study treatment - Concurrent neuromuscular disorder that is associated with potential elevation of Creatine Kinase - Known contraindication to cetuximab administration as per SPC/approved label BRAF V600E-mutant Metastatic Colorectal Cancer Colorectal Neoplasms The presence of a BRAFV600E mutation is considered a marker of poor prognosis in subjects with mCRC. --- V600E ---

Primary Outcomes

Description: Assessment of tumor evaluation change from baseline

Measure: Confirmed Overall Response Rate (cORR) based on local tumor assessments

Time: Duration of the study, approximately 25 months

Secondary Outcomes

Description: Percentage of subjects with complete response (CR) and partial response (PR)

Measure: Confirmed Overall Response Rate (cORR) based on central tumor assessment

Time: globally assessed by subject based on tumor evaluations every 6 weeks for the first 12 weeks and then every 8 weeks.

Description: Percentage of subjects with complete response (CR) and partial response (PR)

Measure: Overall response (ORR) based on local tumor assessments

Time: Globally assessed by subject based on tumor evaluations every 6 weeks for the first 12 weeks and then every 8 weeks.

Description: Percentage of subjects with complete response (CR) and partial response (PR)

Measure: Overall response (ORR) based on central tumor assessments

Time: Globally assessed by subject based on tumor evaluations every 6 weeks for the first 12 weeks and then every 8 weeks.

Description: Time from first radiographic evidence of response assessed based on local radiologist/investigator review to the earliest documented PD or death due to underlying disease

Measure: Duration of Response (DOR) per local assessment

Time: Duration of study approximately 25 months

Description: Time from first radiographic evidence of response review to the earliest documented PD or death due to underlying disease

Measure: Duration of Response (DOR) per central assessment

Time: Duration of study approximately 25 months

Description: Time from first dose until first documented radiographic evidence of response of CR or PR

Measure: Time to Response (TTR) per local review

Time: Duration of study approximately 25 months

Description: Time from first dose until first documented radiographic evidence of response of CR or PR

Measure: Time to Response (TTR) per central review

Time: Duration of study approximately 25 months

Description: Time from first dose to the earliest documented date of disease progression or death due to any cause

Measure: Progression of Free Survival (PFS) per local review

Time: Duration of study approximately 25 months

Description: Time from first dose to the earliest documented date of disease progression or death due to any cause

Measure: Progression of Free Survival (PFS) per central review

Time: Duration of study approximately 25 months

Description: Time from first dose to death due to any cause

Measure: Overall Survival (OS)

Time: Duration of study approximately 25 months

Measure: Safety through the incidence of adverse events

Time: Duration of study approximately 25 months

Description: Plasma concentration of encorafenib

Measure: Plasma concentration of encorafenib

Time: 2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)

Description: Plasma concentration of binimetinib

Measure: Plasma concentration of binimetinib

Time: 2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)

Description: Plasma concentration of cetuximab

Measure: Plasma concentration of cetuximab

Time: 2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)

Description: Change in the Quality of Life Questionnaire for Cancer subjects.

Measure: Comparison of Quality of Life from Baseline to end of the study

Time: At screening, at Cycle 1 Day 1 and at the end of the study (each cycle is 28 days)

152 COMBI-APlus: Open-label, Phase IIIb Study of Dabrafenib in COMBInation With Trametinib in the Adjuvant Treatment of Stage III BRAF V600 Mutation-positive Melanoma After Complete Resection to Evaluate the Impact on Pyrexia Related Outcomes of an Adapted Pyrexia AE-management Algorithm (Plus)

This is an open-label Phase IIIb study of dabrafenib in combination with trametinib in the adjuvant treatment of melanoma after complete resection to evaluate the impact on pyrexia related outcomes of an adapted pyrexia AE-management algorithm, as well as safety, efficacy and health-related outcomes. Approximately 600 subjects will be enrolled to receive dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination therapy for 12 months. At enrollment, subjects will be instructed on the pyrexia management algorithm. This study consists of two Periods for Enrolled subjects: - Treatment Period - subjects will receive up to 12 months of treatment. - Follow-up Period - subjects will be followed through 24 months from their first dose date for relapse, and through end of study for overall survival. Follow-up will start once treatment is complete or is prematurely discontinued and continue through the end of the study, regardless of disease recurrence.

NCT03551626
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Melanoma Fever
HPO:Cutaneous melanoma Fever Melanoma

Higher scores represent a better quality of life.. Inclusion Criteria: - Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)] - V600E/K mutation positive using a validated local test - Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. --- V600E ---

Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ - History or current evidence of cardiovascular risk - A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy Inclusion Criteria: - Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)] - V600E/K mutation positive using a validated local test - Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. --- V600E ---

Primary Outcomes

Description: The composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia by 12 months in overall treated subjects

Measure: Change from baseline in composite rate of pyrexia related events

Time: Baseline up to 12 months

Secondary Outcomes

Description: RFS is defined as the time from the date of first dose of the study medication to the date of disease recurrence or death due to any cause.

Measure: Relapse free survival (RFS) from the first dose to disease recurrence or death from any cause

Time: Baseline up to approximately 24 months

Description: OS is defined as the time from date of the first dose of study medication to date of death due to any cause.

Measure: Overall Survival (OS) from the first dose to date of death due to any cause

Time: Baseline up to approximately 24 months

Description: Percentage of patients who experienced pyrexia and required intervention

Measure: Percentage of patients who require management of pyrexia

Time: Baseline up to 12 months

Description: Participants who permanently discontinued treatment due to any Adverse event during treatment

Measure: The percentage of participants who permanently discontinued treatment due to any Adverse event

Time: Baseline up to 12 months

Description: QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes the FACT-Melanoma subscale (FACT-M MS) questionnaire -specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life.

Measure: Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M MS)

Time: Baseline up to 24 months

153 Study of the Variations of Albumin Level for Patients With Unresecable Stage IIIc or Stage IV Melanoma Treated by Anti BRAF and Anti MEK

The therapeutic arsenal of metastatic melanoma has changed considerably over the past 10 years. The treatment of metastatic melanoma is now based on immunotherapy and targeted therapies, while the place of conventional chemotherapy becomes more restricted. Targeted therapies are indicated for BRAF mutated melanomas. The mutation BRAF leads activation of MAP Kinases pathway and the proliferation of melanoma cell in the body . About 50% of metastatic melanoma is BRAF mutated. The most frequent mutation is the V600E. The targeted therapy by anti BRAF and anti MEK allows the double bloking of the MAP Kinases pathway. This treatment is more efficient than that of the anti BRAF alone. The association of anti BRAF and anti MEK have a global survival global rate of 41% at the 1 year, against 9% for the anti BRAF . In 2014, a program of extended access to the association of anti BRAF and anti MEK (dabrafenib and trametinib) started in many french hospitals (Protocol Mekinist, Novartis laboratory). Patients who were included in this program and followed in Poitiers Hospital, had frequent abnormalities of albumin level without any sign of undernutrition. Hypoabuminemia is a poor prognosis factor described in many cancers, including metastatic melanoma. The only prognostic factor in metastatic melanoma is the rate of LDH . The level of albumin and its prognostic impact have not been studied for patients with a metastatic melanoma and treated by anti BRAF and anti MEK. The objective of this studie was to analyze the variations of albumin level in patients with unresecable stage IIIc or stage IV melanoma treated in our Center by dabrafenib and trametinib

NCT03553329
Conditions
  1. Unresecable Stage IIIc or IV Melanoma
Interventions
  1. Drug: dabrafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

The most frequent mutation is the V600E. --- V600E ---

Primary Outcomes

Description: Biological assessment

Measure: Analyze the variations of albumin level in patients with unresecable stage IIIc or stage IV melanoma treated by dabrafenib and trametinib

Time: 1 months

Description: Biological assessment

Measure: Analyze the variations of albumin level in patients with unresecable stage IIIc or stage IV melanoma treated by dabrafenib and trametinib

Time: 3 months

154 A Phase 1, Open-Label, Dose-Finding Study Of ASN007 In Patients With Advanced Solid Tumors

The study is divided into two parts. The first part of the study will test various doses of ASN007 to find out the highest safe dose to test in five specific groups. The second part of the study will test how well ASN007 can control cancer.

NCT03415126
Conditions
  1. Cancer
  2. Malignancy
  3. Neoplasia
  4. Neoplasm
  5. Neoplasm Metastasis
  6. Colon Cancer
  7. Colonic Neoplasms
  8. Colon Cancer Liver Metastasis
  9. Metastatic Cancer
  10. Metastatic Melanoma
  11. Metastatic Colon Cancer
  12. Metastatic Lung Cancer
  13. Non Small Cell Lung Cancer Metastatic
  14. Pancreatic Cancer
  15. Pancreas Cancer
  16. Pancreas Adenocarcinoma
  17. Pancreas Neoplasm
  18. Metastatic Nonsmall Cell Lung Cancer
  19. Metastatic Pancreatic Cancer
Interventions
  1. Drug: ASN007: ascending doses
  2. Drug: ASN007 RD
MeSH:Lung Neoplasms Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Pancreatic Neoplasms Colonic Neoplasms
HPO:Colon cancer Neoplasm Neoplasm of the colon Neoplasm of the lung Neoplasm of the pancreas Non-small cell lung carcinoma

Group 6: Patients with metastatic MEK1, BRAF V600E, non-BRAF V600E solid tumors or BRAF fusions without prior treatment with BRAF, MEK, ERK inhibitors --- V600E ---

Group 6: Patients with metastatic MEK1, BRAF V600E, non-BRAF V600E solid tumors or BRAF fusions without prior treatment with BRAF, MEK, ERK inhibitors --- V600E --- --- V600E ---

Primary Outcomes

Description: The MTD will be determined by evaluating the number of subjects with treatment related dose limiting toxicity. This is the primary endpoint of Part A

Measure: Part A: Determine the maximum tolerated dose (MTD) of ASN007

Time: First 21 days

Description: This is the primary endpoint for Part B.

Measure: Part B: evaluate the overall response rate (number of Complete Responses + Partial Responses) in subjects receiving ASN007 for the treatment of metastatic melanoma, CRC, NSCLC, or pancreatic cancer.

Time: First 6 months

Secondary Outcomes

Description: Calculate the amount of ASN007 in the bloodstream

Measure: Calculate the pharmacokinetic area under the plasma concentration (AUC) of ASN007

Time: First 21 days

Description: Calculate the maximum amount of ASN007 in the bloodstream

Measure: Calculate the maximum plasma concentration (Cmax) at steady state.

Time: First 21 days

Description: Calculate how fast ASN007 leaves the body

Measure: Calculate the terminal elimination rate (T 1/2).

Time: First 21 days

Other Outcomes

Description: Evaluate the effect of ASN007 on biomarkers

Measure: To evaluate the change from baseline in the intensity of phosphorylated ribosomal S6 kinase (RSK) found in tumor biopsies.

Time: Through the study, average 6 months

Description: Evaluate the effect of ASN007 on biomarkers

Measure: Evaluate the change from baseline in the amount of circulating tumor DNA

Time: Every 8 weeks for the first 24 weeks, then every 12 weeks for up to 1 year

155 A Phase 2 Study of MLN4924 (Pevonedistat) in Combination With Carboplatin and Paclitaxel in Advanced NSCLC Previously Treated With Immunotherapy

This phase II trial studies how well MLN4924 (pevonedistat), carboplatin, and paclitaxel work in treating patients with stage IIIB or IV non-small cell lung cancer. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pevonedistat together with carboplatin and paclitaxel may work better in treating patients with non-small cell lung cancer when compared with other standard chemotherapy drugs.

NCT03965689
Conditions
  1. Metastatic Lung Non-Small Cell Squamous Carcinoma
  2. Metastatic Lung Non-Squa
  3. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  4. Stage IIIB Lung Cancer AJCC v8
  5. Stage IV Lung Cancer AJCC v8
  6. Stage IVA Lung Cancer AJCC v8
  7. Stage IVB Lung Cancer AJCC v8
  8. Unresectable Lung Non-Small Cell Carcinoma
  9. Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
Interventions
  1. Drug: Carboplatin
  2. Drug: Paclitaxel
  3. Drug: Pevonedistat
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Squamous cell carcinoma

sensitizing EGFR, ALK, ROS1, NTRK, BRAF V600E mutation positive) must have received prior treatment with Food and Drug Administration (FDA) approved targeted therapy for patients for which FDA approved targeted therapies is available. --- V600E ---

Primary Outcomes

Description: Defined as the proportion of evaluable subjects with a response. Response will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Patients will be re-evaluated for response every 6 weeks. The number and frequencies of responses will be summarized in tabular format. The ORR will be calculated and reported along with the corresponding 95% confidence interval which will be constructed using the Wilson score method.

Measure: Overall response rate (ORR)

Time: Up to 5 years

Secondary Outcomes

Description: Will be analyzed using the Kaplan-Meier method. Median PFS will be calculated along with the corresponding 95% confidence interval which will be constructed using the non-parametric Brookmeyer-Crowley method.

Measure: Progression free survival (PFS)

Time: From the start of treatment to time of progression or death, whichever occurs first, assessed for up to 5 years

Description: Defined as the duration of time from start of treatment to time of death. Analyzed using the Kaplan-Meier method. Median OS will be calculated along with the corresponding 95% confidence interval which will be constructed using the non-parametric Brookmeyer-Crowley method.

Measure: Overall survival (OS)

Time: From the start of treatment to time of death; assessed for up to 5 years

Description: Evaluated by type and severity using the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All toxicities observed will be summarized in terms of types and severity. Toxicities will be tabulated and summarized by organ systems. Incidence rates of toxicities will be analyzed descriptively.

Measure: Incidence of adverse events

Time: Up to 5 years

Other Outcomes

Description: Summarized using descriptive statistics. Ratios of the day 1 pre-treatment over the 6 hours post-infusion levels will be calculated and reported along with the corresponding 95% confidence intervals. A one sample t-test or Wilcoxon Signed Rank test will be used to evaluate changes from the day 1 pre-treatment to the 6 hours post-infusion assessment. A two-sample t-test or nonparametric Wilcoxon Rank Sum test will be used to compared changes in NQO1 expression levels from day 1 pre-treatment to 6 hours post-infusion between responders and non-responders.

Measure: NQO1 expression levels

Time: Day 1 pre-treatment and 6 hours post-infusion

Description: Summarized using descriptive statistics. Ratios of the day 1 pre-treatment over the 6 hours post-infusion levels will be calculated and reported along with the corresponding 95% confidence intervals. A one sample t-test or Wilcoxon Signed Rank test will be used to evaluate changes from the day 1 pre-treatment to the 6 hours post-infusion assessment. A two-sample t-test or nonparametric Wilcoxon Rank Sum test will be used to compared changes in SLC7A11 expression levels from day 1 pre-treatment to 6 hours post-infusion between responders and non-responders.

Measure: SLC7A11 expression levels

Time: Day 1 pre-treatment and 6 hours post-infusion

Description: Qualitative assessment of tumor NAE1 expression will be conducted by evaluating descriptive summaries of NAE1 expression levels. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: NAE1 expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Qualitative assessment of tumor UBC12 expression will be conducted by evaluating descriptive summaries of UBC12 expression levels. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: UBC12 expression level

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: A linear mixed effects model with patient -specific random effects will be utilized to compared changes in RAD51. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: RAD51 in CTCs

Time: Baseline and after treatment with pevonedistat

Description: A linear mixed effects model with patient -specific random effects will be utilized to compared changes in gammaH2AX. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: GammaH2AX in circulating tumor cells (CTCs)

Time: Baseline and after treatment with pevonedistat

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: ATF3 expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: B2M expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: GCLM expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: GSR expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: MAG1 expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: RPLP0 expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: SRXN1 expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: TXNRD1 expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, and ranges, stratified by assessment time point. Changes from the pre-treatment to post-infusion assessment will be evaluated using a paired t-test or nonparametric Wilcoxon Signed Rank test.

Measure: UBC expression levels

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

Description: Summarized in terms of means, standard deviations, medians, and ranges, stratified by assessment time point. Changes in PK parameters between assessment time points will be evaluated using a paired t-test.

Measure: Pharmacokinetics (PK) parameters

Time: Pre-treatment and 6 hours post-infusion on cycle 1, day 1

156 A Phase Ia/Ib, Open Label, Dose-escalation Study of the Combination of BI 907828 With BI 754091 and BI 754111, Followed by Expansion Cohorts, in Patients With Advanced Solid Tumors

Phase Ia - Dose Escalation The main objective of the dose-escalation part is to determine the maximum tolerated dose (MTD) of BI 907828 in combination with BI 754091 and BI 754111, based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 907828 in combination with BI 754091 and BI 754111, and to evaluate safety and tolerability of BI 907828 in combination with BI 754091 and BI 754111 by monitoring the occurrence and severity of adverse events (AEs). The secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 907828, BI 754091 and BI 754111 based on Cmax and AUC0-tz, and the preliminary assessment of anti-tumor activity. Phase Ib - Dose Expansion The main objective of the dose-expansion part is to assess the preliminary efficacy of the combination of BI 907828, BI 754091, and BI 754111. The secondary and further objectives are to further assess the safety, the PK profiles at the recommended dose for expansion (RDE), and to determine the Recommended Phase II Dose (RP2D).

NCT03964233
Conditions
  1. Neoplasms
Interventions
  1. Drug: BI 907828
  2. Drug: BI 754091
  3. Drug: BI 754111

Patients with NSCLC harboring genomic aberrations for which FDA approved targeted therapy is available such as non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS re-arrangement, and BRAF V600E mutation, must have received prior treatment with FDA-approved targeted therapy. --- T790M --- --- V600E ---

Primary Outcomes

Measure: Phase Ia - maximum tolerated dose (MTD) of BI 907828 in combination with BI 754091 and BI 754111 based on the number of patients with DLTs during the first treatment cycle

Time: Up to 35 Days

Measure: Phase Ib - Objective response (OR)

Time: Up to 24 months

Secondary Outcomes

Measure: Phase Ia - Cmax : Maximum measured plasma concentration of BI 907828, BI 754091, and BI 754111 (during the first cycle)

Time: Up to 21 Days

Measure: Phase Ia - AUC0-tz: Area under the concentration-time curve in plasma for BI 907828, BI 754091 and BI 754111 over the time interval from 0 to the last quantifiable time point (during the first cycle)

Time: Up to 21 Days

Measure: Phase Ia - Number of patients with DLTs observed during the entire treatment period

Time: Up to 24 months

Measure: Phase Ib - Objective Response (OR)

Time: Up to 24 months

Measure: Phase Ib - Disease control (DC)

Time: Up to 24 months

Measure: Phase Ib - Progression-Free Survival (PFS)

Time: Up to 24 months

Measure: Phase Ib - In cohort 3 (liposarcoma and undifferentiated pleomorphic sarcoma): PFS rate at 12 and 24 weeks

Time: 12 and 24 weeks

Measure: Phase Ib - Number of patients with DLTs

Time: Up to 2 years

157 The Prospective Non-randomized Phase II Clinical Trial of Vemurafenib in Combination With Cytarabine and 2-chlorodeoxyadenosine in Children With Langerhans-cell Hisitocytosis With BRAF V600E Mutation

Langerhans cell histiocytosis (LCH) is a disease caused by clonal expansion, proliferation, and dissemination of cells that are phenotypically close to Langerhans cells in different tissues and organs. The clinical presentation of LCH varies greatly from one solid bone tumor to multisystem lesion that involves liver, spleen and bone marrow. The basis of LCH is the clonal proliferation of the pathological cells. These cells express CD1a and CD207 markers on their surface and originate from myeloid progenitors. The main event in life circle of these cells is the MEK-ERK cascade mutation. The most common mutation is the substitution of valine for glutamic acid in position 600 of BRAF gene. The influence of this mutation was confirmed by G.Badalyan-Very et al. in 2010. About 64% of all LCH are caused by clonal proliferation due to BRAF V600E mutation. Despite generally good results of therapy of monosystemic LCH, the treatment of LCH with risk organs lesion is still a challenge: 5-years survival is as low as 40-50%. Combination of cytarabine and 2-chlorodeoxyadenosine was supposed to improve the results, but the cost was a very high toxicity, that limits the application of the regimen in patients with severe infections. Currently, there is a lot of information on BRAF V600E inhibitors in patients with LCH and other histiocytic disorders. Most of them report the dramatic efficacy of BRAF V600E inhibitors but after quick effect patients usually burden minimal disease activity ("plateau" effect). However, discontinuation of the therapy results in quick disease reactivation. Considering this a trial that combines targeted therapy (vemurafenib) and low-dose chemotherapy (cytarabine and 2-chlorodeoxyadenosine) in order to achieve complete response with manageable toxicity is proposed.

NCT03585686
Conditions
  1. Langerhans Cell Hi
  2. Langerhans Cell Histiocytosis
Interventions
  1. Drug: Vemurafenib
  2. Drug: Cytarabine
  3. Drug: 2-chlorodeoxyadenosine
MeSH:Histiocytosis, Langerhans-Cell Histiocytosis
HPO:Histiocytosis

The Prospective Non-randomized Phase II Clinical Trial of Vemurafenib in Combination With Cytarabine and 2-chlorodeoxyadenosine in Children With Langerhans-cell Hisitocytosis With BRAF V600E Mutation. --- V600E ---

A Combination of Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation Langerhans cell histiocytosis (LCH) is a disease caused by clonal expansion, proliferation, and dissemination of cells that are phenotypically close to Langerhans cells in different tissues and organs. --- V600E ---

About 64% of all LCH are caused by clonal proliferation due to BRAF V600E mutation. --- V600E ---

Currently, there is a lot of information on BRAF V600E inhibitors in patients with LCH and other histiocytic disorders. --- V600E ---

Most of them report the dramatic efficacy of BRAF V600E inhibitors but after quick effect patients usually burden minimal disease activity ("plateau" effect). --- V600E ---

OS is a time from the therapy start to death due to any cause or to the last evaluation.. Inclusion Criteria: - 0-18 years old - histologically verified diagnosis of LCH (CD1a+/CD207+) - verified BRAF V600E mutation in the biopsy specimen AND/OR CD34+ isolate (NB! --- V600E ---

In life-threatening cases, vemurafenib can be administered BEFORE BRAF V600E mutation confirmation. --- V600E ---

It's recommended to stop vemurafenib therapy if no clinically significant positive dynamic was achieved after 7 days of intake) - QTc < 0.5 s - no previously documented cardiac diseases - signed informed consent Exclusion Criteria: - withdrawal of informed consent - QTc > 0.5 s or long QT syndrome - use of antiarrhythmic medication - persistent electrolytic disorders Inclusion Criteria: - 0-18 years old - histologically verified diagnosis of LCH (CD1a+/CD207+) - verified BRAF V600E mutation in the biopsy specimen AND/OR CD34+ isolate (NB! --- V600E ---

In life-threatening cases, the treatment can be started empirically, without BRAF V600E detection in any affected tissue. --- V600E ---

During that period their condition will be strictly monitored in order to control BRAF V600E inhibitor side effects. --- V600E ---

With the help of ddPCR, it could be possible to analyze cell-free DNA (cfDNA) harboring BRAF V600E mutation and thus to create a method of disease activity control. --- V600E ---

Primary Outcomes

Description: ORR is the sum of complete response rate (CRR) and partial response rate (PRR) which define as DAS score 0-1 and 2-3 respectfully.

Measure: The overall response rate (ORR) proportion

Time: 16 weeks

Secondary Outcomes

Description: RFS is a time from the therapy start to reactivation, progression or death due to any cause or to last evaluation up to the time of analysis. Analysis will be made with Kaplan-Mayer method with 95% confidence interval.

Measure: The reactivation/progression free survival

Time: 1 year

Description: The proportion of of patients with severe adverse effects of therapy according to CTCAE (ver 4.0)

Measure: The proportion of of patients with severe adverse effects

Time: 30 days

Description: OS is a time from the therapy start to death due to any cause or to the last evaluation.

Measure: Overall survival

Time: 2 years

158 An Open Label, Dose-Escalation, Phase I Study to Evaluate the Safety, Tolerability, Preliminary Efficacy and Pharmacokinetics of TAK-981 in Adult Patients With Advanced or Metastatic Solid Tumors or Relapsed/Refractory Hematologic Malignancies and in a Subset With Coronavirus Disease 2019

The primary objective of this study is to determine the safety and tolerability of TAK-981 as a single agent in participants with advanced or metastatic solid tumors and lymphomas in Phase 1, to evaluate preliminary efficacy of TAK-981 in participants with select solid tumors or relapsed/refractory CD20-positive (CD20+) non-hodgkin lymphoma (NHL) indications in Phase 2, and to assess change in severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) viral load within 8 days of TAK-981 administration in COVID-19 Expansion.

NCT03648372
Conditions
  1. Neoplasms
  2. Lymphoma
  3. Hematologic Neoplasms
  4. Coronavirus Disease
Interventions
  1. Drug: TAK-981
  2. Drug: Standard of care
MeSH:Coronavirus Infections Neoplasms Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia Neoplasm

Note: Participants with known driver mutations/genomic aberrations (example- epidermal growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. --- V600E ---

Note: Participants with known driver mutations/genomic aberrations (example- epidermal growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. --- V600E --- --- V600E ---

Primary Outcomes

Measure: Phase 1: Number of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs)

Time: Up to 48 months

Description: Severity grade will be evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, except for Cytokine Release Syndrome (CRS), which will be assessed by American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria.

Measure: Phase 1: Number of Participants Based on Severity of TEAEs

Time: Up to 48 months

Measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: Up to Cycle 1 (Cycle length is equal to [=] 21 days)

Measure: Phase 1: Number of Participants With Clinically Significant Laboratory Values

Time: Up to 48 months

Description: ORR is defined as percentage of participants who achieve complete response (CR) and partial response (PR), as determined by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) for participants with solid tumors or Lugano classification for lymphoma.

Measure: Phase 2: Overall Response Rate (ORR)

Time: From the first dose until best response is achieved (up to 4 years)

Measure: COVID-19 Expansion: Number of Participants With Greater Than or Equal to (>=) 2 log Reduction From Baseline in Viral Load or Below Level of Detection (Negative) in Nasopharyngeal or Oropharyngeal Samples

Time: Up to 9 months

Secondary Outcomes

Measure: Phase 2: Number of Participants Reporting one or More TEAEs

Time: Up to 48 months

Description: Severity grade will be evaluated as per the NCI CTCAE Version 5.0, except for CRS, which will be assessed by ASTCT consensus grading criteria.

Measure: Phase 2: Number of Participants Based on Severity of TEAEs

Time: Up to 48 months

Measure: Phase 2, Cmax: Maximum Observed Plasma Concentration for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length is equal to [=] 21 days)

Measure: Phase 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

Measure: Phase 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

Measure: Phase 2, AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

Measure: Phase 2, Terminal Disposition Phase Half-life (t1/2z) for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

Measure: Phase 2, Total Clearance (CL) After Intravenous Administration for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

Measure: Phase 2, Volume of Distribution at Steady State After Intravenous Administration (Vss) for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

Description: ORR is defined as percentage of participants who achieve CR and PR through the study (approximately 4 years), as determined by the investigator according to the RECIST V1.1 for participants with solid tumors or Lugano classification for lymphoma.

Measure: Phase 2: ORR

Time: From the first dose until best response is achieved (up to 4 years)

Description: DOR is the time from the date of first documentation of a PR or better to the date of first documentation of progressive disease for responders (PR or better) and will be determined by the investigator according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma.

Measure: Phase 2: Duration of Response (DOR)

Time: From the time of documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study (up to 4 years)

Description: DCR is defined as the percentage of participants who achieve stable disease (SD) or better (determined by the investigator according to RECIST v1.1 criteria for solid tumors or Lugano classification for lymphoma) greater than (>) 6 weeks during the study in the response-evaluable population.

Measure: Phase 2: Disease Control Rate (DCR)

Time: From the first dose until best response is achieved (up to 4 years)

Description: TTR is defined as the time from the date of first study drug administration to the date of first documented PR or better by the investigator for responders according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma.

Measure: Phase 2: Time to Response (TTR)

Time: From the date of first study drug administration to the date of first documented PR or better (up to 4 years)

Description: TTP is defined as the time from the date of the first dose administration to the date of first documented progressive disease and will be determined by the investigator according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma.

Measure: Phase 2: Time to Progression (TTP)

Time: From the date of first study drug administration to the date of first documented PD (up to 4 years)

Description: PFS is defined as the time from the date of the first dose administration to the date of first documentation of progressive disease or death due to any cause, whichever occurs first and will be determined by the investigator according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma.

Measure: Phase 2: Progression-free Survival (PFS)

Time: From the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study (up to 4 years)

Description: OS is defined as the time from the date of the first dose administration to the date of death.

Measure: Phase 2: Overall Survival (OS)

Time: From the date of first study drug administration to the date of death (up to 4 years)

Measure: Phase 2: Number of Participants With TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation and SUMO Pathway Inhibition in Skin/Blood

Time: Up to 48 months

Measure: COVID-19 Expansion: Number of Participants Reporting one or More TEAEs

Time: Up to 9 months

Description: Severity Grades will be evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), version 5.0.

Measure: COVID-19 Expansion: Number of Participants Based on Severity of TEAEs

Time: Up to 9 months

Measure: COVID-19 Expansion: Duration of TEAEs

Time: Up to 9 months

Description: NEWS determines the degree of illness of participants and prompts critical care intervention. It will be based on the score allocated to respiratory rate, peripheral capillary oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness.

Measure: COVID-19 Expansion: Change from Baseline in National Early Warning Score (NEWS)

Time: Up to 9 months

Description: Percentage of participants will be reported based on severity rating on a 6-point ordinal scale, which will include: 1 (death); 2 (hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation, hospitalized); 3 (on non-invasive ventilation or high flow oxygen devices); 4 (hospitalized, requiring supplemental oxygen); 5 (hospitalized, not requiring supplemental oxygen); and 6 (not hospitalized).

Measure: COVID-19 Expansion: Percentage of Participants Reporting Each Hospitalization Severity Rating

Time: Up to 9 months

Description: Change from Baseline in SARS-CoV-2 viral Load in nasopharyngeal or oropharyngeal samples will be determined by viral response. The nasopharyngeal swab will be collected from both nostrils or from the same nostril every time.

Measure: COVID-19 Expansion: Change From Baseline in SARS-CoV-2 Viral Load in Nasopharyngeal or Oropharyngeal Samples

Time: Up to 9 months

Measure: COVID-19 Expansion: Percentage of Participants Requiring Oxygen Supplementation; Assisted or Positive Pressure Non-invasive Ventilation; and Invasive Ventilation, on Days 3, 5, 8, 11, 15, and 30

Time: Days 3, 5, 8, 11, 15, and 30

Measure: COVID-19 Expansion: Percentage of Participants That met Intensive Care Unit (ICU) Criteria

Time: Up to 9 months

Measure: COVID-19 Expansion: Duration of Hospitalization

Time: Up to 9 months

Description: Time from the first dose of TAK-981 to viral load negativity (below level of detection).

Measure: COVID-19 Expansion: Time to Viral Ribonucleic Acid (RNA) Negativity in Nasopharyngeal or Oropharyngeal Samples

Time: Up to 9 months

Description: Time from first dose of TAK-981 to participant's discharge or to NEWS score <=3. NEWS determines the degree of illness of participants and prompts critical care intervention. It will be based on the score allocated to respiratory rate, peripheral capillary oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness.

Measure: COVID-19 Expansion: Time to Discharge or to a NEWS of Less Than or Equal to (<=) 3 and Maintained for 24 Hours

Time: Up to 9 months

Measure: COVID-19 Expansion: Number of Deaths in Hospital due to any Cause in First 30 Days and in 90 Days

Time: Days 30 and 90

159 A Phase 1b/2a Pilot Study to Evaluate the Safety and Tolerability of Autologous T-Cells Expressing Enhanced TCRs (T Cell Receptors) Specific for NY-ESO-1/LAGE-1a (GSK3377794) Alone, or in Combination With Pembrolizumab in HLA-A2+ Participants With NY-ESO-1- or LAGE-1a-Positive Advanced or Recurrent Non-Small Cell Lung Cancer

Adoptive T-cell therapy (ACT) is a therapeutic approach that uses T lymphocytes of participants with cancer, obtained by leukapheresis with the aim of generating an anti-tumor T-cell immune response. New York esophageal squamous cell carcinoma 1 (NY-ESO-1) and cancer testis antigen 2 (LAGE-1a) antigens are tumor-associated proteins that have been found in several tumor types. Clinical trials using ACT with T-cells directed against NY-ESO-1/LAGE-1a have shown objective responses in participants with cancer. Pembrolizumab is a monoclonal antibody that acts specifically on tumor targeting T-cells and increases T-cell anti-tumor function. Pembrolizumab will be used in combination with NY-ESO-1/LAGE-1a T Cell Receptors (TCR) engineered participant T-cells (GSK3377794) to potentially further improve therapy for participants. The primary objective of the study is to evaluate the safety and tolerability of autologous genetically modified T-cells (GSK3377794) in human leukocyte antigen (HLA) positive participants with NY-ES0-1/ LAGE-1a positive advanced non-small cell lung cancer (NSCLC) alone (Arm A) or GSK3377794 in combination with pembrolizumab in participants with NSCLC with wildtype epidermal growth factor receptor (WT EGFR) and WT anaplastic lymphoma kinase/ c-ros oncogene 1 (ALK/ROS1) (Arm B) and participants with NSCLC with EGFR or ALK/ROS1 aberration (Arm C). This study consists of screening phase, Leukapheresis/ GSK3377794 manufacture, lymphodepletion/treatment phase and follow-up. Participants will receive GSK3377794 as monotherapy (Arm A); or as a combination therapy with pembrolizumab (Arm B), and participants in Arm C will receive the same treatment as participants in the Arm B. Approximately 54 participants will be enrolled into the study.

NCT03709706
Conditions
  1. Neoplasms
Interventions
  1. Drug: letetresgene autoleucel
  2. Drug: Pembrolizumab

Exclusion Criteria: For Screening (Part 1): - NSCLC with B-Raf gene (BRAF) V600E mutation, Neurotrophic Tropomyosin-Related Kinase (NTRK) gene fusion, and/or any other actionable genetic aberration that can be treated with targeted SoC (NCCN recommended) therapy. --- V600E ---

Primary Outcomes

Description: An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation as per Medical or scientific judgment.

Measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs) in participants who received GSK3377794 alone or in combination with pembrolizumab

Time: Up to 106 weeks

Description: The severity of AEs will be graded according to National Cancer Institute-Common terminology criteria for adverse events (NCI-CTCAE) version 4.03.

Measure: Number of participants with adverse events of different severity in participants who received GSK3377794 alone or in combination with pembrolizumab

Time: Up to 106 weeks

Description: Number of participants with AEs and SAEs leading to dose delays will be reported.

Measure: Number of participants with AEs and SAEs leading to dose delays

Time: Up to 106 weeks

Description: Number of participants with AEs and SAEs leading to withdrawals will be reported.

Measure: Number of participants with AEs and SAEs leading to withdrawals

Time: Up to 106 weeks

Description: Blood samples will be collected for analysis of hematology parameters including platelet counts, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell count (RBC), hemoglobin and hematocrit.

Measure: Number of participants with abnormal findings for hematology parameters

Time: Up to 106 weeks

Description: Blood samples will be collected for analysis of clinical chemistry parameters including blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), total and direct bilirubin, creatinine, sodium, alanine aminotransferase (ALT), total protein, glucose, calcium, alkaline phosphatase, chloride, albumin, phosphorus, low density lipid (LDH), urea, potassium, magnesium and bicarbonate.

Measure: Number of participants with abnormal findings for clinical chemistry parameters

Time: Up to 106 weeks

Description: Urine samples will be collected for the analysis of the following urine parameters: specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite and leukocyte esterase by dipstick.

Measure: Number of participants with abnormal findings for urinalysis parameters

Time: Up to 106 weeks

Description: Vital sign parameters including systolic and diastolic blood pressure, respiratory rate, pulse rate, and temperature will be assessed.

Measure: Number of of participants with abnormal findings for vital signs

Time: Up to 106 weeks

Description: ECOG performance status is a measure of the participant's ability to carry out activities of daily living on a 6-point scale ranging from 0 (fully active) to 5 (Dead).

Measure: Mean Eastern Cooperative Oncology Group (ECOG) performance status score

Time: Up to 106 weeks

Description: Twelve-lead ECG will be obtained using an ECG machine.

Measure: Number of participants with abnormal electrocardiogram (ECG) findings

Time: Up to 106 weeks

Description: ORR is the percentage of participants with a confirmed complete response (CR) or a partial response (PR) at any time as per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by the local investigators.

Measure: Overall response rate (ORR)

Time: Up to 106 weeks

Secondary Outcomes

Description: PFS is defined as the time from the date of T-cell infusion until the earliest date of disease progression as per RECIST version 1.1 as determined by the local investigators, or death due to any cause.

Measure: Progression-Free Survival (PFS)

Time: Up to 106 weeks

Description: DCR is defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) for at least 6 months as per RECIST version 1.1 as determined by the local investigators.

Measure: Disease Control Rate (DCR)

Time: Up to 106 weeks

Description: DoR is defined as, in the subset of participants who show a confirmed CR or PR as determined by the local investigators, the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.

Measure: Duration of Response (DoR)

Time: Up to 106 weeks

Description: TTR is the time from the date of T-cell infusion to the first documented evidence of response (PR or better) in the subset of participants who achieved a confirmed PR or CR as determined by the local investigators.

Measure: Time to Response (TTR)

Time: Up to 106 weeks

Description: Blood samples will be collected for pharmacokinetic analysis.

Measure: Maximum observed concentration (Cmax) following administration of monotherapy of GSK3377794

Time: Up to 106 weeks post-dose

Description: Blood samples will be collected for pharmacokinetic analysis.

Measure: Cmax following administration of combination therapy of GSK3377794

Time: Up to 106 weeks post-dose

Description: Blood samples will be collected for pharmacokinetic analysis

Measure: Time to Cmax (Tmax) following administration of monotherapy of GSK3377794

Time: Up to 106 weeks post-dose

Description: Blood samples will be collected for pharmacokinetic analysis.

Measure: Tmax following administration of combination therapy of GSK3377794

Time: Up to 106 weeks post-dose

Description: Blood samples will be collected for pharmacokinetic analysis.

Measure: Area under the time curve from zero to time t (AUC[0 to t]) following administration of monotherapy of GSK3377794

Time: Up to 106 weeks post-dose

Description: Blood samples will be collected for pharmacokinetic analysis.

Measure: AUC(0 to t) following administration of combination therapy of GSK3377794

Time: Up to 106 weeks post-dose

160 Assessment of the V600E Mutation in the B-RAF Gene in Chronic Lymphoproliferative Disease.

The presence of a specific mutation in the gene known as B-RAF has been found in patients who have Hairy Cell Leukemia. In this study this specific mutation known as V600E will be ascertained in peripheral blood samples of patients who have this disease and in a group of patients who have a similar chronic lymphoproliferative conditions such as splenic marginal lymphoma. The finding of this specific mutation will help to verify or exclude the diagnosis of Hairy Cell Leukemia and determine whether patients are in remission.

NCT01720758
Conditions
  1. Hairy Cell Leukemia
  2. Splenic Marginal Zone Lymphoma
MeSH:Lymphoma, B-Cell, Marginal Zone Leukemia, Hairy Cell Lymphoproliferative Disorders
HPO:Lymphoproliferative disorder

Assessment of the V600E Mutation in the B-RAF Gene in Chronic Lymphoproliferative Disease.. Assessment of the V600E Mutation in the B-RAF Gene in Chronic Lymphoproliferative Disease The presence of a specific mutation in the gene known as B-RAF has been found in patients who have Hairy Cell Leukemia. --- V600E ---

Assessment of the V600E Mutation in the B-RAF Gene in Chronic Lymphoproliferative Disease.. Assessment of the V600E Mutation in the B-RAF Gene in Chronic Lymphoproliferative Disease The presence of a specific mutation in the gene known as B-RAF has been found in patients who have Hairy Cell Leukemia. --- V600E --- --- V600E ---

In this study this specific mutation known as V600E will be ascertained in peripheral blood samples of patients who have this disease and in a group of patients who have a similar chronic lymphoproliferative conditions such as splenic marginal lymphoma. --- V600E ---

detection of the B-RAF V600E mutation. --- V600E ---

Primary Outcomes

Measure: detection of the B-RAF V600E mutation

Time: 2 weeks

161 LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations

This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression.If a subject is removed from the study for one of a variety of reasons including, but not limited to, an inability to tolerate the combination of dabrafenib and trametinib, a need to receive other therapy or completion of 3-years of study treatment without progression, and the subject later receives, as part of his/her standard of care, the combination of dabrafenib and trametinib and progresses on the standard of care regimen, then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

NCT01726738
Conditions
  1. Stage III Melanoma
  2. Stage IV Melanoma
  3. Unresectable Melanoma
  4. BRAF Mutant Melanoma
Interventions
  1. Drug: BRAF inhibitor dabrafenib and MEK inhibitor trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: - Absolute neutrophil count >1.2 × 109/L - Hemoglobin >9 g/dL, platelets >75 × 109/L - PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) - Albumin >2.5 g/dL - Total bilirubin <1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) - AST and ALT < 2.5× ULN - CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. --- V600E ---

Primary Outcomes

Description: The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry (MS) and reported as a sum of the Log 2 Fold Change between baseline and one year post treatment across all patients

Measure: Change in Kinase Expression

Time: Baseline and One year post treatment

Description: Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.

Measure: Kinome Signature Predictive of Resistance

Time: One year post treatment

Secondary Outcomes

Description: The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using Next Generation (NextGen) DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) or Cancer Osaka Thyroid (COT), and PTEN).

Measure: BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes

Time: One year

Description: To determine the disease overall response rate (ORR: complete response (CR) + partial response (PR)/total number of patients) as measured radiographically via Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. CR is defined as the disappearance of all target lesions; PR is a >=30% decrease in the sum of the longest diameter of target lesions

Measure: Overall Response Rate (ORR)

Time: One year post treatment

Description: Duration of overall response is defined as the time from documentation of response (Complete or Partial) to time of disease progression or death. Response was measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. Complete Response is defined as the disappearance of all target lesions; Partial Response as a >=30% decrease in the sum of the longest diameter of target lesions, and Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.

Measure: Duration of Overall Response

Time: One year post treatment

Description: PFS is defined as the time from Day 1 of protocol treatment to the date of progression as measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or to the date of death. Per RECIST, Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.

Measure: Progression Free Survival (PFS)

Time: One year post treatment

Description: The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment

Measure: Rate of Overall Survival (OS) at 12 Months

Time: One year post treatment

162 A Phase II, Single Arm, Open-label, Multicenter, Study of Oral LGX818 in Patients With BRAF V600 Mutant, Advanced Non-small Cell Lung Cancer (NSCLC) That Have Progressed During or After at Least One Prior Chemotherapy

This is an open-label, multi-center, single arm phase II study to evaluate the efficacy and safety of novel BRAF (B-raf murine sarcoma viral oncogene homolog B1) inhibitor encorafenib (LGX818) when used as single agent in patients with advanced or metastatic (stage IIIB or IV) BRAF V600 mutant NSCLC. Patients must have progressed on or after at least one previous systemic, anti-cancer therapy for locally advanced or metastatic NSCLC.

NCT02109653
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: LGX818
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Presence of BRAF V600E mutation in tumor tissue - Histologically or cytologically confirmed diagnosis of Stage IIIB or IV NSCLC - At least one measurable lesion as defined by RECIST v1.1 - Patients must have progressed during or after at least one previous systemic, anti-cancer treatment for locally advanced or metastatic NSCLC. --- V600E ---

- Impaired cardiovascular function or clinically significant cardiovascular diseases - Pregnant or lactating women or woman of childbearing potential Inclusion Criteria: - Presence of BRAF V600E mutation in tumor tissue - Histologically or cytologically confirmed diagnosis of Stage IIIB or IV NSCLC - At least one measurable lesion as defined by RECIST v1.1 - Patients must have progressed during or after at least one previous systemic, anti-cancer treatment for locally advanced or metastatic NSCLC. --- V600E ---

Primary Outcomes

Description: ORR per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by investigator

Measure: Overall Response Rate (ORR)

Time: up to 24 weeks

Secondary Outcomes

Description: ORR per RECIST 1.1 as assessed by by Blinded independent review committee (BIRC)

Measure: Overall Response Rate (ORR)

Time: baseline, every 6 weeks up to 24 weeks

Description: PFS determined by investigator and BIRC.

Measure: Progression-Free Survival (PFS)

Time: baseline, every 6 weeks up to 24 weeks

Description: DOR by investigator and BIRC assessments.

Measure: Duration of Response (DOR)

Time: baseline, every 6 weeks up to 24 weeks

Description: Overall survival (OS)

Measure: Overall survival (OS)

Time: baseline, every 6 weeks up to 24 weeks

Description: Adverse events and laboratory abnormalities

Measure: Safety Profile

Time: baseline, every 3 weeks up to 24 weeks

Description: DCR by investigator and BIRC assessments.

Measure: Disease Control Rate (DCR)

Time: baseline, every 6 weeks up to 24 weeks

Description: Plasma concentration-time profiles of encorafenib (LGX818).

Measure: Pharmacokinetics profile

Time: baseline, every 3 weeks up to 18 weeks

Description: Concordance rate between BRAF mutation status obtained using the investigational diagnostic test and the companion diagnostic assay which will be submitted for Pre-market approval (PMA)

Measure: Concordance between the BRAF mutation status from investigational diagnostic test and the companion diagnostic assay

Time: screening, up to 24 weeks

163 Evaluation of Photosensitivity in Dabrafenib or Vemurafenib Treated Metastatic Melanoma Patients - a Phase IIa/IIb Study

The BRAF inhibitors dabrafenib and vemurafenib belong both two a new class of potent anti-cancer drugs and are highly efficacious in tumors harboring the BRAF V600E mutation. Both drugs seem to be equally efficacious; however, their toxicity profile seems to differ. Serious phototoxicity has been observed in ~ 30% of patients treated with vemurafenib and in ~2 percent of patients treated with dabrafenib. These phototoxic reactions have developed in spite of informing the patients of this possible adverse event and instructing them to protect themselves. Manifestation of phototoxic reactions depends on the patient's habits of exposure and their efforts to protect themselves. The true frequency of photosensitivity can only be established by systematic photo-testing. In dermatology, standard test procedures with different UV-wavelengths and dosages have been established and the primary goal of this study will be to clarify the true rate of photosensitivity by these two BRAF-inhibitors. Furthermore, systematic experience will be collected how to best protect patients from phototoxic events. Dabrafenib and Vemurafenib are commercially available and considered standard of care for BRAF mutant metastatic melanoma in Germany. As the number of patients will not allow any conclusion with regard to efficacy or safety of vemurafenib, patients randomized to vemurafenib in part 2 will only remain on study until completion of phototesting.

NCT02052193
Conditions
  1. Metastatic Melanoma (Carrying BRAF V600 Mutation)
Interventions
  1. Drug: Dabrafenib
  2. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Evaluation of Photosensitivity in Dabrafenib or Vemurafenib Treated Metastatic Melanoma Patients - a Phase IIa/IIb Study The BRAF inhibitors dabrafenib and vemurafenib belong both two a new class of potent anti-cancer drugs and are highly efficacious in tumors harboring the BRAF V600E mutation. --- V600E ---

Primary Outcomes

Measure: Degree of Solar Dermatitis due to Standardized UV Exposure in Patients treated with Dabrafenib

Time: day 2-5

Measure: Degree of Solar Dermatitis due to Standardized UV Exposure in Patients treated with Dabrafenib or Vemurafenib

Time: day 2-5

Secondary Outcomes

Measure: Number of Participants with Adverse Events treated with dabrafenib

Time: day 1-28

Measure: Best overall response rates and progression free survival in patients treated with dabrafenib or vemurafenib using RECIST v1.1 criteria

Time: Every 3 months

164 An Open-label, Single-arm, Phase I/II, Multicentre Study to Evaluate the Safety and Efficacy of the Combination of Dabrafenib, Trametinib and Palliative Radiotherapy in Patients With Unresectable (Stage IIIc) and Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma

The purpose of this study is to investigate the side effects and safety, and effectiveness of combining dabrafenib and trametinib with radiotherapy. Previous and ongoing clinical trials have demonstrated the effectiveness and safety of combining both dabrafenib and trametinib compared with dabrafenib alone. This has led to the approval for the use of both drugs in combination in people with metastatic melanoma with the BRAF mutation. Melanoma that has spread to other parts of the body may also benefit from radiotherapy to help reduce symptoms from melanoma. Previous studies have shown that melanoma may be sensitive to radiotherapy and that it can help to improve quality of life. The intention of the CombiRT study is to establish if dabrafenib, trametinib and radiotherapy combined is a safe and effective treatment for metastatic melanoma.

NCT02392871
Conditions
  1. Metastatic Melanoma
Interventions
  1. Radiation: Palliative radiotherapy
  2. Drug: Dabrafenib and trametinib (combination)
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

An Open-label, Single-arm, Phase I/II, Multicentre Study to Evaluate the Safety and Efficacy of the Combination of Dabrafenib, Trametinib and Palliative Radiotherapy in Patients With Unresectable (Stage IIIc) and Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma. --- V600E ---

3. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive as determined by a BRAF mutation assay. --- V600E ---

Primary Outcomes

Measure: Toxicity profile for patients receiving dabrafenib and trametinib in combination with RT, by measuring adverse events and radiotherapy associated toxicities.

Time: 0-12 months

Secondary Outcomes

Measure: Patients' pain using a visual analog scale (questionnaire)

Time: 0-12 months

Measure: Overall disease response by measuring progression free survival and overall survival.

Time: 0-12 months

Measure: Local treatment response in the irradiated index lesion(s).

Time: 0-12 months

Measure: Time to local progression in the irradiated index lesion(s).

Time: 0-12 months

165 A Randomized Controlled Study Of Neurocognitive Outcomes In Patients With Five Or More Brain Metastases Treated With Radiosurgery Or Whole-Brain Radiotherapy

This is randomized study of neurocognitive outcomes in patients with five or more brain metastases treated with stereotactic radiosurgery (SRS), specifically the Gamma Knife (GK) system, or whole-brain radiation therapy (WBRT). The primary aim of this study is to compare the change in neurocognitive function outcome between baseline and 6 months in WBRT versus SRS treatment groups.

NCT01731704
Conditions
  1. Brain Metastases
Interventions
  1. Radiation: Stereotactic radiosurgery (SRS)
  2. Radiation: Whole brain radiation therapy (WBRT)
MeSH:Neoplasm Metastasis Neoplasms, Second Primary Brain Neoplasms
HPO:Brain neoplasm

The goal of the study is to enroll 120 patients with at least five (≥5) newly-diagnosed brain metastases from non-melanoma, except melanoma patients with BRAF V600E B-Raf protein mutation, primary cancers with the largest intracranial tumor volume ≤10 cc, ≤15 cc total tumor volume, absence of leptomeningeal disease on MRI, and Karnofsky performance status (KPS) score ≥70 (unless due to intracranial disease), and KPS expected to improve to ≥70 with treatment. --- V600E ---

Primary Outcomes

Description: All participants will be asked to complete: Online brain function testing: Complete a short 20-minute online brain function (cognitive) assessment every 2 weeks (twice per month, at least 10-14 days apart). Quality of Life Questionnaire: Complete a self-reported (if patient) and caregiver quality of life questionnaires every 10-12 weeks (2.5-3 months). These questionnaires take approximately 15-20 minutes to complete and can be done online or in clinic during follow-up visits.

Measure: To compare the relative change in neurocognitive outcomes (change in oNCF z-score) between baseline and 6 months for surviving patients in upfront WBRT vs. SRS treatment groups.

Time: Every 3 months for 12 months

Secondary Outcomes

Description: Neurocognitive function, 12-months post whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS)specifically the Gamma Knife (GK) system, treatment as measured by the online neurocognitive function (oNCF) composite z-score. Neurocognitive function at all time points as measured by the online neurocognitive function (oNCF) composite z-score.

Measure: To compare the relative change in neurocognitive outcomes (change in oNCF z-score) between baseline and 12 months for surviving patients in upfront WBRT vs. SRS treatment groups.

Time: Every 10-12 weeks for 12 months after treatment

Description: • Quality of life (patient-reported measures) as measured by Beck Depression Inventory, Beck Anxiety Inventory, FACT-Br, FACT-Cog, Fatigue Severity Scale, EuroQol(EQ5D), EORTC-BN20, and QOL-30.

Measure: To compare the relative impact of initial therapy on patients' quality of life (QoL) as measured by caregiver assessments

Time: Every 10-12 weeks for 12 months after treatment

Description: Quality of life as measured by caregiver assessments including Frontal Systems Behavior Scale, Neuropsychiatric Inventory, Functional Activities Questionnaire, and Everyday Cognition Questionnaire.

Measure: To compare the relative impact of initial therapy on patients' quality of life (QoL) as measured by caregiver assessments

Time: Every 10-12 months

Measure: To estimate consistency and change in z-scores for oNCF assessments over all study endpoints in surviving patients treated with upfront whole brain radiation therapy (WBRT) vs. stereotactic radiosurgery (SRS).

Time: Every 10-12 months

Measure: To compare proportions of patients in the two treatment groups that require salvage therapy as a function of systemic disease control (controlled vs. uncontrolled).

Time: 3, 6, 9, and 12 months

Measure: To compare the overall survival between patients in upfront whole brain radiation therapy (WBRT) vs. stereotactic radiosurgery (SRS) treatment groups

Time: baseline to study completion

Other Outcomes

Description: To determine what healthcare cost data can be collected in patients with metastatic disease within a context of a multi-institutional clinical trial.

Measure: Cost analysis

Time: Prior to treatment up to 12 months after treatment is complete

166 Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects With Advanced BRAF V600-Mutation Positive Solid Tumors

This is a 2-part, study to determine the safety, tolerability and pharmacokinetics of oral dabrafenib in children and adolescent subjects with advanced BRAF V600 mutation-positive solid tumors. Part 1 (dose escalation study) will identify the recommended Part 2 (tumor-specific expansion study) dose and regimen using a dose-escalation procedure. Approximately 6 to 18 subjects will participate in Part 1 and will receive a starting dose of 3 mg/kg and dose will deescalate or escalate between 1.5 milligram (mg)/kilogram (kg) and 6 mg/kg. Up to 6 subjects will be enrolled at one dose level dependent upon the number of subjects at the current dose level, the number of subjects who have experienced a dose limiting toxicity (DLT) at the current dose level, and the number of subjects enrolled but with data pending at the current dose level. Escalation may proceed until either a maximum tolerated dose (MTD) is established, or until the dose in which the median pharmacokinetic parameters consistent with exposure in adults are achieved. Cohorts may be added in order to evaluate additional dose levels. Part 2 consists of four disease-specific cohorts of subjects with tumors known to have BRAF V600 activation (pediatric low-grade gliomas, pediatric high-grade gliomas, Langerhans cell histiocytosis [LCH], and other tumors such as melanoma and papillary thyroid carcinoma [PTC]). Each cohort will enroll at least 10 subjects with a pre-dose and at least 1 post-dose disease assessment. In both the parts of the study, on Day 1, a single first dose will be administered, and repeat dosing will begin on Day 2. PK sampling will be performed on Day 1 and Day 15 for subjects >=25 kg in weight. For subjects <25 kg and >=10 kg in weight, blood samples for PK analysis will be collected on Day 1 and Day 15. For subjects <10kg in weight, blood samples for PK analysis will be collected after repeated administration on Day 15 only. Safety and tolerability will be assessed throughout the study. Treatment with dabrafenib will be continued until disease progression or until no clinical benefit or development of an unacceptable toxicity, or until they withdraw consent or begin a new therapy. At the end of treatment, a final study visit will occur.

NCT01677741
Conditions
  1. Neoplasms, Brain
Interventions
  1. Drug: Dabrafenib
MeSH:Brain Neoplasms
HPO:Brain neoplasm

- BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing; centralized testing can confirm V600E and V600K mutations only). --- V600E ---

Primary Outcomes

Description: Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.

Measure: Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by number of subjects with adverse events (AEs)

Time: Up to 6 months

Description: Safety and tolerability parameters will include the electrocardiogram (ECG) readings at Baseline and at end of Part 1 and Part 2 of the study.

Measure: Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECG readings

Time: Up to 6 months

Description: Safety and tolerability parameters will include recording of echocardiogram (ECHO) at Baseline and at end of Part 1 and Part 2 of the study.

Measure: Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECHO findings

Time: Up to 6 months

Description: Safety and tolerability parameters will include laboratory values at Baseline and at end of Part 1 and Part 2 of the study.

Measure: Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in laboratory values

Time: Up to 6 months

Description: Safety and tolerability parameters will include vital signs at Baseline and at end of Part 1 and Part 2 of the study.

Measure: Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in vital signs

Time: Up to 6 months

Description: To calculate the dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents), the Cmax of dabrafenib that achieves similar exposure to the dabrafenib adult dose will be evaluated.

Measure: Maximum concentration (Cmax) of dabrafenib dose(s)

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: To calculate the dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) the AUC(0-τ) and AUC(0-inf) of dabrafenib that achieves similar exposure to the dabrafenib adult dose will be evaluated.

Measure: Area under the concentration-time curve over the dosing interval (AUC(0-τ)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib dose(s)

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Secondary Outcomes

Description: Pharmacokinetic data will include C trough of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).

Measure: Pre-dose (trough) concentration (C tau) of dabrafenib and its metabolites

Time: Day 1-Predose, Day 15-Predose

Description: Pharmacokinetic data will include area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]), AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).

Measure: The AUC(0-t) and AUC(0-tau) of dabrafenib and its metabolites

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: Pharmacokinetic data will include CL/F of dabrafenib.

Measure: Apparent clearance following oral dosing (CL/F) of dabrafenib

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: Pharmacokinetic data will include Cmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).

Measure: Cmax of dabrafenib, and its metabolites

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: Pharmacokinetic data will include tmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).

Measure: Time from administration to Cmax (tmax) of dabrafenib and its metabolites

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: Pharmacokinetic data will include t½ of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).

Measure: Elimination half life (t½) of dabrafenib and its metabolites

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.

Measure: Longer term safety and tolerability of dabrafenib as assessed by number of subjects with AEs

Time: Up to 6 months

Description: Safety and tolerability parameters will include the electrocardiogram (ECG) readings at Baseline and at end of Part 1 and Part 2 of the study

Measure: Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in ECG readings

Time: Up to 6 months

Description: Safety and tolerability parameters will include laboratory values at Baseline and at end of Part 1 and Part 2 of the study.

Measure: Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in laboratory values

Time: Up to 6 months

Description: Safety and tolerability parameters will include vital signs at Baseline and at end of Part 1 and Part 2 of the study.

Measure: Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in vital signs

Time: Up to 6 months

Description: Anti-tumor activity will be assessed based on clinical evidence and the response evaluation criteria in solid tumors (RECIST) version 1.1 criteria for solid tumors, response assessment in neuro-oncology (RANO) criteria (glioma subjects) and langerhans cell histiocytosis (LCH) scoring system.

Measure: Overall tumor response of dabrafenib

Time: Up to 6 months

Description: The CL/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.

Measure: Effect of age and weight on CL/F of dabrafenib

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: The V/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.

Measure: Effect of age and weight on volume of distribution (V/F) of dabrafenib

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: The ka data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.

Measure: Effect of age and weight on absorption rate (ka) of dabrafenib

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Description: The coefficients for significant covariates data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.

Measure: Effect of age and weight on coefficients for significant covariates of dabrafenib

Time: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

167 Phase I/II Study of Dabrafenib, Trametinib, and Navitoclax in BRAF Mutant Melanoma (Phase I and II) and Other Solid Tumors (Phase I Only)

This phase I/II trial studies the side effects and best dose of dabrafenib, trametinib, and navitoclax and to see how well they work in treating patients with BRAF mutant melanoma or solid tumors that have spread to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). Dabrafenib, trametinib, and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01989585
Conditions
  1. Malignant Solid Neoplasm
  2. Metastatic Melanoma
  3. Stage III Cutaneous Melanoma AJCC v7
  4. Stage IIIA Cutaneous Melanoma AJCC v7
  5. Stage IIIB Cutaneous Melanoma AJCC v7
  6. Stage IIIC Cutaneous Melanoma AJCC v7
  7. Stage IV Cutaneous Melanoma AJCC v6 and v7
  8. Unresectable Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Other: Laboratory Biomarker Analysis
  3. Biological: Navitoclax
  4. Other: Pharmacological Study
  5. Drug: Trametinib
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Descriptive statistics including mean, standard deviation, coefficient of variation, geometric mean, median, minimum and maximum will be computed for each pharmacokinetic variable; descriptive statistics for natural-log transformed pharmacokinetic variables will also be provided.. Inclusion Criteria: - PHASE I SUBJECTS ONLY: Prior therapy is allowed; for patients enrolled in the Phase I portion of the study, patients may have received any number of prior lines of therapy including treatment with a BRAF and/or MEK inhibitor; prior navitoclax use will not be allowed, unless the patient received < 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression - Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using validated, commercially available assay performed in a Clinical Laboratory Improvement Act [CLIA]-approved laboratory) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - If test at CLIA-certified lab used a non-Food and Drug Administration (FDA) approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; for patients enrolled in the Phase II portion of the study, patients may have received prior immunotherapy (including high-dose IL-2, ipilimumab, nivolumab, and other anti-PD1/PDL1 antibodies) or chemotherapy; however prior navitoclax, BRAF inhibitor and/or MEK inhibitor therapy will not be allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1 x 10^9/L - Hemoglobin >= 9 g/dl (patients may be transfused to this level) - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x institutional upper limit of normal OR > 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL OR creatinine clearance >= 50 mL/min/1.73 --- V600E ---

thyroiditis/hypothyroidism, adrenal insufficiency, hypophysitis) requiring replacement therapy, at the time of randomization - Due to the expected dose-limiting toxicity of thrombocytopenia, the following concomitant medications are not allowed during navitoclax administration: clopidogrel, ibuprofen, tirofiban, warfarin, and other anticoagulants, drugs, or herbal supplements that affect platelet function are excluded, with the exception of low-dose anticoagulation medications (such as heparin) that are used to maintain the patency of a central intravenous catheter; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - Because the composition, pharmacokinetics (PK), and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Anticoagulants or antiplatelet agents except for low-dose, aspirin - Preclinical studies indicate that navitoclax is metabolized by CYP3A4, is a moderate inhibitor of CYP2C8, and is a strong inhibitor of CYP2C9; there is also evidence of interactions with dabrafenib; therefore, caution should be exercised when dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates; common CYP2C8 substrates include paclitaxel, statins, and glitazones, whereas CYP2C9 substrates include phenytoin; when possible, investigators should switch to alternative medications or monitor the patients closely; CYP3A inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during navitoclax administration - Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of permeability-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; below are a few examples of the agents: - Strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be decreased: - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Strong inhibitors of CYP3A or CYP2C8 since concentrations of dabrafenib may be increased: - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressants: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellane Inclusion Criteria: - PHASE I SUBJECTS ONLY: Prior therapy is allowed; for patients enrolled in the Phase I portion of the study, patients may have received any number of prior lines of therapy including treatment with a BRAF and/or MEK inhibitor; prior navitoclax use will not be allowed, unless the patient received < 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression - Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using validated, commercially available assay performed in a Clinical Laboratory Improvement Act [CLIA]-approved laboratory) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - If test at CLIA-certified lab used a non-Food and Drug Administration (FDA) approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; for patients enrolled in the Phase II portion of the study, patients may have received prior immunotherapy (including high-dose IL-2, ipilimumab, nivolumab, and other anti-PD1/PDL1 antibodies) or chemotherapy; however prior navitoclax, BRAF inhibitor and/or MEK inhibitor therapy will not be allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1 x 10^9/L - Hemoglobin >= 9 g/dl (patients may be transfused to this level) - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x institutional upper limit of normal OR > 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL OR creatinine clearance >= 50 mL/min/1.73 --- V600E ---

Primary Outcomes

Description: Determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events.

Measure: Recommended phase II dose of the combination of dabrafenib, trametinib, and navitoclax (Phase I)

Time: Up to 28 days

Description: Assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in the cohort of patients treated with dabrafenib, trametinib, and navitoclax (DTN). The proportion of patients with a best response of CR will be presented with a 95% confidence interval calculated using the method of Atkinson and Brown.

Measure: Proportion of patients with a complete response (CR) (Phase II)

Time: Up to 4 weeks after last study treatment

Description: A comparison between the maximal tumor regression for patients treated with DTN and dabrafenib and trametinib (DT) will be conducted using a Wilcoxon rank-sum test.

Measure: Maximal degree of tumor regression (Phase II)

Time: Up to 4 weeks after last study treatment

Secondary Outcomes

Description: PFS will be summarized using the Kaplan-Meier. Log-rank tests will be used to assess for indications of differences between the two treatment modalities.

Measure: Progression free survival (PFS) (Phase II)

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed for up to 4 years

Description: OS will be summarized using the Kaplan-Meier. Log-rank tests will be used to assess for indications of differences between the two treatment modalities.

Measure: Overall survival (OS) (Phase II)

Time: Up to 4 years

Description: ORRs will be presented with 95% exact, binomial confidence intervals.

Measure: Objective response rate (ORR) (Phase II)

Time: Up to 4 weeks after last study treatment

Other Outcomes

Description: Fold changes of TUNEL will be calculated (post/pre). A Wilcoxon rank-sum test will be used to compare the ratios (or equivalently, the difference in the natural logs) of baseline and follow-up levels of TUNEL between DTN and DT treatment arms.

Measure: Change in terminal deoxynucleotidyl transferase 2´-deoxyuridine, 5´-triphosphate (dUTP) nick end labeling assay (TUNEL) staining

Time: Baseline to up to 1 week

Description: Will be primarily descriptive.

Measure: Change in B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2)

Time: Baseline to up to 1 week

Description: Will be primarily descriptive.

Measure: Change in Ki67

Time: Baseline to up to 1 week

Description: Will be primarily descriptive.

Measure: Change in phosphatase and tensin homolog (PTEN) status

Time: Baseline to up to 1 week

Description: Fold-changes in assay response will be calculated (post/pre). Fold changes in the assay will be compared across RECIST responses using the Kruskal-Wallis test. In addition, for assay-based response or progression, the proportions of patients with CR/partial response (PR), stable disease (SD), or progressive disease (PD) will be presented with exact 90% confidence intervals. Assay performance data will be compared with response. The proportions will be summarized and compared using exact confidence intervals. Behavior of the blood assay will be summarized graphically.

Measure: Fold changes in BRAF-mutation assay

Time: Baseline to up to 4 weeks after last study treatment

Description: Assay fold changes will be compared with fold changes in tumor burden (post/pre). The relationship will be summarized graphically and using the Spearman rank correlation. Differences in the behavior of the assay will be explored using a general linear model of log (fold-change) with study, baseline tumor burden, and log (fold-change tumor burden) as predictors.

Measure: Fold changes in tumor burden

Time: Baseline to up to 4 weeks after last study treatment

Description: Descriptive statistics including mean, standard deviation, coefficient of variation, geometric mean, median, minimum and maximum will be computed for each pharmacokinetic variable; descriptive statistics for natural-log transformed pharmacokinetic variables will also be provided.

Measure: Pharmacokinetic parameters, including maximal plasma or serum concentration (Cmax), area under the curve to the last collection point (AUClast), area under the curve for dose interval (AUC0-t), and time of maximal concentration (Tmax)

Time: Pre-treatment, 1, 2, 4, 6, 8, and 24 hours post-treatment on days 1 and 15 of cycle 1, and day 1 of cycles 2, 4, 8, and 12 (each cycle = 28 days)

168 Randomised Study to Investigate FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab as First-line Treatment of BRAF-mutated Metastatic Colorectal Cancer

Once randomisation has been completed, the study treatment should be started preferably immediately; at the latest within one week following randomisation. The patients will be randomised in a ratio of 1:2 to the following two treatment arms. Patients in both treatment arms will receive standard chemotherapy with FOLFOXIRI as background treatment, which can be de-escalated to FOLFIRI in case of toxicity. Standard arm A: The patient will be treated with FOLFOXIRI plus bevacizumab for up to 12 cycles (24 weeks) or until progression (if the latter occurs before completing the 12 cycles). Within the 12 cycles, the FOLFOXIRI plus bevacizumab regimen may be de-escalated, owing to toxicity, to FOLFIRI and bevacizumab at the treating physician's discretion. After 12 cycles of the study treatment, a switch to a maintenance regimen with a fluoropyrimidine (5-FU infusion or capecitabine) plus bevacizumab, administered until progression occurs, is recommended. The recommended maintenance phase of the study is not part of the study treatment. However, maintenance therapy will be counted as first-line therapy. Experimental arm B: The patient will be treated with FOLFOXIRI plus weekly administration of cetuximab for up to 12 cycles (24 weeks) or until progression (if the latter occurs before completing the 12 cycles). Within the 12 cycles, the FOLFOXIRI plus cetuximab regimen may be de-escalated owing to toxicity, to FOLFIRI and cetuximab at the treating physician's discretion. After 12 cycles, a switch to a maintenance regimen with 5-FU and cetuximab or with irinotecan and cetuximab, administered until progression occurs, is recommended. The recommended maintenance phase of the study is not part of the study treatment. However, maintenance therapy will be counted as first-line therapy.

NCT04034459
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: Bevacizumab
  2. Drug: Irinotecan
  3. Drug: Folinic acid
  4. Drug: Oxaliplatin
  5. Drug: 5-FU
  6. Drug: Cetuximab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Inclusion Criteria: - Histologically confirmed UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer [mCRC]); metastases primarily non-resectable or surgery refused by the patient - RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis) - BRAF-mutant (V600E) tumour (proven in the primary tumour or metastasis) - Age ≥18 years - ECOG performance status 0-1 - Patients suitable for chemotherapy administration - Patient's written declaration of consent obtained - Estimated life expectancy > 3 months - Presence of at least one measurable lesion according to the RECIST 1.1 - criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation) - Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of the tumour material. --- V600E ---

- Absent or restricted legal capacity Inclusion Criteria: - Histologically confirmed UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer [mCRC]); metastases primarily non-resectable or surgery refused by the patient - RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis) - BRAF-mutant (V600E) tumour (proven in the primary tumour or metastasis) - Age ≥18 years - ECOG performance status 0-1 - Patients suitable for chemotherapy administration - Patient's written declaration of consent obtained - Estimated life expectancy > 3 months - Presence of at least one measurable lesion according to the RECIST 1.1 - criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation) - Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of the tumour material. --- V600E ---

Primary Outcomes

Description: (overall response rate) measured in percentage of all treated patients according to RECIST 1.1 criteria

Measure: Overall Response Rate (ORR)

Time: up to 48 months

Secondary Outcomes

Description: Investigation of progression-free survival (PFS) from randomisation

Measure: Progression Free Survival (PFS)

Time: up to 60 months

Description: Investigation of overall survival (OS) from randomisation

Measure: Overall Survival (OS)

Time: up to 60 months

Description: Investigation of early tumour shrinkage (ETS)

Measure: Investigation of Early Tumour Shrinkage (ETS) as early-on-Treatment predictor for treatment

Time: up to 48 months

Description: Investigation of depth of response (DpR)

Measure: Investigation of Depth of Response (DpR) to define nadir for tumour response.

Time: up to 48 months

Description: Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance of an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)

Measure: Investigation of Molecular Biomarkers for Prediction of an Anti-EGFR Treatment

Time: up to 48 months

Description: Investigation of prospective analysis of tumour marker level evolution (CEA and CA 19-9)

Measure: Prospective Analysis of Tumour Marker Level Evolution (CEA and CA 19-9)

Time: up to 48 months

Description: Recording of the safety and tolerability (NCI-CTCAE version 4.03 criteria) of the treatment

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Time: up to 48 months

169 Safety, Activity, and Pharmacology of Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer and Pre-existing Autoimmune Disease

The purpose of this study is to explore the safety, tolerability and activity of Nivolumab, a PD-1 inhibitor, in cohorts of patients with autoimmune disease. Two cohorts of patients will be enrolled, based on autoimmune disease type. Patients will be screened within 28 days prior to the start of dosing. Eligible patients will be enrolled in either of the two cohorts. Patients will receive treatment every two weeks, in an outpatient setting. One cycle is a 28-day period, with Nivolumab given on days 1 and 15 of a 28-day cycle. Subjects will be permitted to continue treatment beyond initial RECIST 1.1.

NCT03656627
Conditions
  1. Autoimmune Diseases
  2. Non-small Cell Lung Cancer
  3. Rheumatoid Arthritis
  4. Psoriasis
  5. Giant Cell Arteritis
  6. Polymyalgia Rheumatica
  7. Systemic Lupus Erythematosus
  8. Crohn Disease
  9. Multiple Sclerosis
  10. Ulcerative Colitis
Interventions
  1. Drug: Nivolumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Arthritis Arthritis, Rheumatoid Polymyalgia Rheumatica Crohn Disease Colitis Colitis, Ulcerative Multiple Sclerosis Giant Cell Arteritis Arteritis Psoriasis Lupus Erythematosus, Systemic Autoimmune Diseases Sclerosis
HPO:Arteritis Arthritis Autoimmunity Colitis Crohn's disease Neoplasm of the lung Non-small cell lung carcinoma Palmoplantar pustulosis Polyarticular arthritis Psoriasiform dermatitis Rheumatoid arthritis Systemic lupus erythematosus Ulcerative colitis

4. Patients should have received at least one platinum-based chemotherapy regimen for recurrent or metastatic disease or have received platinum-based chemotherapy as part of adjuvant or neoadjuvant therapy and experienced progression of disease within 6 months of completing therapy. 5. Patients with tumor genetic alterations such as EGFR, ALK, ROS1 or BRAF V600E alterations for which there is FDA-approved targeted therapy must have been treated with the appropriate targeted inhibitors in prior therapy 6. --- V600E ---

Primary Outcomes

Description: The DLT determination period is the first six weeks after cycle 1 day 1. Dose limiting toxicities are further defined in the trial protocol.

Measure: Dose-Limiting Toxicity (DLT)

Time: 48 Months

Secondary Outcomes

Description: Overall response rate is defined to be the best objective status recorded from the start of the treatment until disease progression/recurrence

Measure: Overall Response Rate

Time: 48 Months

Description: Progression-free survival will be evaluated for each cohort using Kaplan-Meier estimator.

Measure: Progression-Free Survival

Time: 48 Months

Description: Overall survival will be evaluated for each cohort using Kaplan-Meier estimator.

Measure: Overall Survival

Time: 48 Months

170 A Biospecimen Collection Study to Evaluate the Pharmacokinetic, Pharmacodynamic, and Resistance Profile to Trametinib and Dabrafenib in BRAF-V600E Mutated Recurrent Gliomas

This is a surgical biospecimen collection study. The purpose of this study is to understand how much of two drugs (dabrafenib and trametinib) are able to penetrate brain tumors and turn off the RAF signaling pathway. This is important because these drugs are currently FDA approved for other tumors and may have efficacy in brain tumors with the BRAF V600E mutation.

NCT03593993
Conditions
  1. Glioma
  2. BRAF V600E
  3. Pleomorphic Xantho-Astrocytoma
  4. Glioblastoma
Interventions
  1. Procedure: Surgical Cohort
MeSH:Glioblastoma Glioma Astrocytoma
HPO:Astrocytoma Glioblastoma multiforme Glioma Subependymal giant-cell astrocytoma

A Biospecimen Collection Study to Evaluate the Pharmacokinetic, Pharmacodynamic, and Resistance Profile to Trametinib and Dabrafenib in BRAF-V600E Mutated Recurrent Gliomas. --- V600E ---

A Biospecimen Collection Study in BRAF-V600E Mutated Recurrent Gliomas This is a surgical biospecimen collection study. --- V600E ---

This is important because these drugs are currently FDA approved for other tumors and may have efficacy in brain tumors with the BRAF V600E mutation. --- V600E ---

Allowable mutations include V600E, V600K, V600R, and V600D. --- V600E ---

Glioma BRAF V600E Pleomorphic Xantho-Astrocytoma Glioblastoma Glioblastoma Glioma Astrocytoma The primary goal of this study is to establish concentrations of dabrafenib and trametinib in enhancing brain tissue and cerebrospinal fluid from people with BRAF-V600E mutant recurrent gliomas who undergo tumor resection. --- V600E ---

Glioma BRAF V600E Pleomorphic Xantho-Astrocytoma Glioblastoma Glioblastoma Glioma Astrocytoma The primary goal of this study is to establish concentrations of dabrafenib and trametinib in enhancing brain tissue and cerebrospinal fluid from people with BRAF-V600E mutant recurrent gliomas who undergo tumor resection. --- V600E --- --- V600E ---

Primary Outcomes

Description: Obtain single time-point concentration of dabrafenib in enhancing brain tissue (ng/mL) using liquid chromatography/mass spectrometry with one single, random sample

Measure: Concentration of dabrafenib in brain tumor

Time: Day 1

Description: Obtain single time-point concentration of trametinib in enhancing brain tissue (ng/mL) using liquid chromatography/mass spectrometry with one single, random sample

Measure: Concentration of trametinib in brain tumor

Time: Day 1

171 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Gefitinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with gefitinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population. In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03599518
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: DS-1205c
  2. Drug: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Is willing to provide archival tumor tissue from a biopsy performed after progression during treatment with gefitinib, erlotinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy 9. Demonstrates absence of EGFR T790M mutation in tumor tissue since progression during gefitinib, erlotinib, afatinib, or osimertinib treatment 10. Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with no deterioration over the previous 2 weeks Exclusion Criteria: 1. Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in screening biopsy performed since progression 2. Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, rearranged during transfection (RET) rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation - no new testing for these genomic alterations is required for Screening 3. Has received treatment with any of the following: 1. --- T790M --- --- V600E ---

Primary Outcomes

Measure: Number pf participants with dose-limiting toxicities during the Dose Escalation period

Time: within 28 days

Description: An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

Measure: Number of participants with adverse events (AEs)

Time: within 36 months

Secondary Outcomes

Measure: Plasma concentration of DS-1205a versus time

Time: during the 7 day run-in period

Measure: Maximum observed analyte concentration (Cmax)

Time: during the 7 day run-in period

Measure: Actual sampling time to reach Cmax (Tmax)

Time: during the 7 day run-in period

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau)

Time: during the 7 day run-in period

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough)

Time: during the 7 day run-in period

Description: Categories: DS-1205a, gefitinib

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: within 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: within 36 months

Measure: Overall survival (OS)

Time: within 36 months

172 A Bioimaging Study of 89Zr-M7824 PET Scans in Patients With Advanced or Metastatic NSCLC Receiving M7824 Alone or in Combination With Chemotherapy

This is a bioimaging study of 89Zr-M7824 PET scans in patients with advanced or metastatic non-small cell lung cancer who will be receiving M7824 alone or with standard of care chemotherapy. M7824 is a bifunctional fusion protein that combines an anti-PD-L1 antibody and the extracellular domain of TGFβ receptor II (TGFβRII) as a TGFβ neutralizing 'trap', into a single molecule.

NCT04297748
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Combination Product: 89Zirconium-M7824
  2. Drug: M7824
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Out of range values that are not clinically significant will be permitted, except for the following laboratory parameters, which must be within the ranges specified: Hemoglobin ≥ 9 g/dL Neutrophils ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L INR ≤ 1.4 Serum creatinine ≤1.3 x ULN Estimated creatinine clearance ≥ 30 ml/min according to the Cockcroft Gault formula or local normal range Serum AST and ALT ≤2.5 x ULN Serum bilirubin ≤ 1.5 x ULN Available archived formalin-fixed paraffin embedded or frozen tumour tissue; or consents to tumour biopsy at enrolment (the latter is strongly preferred) Presence of a suitable reference tumour lesion for PET imaging i.e. measuring > 1.5cm and not located in the mediastinum Exclusion Criteria: - Prior systemic immunotherapy for advanced NSCLC - Patients who are unsuitable for chemotherapy in the investigator's judgement - The participant's tumour harbors an EGFR sensitizing (activating) mutation, ALK translocation, ROS1 rearrangement, or BRAF V600E mutation - Use of anti-cancer therapy including surgery, chemotherapy, immunotherapy, radiotherapy to a non-thoracic site or any investigational therapy within 28 days prior to Study Day 1 - Has received thoracic radiotherapy > 30 Gy within 6 months of the dose of study drug - Previous malignant disease (other than NSCLC) within the last 3 years. --- V600E ---

Primary Outcomes

Description: The biodistribution of 89Zr-M7824 will be evaluated by qualitative assessment of organ uptake and clearance from PET imaging following infusion of 89Zr-M7824. Patterns of expected normal tissue uptake due to blood pool activity, and PD-L1 expression, as well as catabolism of 89Zr-M7824, will be assessed.

Measure: Biodistribution of 89Zr-M7824 in NSCLC patients

Time: Cycle 1 - 7 weeks

Secondary Outcomes

Description: Adverse responses of any grade following commencement of treatment will be recorded and quantified.

Measure: Number of participants with 89Zr-M7824 treatment-related adverse events as assessed using CTCAE v5.0.

Time: 0-12 months

Description: Adverse responses of any grade following commencement of treatment will be recorded and quantified.

Measure: Number of participants with M7824 or M7824 combined with chemotherapy treatment-related adverse events as assessed using CTCAE v5.0.

Time: 0-36 months

Other Outcomes

Description: Describe response rates to M7824 monotherapy or M7824 combined with conventional chemotherapy, defined as number of patient achieving a complete disease response, partial disease response or stable disease response determined by medical imaging of tumours.

Measure: Clinical outcomes assessed via response evaluation criteria in solid tumors (RECIST) V1.1

Time: 0-36 months

Description: To determine association of response to M7824 monotherapy with tumour uptake of 89Zr-M7824.

Measure: Correlation of clinical outcome of monotherapy with M7824 (assessed via RECIST) with tumour uptake of 89Zr-M7824 as quantified by PET imaging.

Time: 0-12 months

Description: To determine the association between PD-L1 expression determined by IHC and tumour uptake in a given lesion as measured by 89Zr-M7824 biodistribution.

Measure: Quantification of PD-L1 expression IHC and tumour uptake in a given lesion as measured by 89Zr-M7824 biodistribution.

Time: 0-12 months

173 Immune Monitoring During Systemic Therapy of Metastatic Malignant Melanoma

The mean survival time in the advanced tumor stage in the presence of distant metastases in malignant melanoma was less than 9 months until a few years ago. Intensive research efforts have led to the development of promising new therapeutic strategies and their clinical application. These include on the one hand mutation-specific inhibitors of important for cell division serine-threonine kinase BRAF such as vemurafenib, dabrafenib and encorafenib and inhibitors of the downstream target protein, the mitogen-activated protein kinase kinase (MEK), such as trametinib, binimetinib and cobimetinib. The group of immunotherapeutics is a second new class of drugs, in which great hope for the treatment of metastatic melanoma is placed. Antibody-mediated blockage of surface molecules expressed on immune cells, referred to as immune checkpoints, results in activation of the immune system. As a result, an anti-tumor immune response is triggered, which has led to considerable therapeutic success in metastatic melanoma. To date, three checkpoint inhibitors have been approved for the treatment of metastatic melanoma. Ipilimumab is an antibody that binds cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); Pembrolizumab and nivolumab cause immune stimulation by binding the Programmed Death Receptor (PD1). However, the impact of the therapy on the immune system as a whole is largely unknown. A comprehensive understanding of these effects is crucial to be able to further develop the therapy and to evaluate useful combination therapies with other immunomodulatory agents. Within the framework of this project changes of the immune response under a systemic therapy of the malignant melanoma are to be characterized. The material for the analysis comes from blood samples collected during routine patient check-ups. The aim of the analyzes is to precisely characterize the effects of the different therapeutics on the function of the immune system. In particular, the study will investigate whether certain therapeutic agents can weaken or activate the immune system and thus, in addition to the direct effect on the tumor cells, mediate indirect therapeutic effects via immune modulation. In the long term, the investigators want to use the knowledge gained to further improve the already existing therapeutic strategies of malignant melanoma by additional modulation of the immune system.

NCT04158544
Conditions
  1. Metastatic Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

The two most common BRAF mutations (V600E and V600K) constitutively activate the MAP kinase signaling pathway that drives the proliferation and survival of cancer cells. --- V600E ---

Primary Outcomes

Description: As part of the course of therapy during routine check-up, blood samples are collected and then analyzed by flow cytometry (ONE study panel). Frequency of surface antigens of PBMC are analyzed and the characterized sub-populations are monitored during the follow-up. Thereby, changes in frequency of surface antigens will be assessed compared to baseline (before start of treatment). This allows to determine the individual immunophenotype of a patient.

Measure: Change in frequency of peripheral immune cell populations assessed by immune monitoring through flow cytometry (ONE study FACS panel)

Time: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year

Description: As part of the course of therapy during routine check-up, blood samples are collected and then analyzed by flow cytometry (ONE study panel). Expression level of surface antigens of PBMC are analyzed and the characterized sub-populations are monitored during the follow-up. Thereby, changes in expression level of surface antigens will be assessed compared to baseline (before start of treatment). This allows to determine the individual immunophenotype of a patient.

Measure: Change in activation status of peripheral immune cell populations assessed by immune monitoring through flow cytometry (ONE study FACS panel)

Time: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year

Secondary Outcomes

Description: Screening for liver inflammation (serum ALT U/l)

Measure: Liver inflammation (ALT)

Time: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year

Description: Screening for liver inflammation (serum AST U/l)

Measure: Liver inflammation (AST)

Time: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year

174 A Phase 1/2, Randomized Study Evaluating Multiple Nivolumab Combination Therapies in Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) After Failure of Platinum-Based Chemotherapy and Anti-PD-1 (L)1 Immunotherapy

This study is for participants with Non-small Cell Lung Cancer that has spread or has reoccurred after failure of Chemotherapy and Immunotherapy

NCT04151563
Conditions
  1. Carcinoma, Non-small Cell Lung Cancer
Interventions
  1. Biological: nivolumab
  2. Biological: ipilimumab
  3. Drug: cabozantinib
  4. Biological: docetaxel
  5. Biological: ramucirumab
  6. Drug: lucitanib
MeSH:Lung Neoplasms Carcinoma, Non-Small- Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria - Prior treatment with Docetaxel - Untreated CNS metastases, carcinomatous meningitis or leptomeningeal metastases - Any tumor invading the Superior Vena Cava other blood vessel, GI Tract or Trachea - EGFR mutations, ALK translocations, ROS1 translocations which are sensitive to inhibitor therapy - History of cerebrovascular accident and coagulation disorders - Participants with interstital lung disease, history of cerebrovascular accident or history of abdominal fistula, gastrointestinal perforation, bowel obstruction, intra-abdominal abscess or grade 3-4 bleeding event within 6 months prior to randomization - Known toxicity on prior checkpoint inhibitor treatment - Participants who received more than one line of anti- PD-1/PD-L1 treatment - Participants who received previous CTLA-4 inhibitor treatment - Participants with known BRAF V600E mutation which are sensitive to available targeted inhibitor therapy are excluded Other protocol defined inclusion/exclusion criteria could apply For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com --- V600E ---

Exclusion Criteria - Prior treatment with Docetaxel - Untreated CNS metastases, carcinomatous meningitis or leptomeningeal metastases - Any tumor invading the Superior Vena Cava other blood vessel, GI Tract or Trachea - EGFR mutations, ALK translocations, ROS1 translocations which are sensitive to inhibitor therapy - History of cerebrovascular accident and coagulation disorders - Participants with interstital lung disease, history of cerebrovascular accident or history of abdominal fistula, gastrointestinal perforation, bowel obstruction, intra-abdominal abscess or grade 3-4 bleeding event within 6 months prior to randomization - Known toxicity on prior checkpoint inhibitor treatment - Participants who received more than one line of anti- PD-1/PD-L1 treatment - Participants who received previous CTLA-4 inhibitor treatment - Participants with known BRAF V600E mutation which are sensitive to available targeted inhibitor therapy are excluded Other protocol defined inclusion/exclusion criteria could apply Carcinoma, Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small- Carcinoma, Non-Small-Cell Lung null --- V600E ---

Primary Outcomes

Measure: Overall Reponse Rate (ORR) using RECIST 1.1 per Blinded Independent Central Review (BICR) assessment

Time: approximately 33 months

Secondary Outcomes

Measure: Overall Survival (OS)

Time: Up to 5 Years

Measure: Duration of Response (DOR) by BICR using RECIST 1.1

Time: approximately 33 months

Measure: Progression-Free Survival (PFS) by BICR using RECIST 1.1

Time: Up to 5 Years

Measure: Incidence of Adverse Events (AEs)

Time: Up to 5 Years

Measure: Incidence of Serious Adverse Events (SAEs)

Time: Up to 5 Years

Measure: Incidence of Select AEs

Time: Up to 5 Years

175 Myeloma-Developing Regimens Using Genomics (MyDRUG) (Genomics Guided Multi-arm Trial of Targeted Agents Alone or in Combination With a Backbone Regimen)

The MyDRUG study is a type of Precision Medicine trial to treat patients with drugs targeted to affect specific genes that are mutated as part of the disease. Mutations in genes can lead to uncontrolled cell growth and cancer. Patients with a greater than 30% mutation to any of the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled to one of the treatment arms. These arms have treatments specifically directed to the mutated genes. Patients that do not have a greater than 30% mutation to the genes listed can be enrolled to a non-actionable treatment arm. The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002 study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies. (NCT02884102).

NCT03732703
Conditions
  1. Relapsed Refractory Multiple Myeloma
Interventions
  1. Drug: Abemaciclib, dexamethasone, ixazomib, pomalidomide
  2. Drug: Enasidenib, dexamethasone, ixazomib, pomalidomide
  3. Drug: Cobimetinib, dexamethasone, ixazomib, pomalidomide
  4. Drug: Erdafitinib, dexamethasone, ixazomib, pomalidomide
  5. Drug: Venetoclax, dexamethasone, ixazomib, pomalidomide
  6. Drug: Daratumumab, dexamethasone, ixazomib, pomalidomide
MeSH:Multiple Myeloma Neoplasms, Plasma Cell
HPO:Multiple myeloma

Patients with a greater than 30% mutation to any of the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled to one of the treatment arms. --- V600E ---

Primary Outcomes

Description: • To evaluate the overall response rate (ORR) with targeted agents used in combination with backbone regimen ixazomib, pomalidomide and dexamethasone (IPd) in patients with an actionable genetic alteration per the International Myeloma Working Group [IMWG] consensus criteria (Kumar et al, 2016)

Measure: Overall Response Rate - Actionable Genetic Alteration

Time: Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years

Description: • To evaluate the ORR with agents used in combination with backbone (or IPd) regimen in patients with no actionable genetic alteration per IMWG consensus criteria (Kumar et al, 2016).

Measure: Overall Response Rate - Non-Actionable Genetic Alteration

Time: Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years

176 A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of ADU-1604, an Anti-CTLA-4 Antibody, in Adults With Metastatic Melanoma

This study is a first-in-human, open-label, multicenter, dose-escalation study designed to evaluate the safety, PK, and PD of ADU-1604 and explore initial clinical activity in adults with metastatic melanoma.

NCT03674502
Conditions
  1. Metastatic Melanoma
Interventions
  1. Drug: ADU-1604
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Subjects must have BRAF mutation status confirmed; if a subject is BRAF V600E/K positive, they must have received a BRAF- targeted regimen prior to entering the study, unless the patient was deemed ineligible for such treatment 4. Measurable disease according to RECIST (v1.1) [NOT required during Dose Escalation] 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Exclusion Criteria: 1. Prior diagnosis of uveal or mucosal melanoma 2. Prior treatment with CTLA-4-directed therapy in the metastatic setting. --- V600E ---

Primary Outcomes

Measure: Identify the recommended P2 dose (RP2D) of ADU-1604 administered as an IV infusion

Time: 9 months

177 A Phase III, Randomised, Open-label Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to the BRAF Inhibitor Vemurafenib in Subjects With Unresectable (Stage IIIc) or Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma

This is a two-arm, open-label, randomised, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to vemurafenib. Subjects with histologically confirmed cutaneous melanoma that is either stage IIIc (unresectable) or stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 694 subjects will be randomised 1:1 (combination therapy:vemurafenib). The primary endpoint is overall survival (OS) for subjects receiving the combination therapy compared with those receiving vemurafenib.

NCT01597908
Conditions
  1. Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Vemurafenib
  3. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Phase III, Randomised, Open-label Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to the BRAF Inhibitor Vemurafenib in Subjects With Unresectable (Stage IIIc) or Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma. --- V600E ---

Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma This is a two-arm, open-label, randomised, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to vemurafenib. --- V600E ---

Subjects with histologically confirmed cutaneous melanoma that is either stage IIIc (unresectable) or stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. --- V600E ---

Data are summarized per RECIST, Version 1.1.. Inclusion Criteria: - >= 18 years of age - Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma - Measurable disease according to RECIST 1.1 - Women of childbearing potential with negative serum pregnancy test prior to randomisation - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 - Adequate baseline organ function Exclusion Criteria: - Any prior use of a BRAF or MEK inhibitor - Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed - History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer) - Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed) - Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for >= 12 weeks, and are asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation - History or evidence of cardiovascular risk (LVEF < LLN; QTcB >= 480 msec; blood pressure or systolic >=140 mmHg or diastolic >= 90 mmHg which cannot be controlled by anti-hypertensive therapy) - History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) Inclusion Criteria: - >= 18 years of age - Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma - Measurable disease according to RECIST 1.1 - Women of childbearing potential with negative serum pregnancy test prior to randomisation - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 - Adequate baseline organ function Exclusion Criteria: - Any prior use of a BRAF or MEK inhibitor - Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed - History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer) - Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed) - Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for >= 12 weeks, and are asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation - History or evidence of cardiovascular risk (LVEF < LLN; QTcB >= 480 msec; blood pressure or systolic >=140 mmHg or diastolic >= 90 mmHg which cannot be controlled by anti-hypertensive therapy) - History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) Melanoma Melanoma null --- V600E ---

Data are summarized per RECIST, Version 1.1.. Inclusion Criteria: - >= 18 years of age - Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma - Measurable disease according to RECIST 1.1 - Women of childbearing potential with negative serum pregnancy test prior to randomisation - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 - Adequate baseline organ function Exclusion Criteria: - Any prior use of a BRAF or MEK inhibitor - Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed - History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer) - Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed) - Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for >= 12 weeks, and are asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation - History or evidence of cardiovascular risk (LVEF < LLN; QTcB >= 480 msec; blood pressure or systolic >=140 mmHg or diastolic >= 90 mmHg which cannot be controlled by anti-hypertensive therapy) - History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) Inclusion Criteria: - >= 18 years of age - Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma - Measurable disease according to RECIST 1.1 - Women of childbearing potential with negative serum pregnancy test prior to randomisation - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 - Adequate baseline organ function Exclusion Criteria: - Any prior use of a BRAF or MEK inhibitor - Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed - History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer) - Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed) - Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for >= 12 weeks, and are asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation - History or evidence of cardiovascular risk (LVEF < LLN; QTcB >= 480 msec; blood pressure or systolic >=140 mmHg or diastolic >= 90 mmHg which cannot be controlled by anti-hypertensive therapy) - History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Description: Overall survival is defined as the time from randomization until death due to any cause.

Measure: Overall Survival

Time: From randomization until death due to any cause (up to Study Week 92)

Secondary Outcomes

Description: Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression or death due to any cause. PFS for investigator-assessed response was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Measure: Progression-free Survival, as Assessed by the Investigator

Time: From randomization to the first documented occurrence of disease progression or death due to any cause (up to Study Week 80)

Description: Overall response is defined as the number of responders (complete response [CR] + partial response [PR] per RECIST, Version 1.1) as summarized by Investigator assessment. CR is defined as the disappearance of all evidence of target lesions. PR is defined as at least a 30% reduction from Baseline in the sum of the longest diameter (LD) of all target lesions. Data are reported as those participants with measureable disease.

Measure: Overall Response, as Assessed by the Investigator

Time: Screening, Week 8 and every 8 weeks thereafter through Week 56, and then every 12 weeks

Description: Duration of response is defined as the time from the first documented evidence of a CR (disappearance of all evidence of target lesions) or a PR (at least a 30% reduction from Baseline in the sum of the longest diameter of all target lesions) until disease progression or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of at least1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Data are summarized per RECIST, Version 1.1.

Measure: Duration of Response, as Assessed by the Investigator

Time: From the first documented evidence of a CR or PR until the earliest date of disease progression or death due to any cause (up to Study Week 80)

178 A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia

The purpose of this study is to find out what effects, good and/or bad, treatment with vemurafenib (also known as Zelboraf™) has on the patient and on leukemia. Specifically, the researchers want to know how well vemurafenib eliminates leukemia from the blood.

NCT01711632
Conditions
  1. Hairy Cell Leukemia
Interventions
  1. Drug: Vemurafenib
MeSH:Leukemia Leukemia, Hairy Cell
HPO:Leukemia

Exclusion Criteria: - Pregnant or breast-feeding - Have had chemotherapy (including purine analogs, rituximab, and other investigational agents) within six weeks prior to entering the study - Major surgery within 4 weeks prior to entering the study - Invasive malignancy within the past 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, melanoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug - Prior treatment with MEK or BRAF inhibitors - Active HIV, hepatitis B and hepatitis C - Patients with HCL variant (as defined by absence of expression of CD25 or absence of BRAF V600E mutation) Inclusion Criteria: - ≥ 18 years of age - Histologically confirmed classical HCL with one of the following: - Intolerance to purine analogs or considered to be poor candidates for purine analog-based therapy - Failure to achieve any response (CR or PR) to the initial purine analog-based therapy - Relapse ≤ 2 years of purine analog-based therapy - ≥ 2 relapses Histologic confirmation of diagnosis will be performed at MSKCC or a participating site. --- V600E ---

Exclusion Criteria: - Pregnant or breast-feeding - Have had chemotherapy (including purine analogs, rituximab, and other investigational agents) within six weeks prior to entering the study - Major surgery within 4 weeks prior to entering the study - Invasive malignancy within the past 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, melanoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug - Prior treatment with MEK or BRAF inhibitors - Active HIV, hepatitis B and hepatitis C - Patients with HCL variant (as defined by absence of expression of CD25 or absence of BRAF V600E mutation) Hairy Cell Leukemia Leukemia Leukemia, Hairy Cell null --- V600E ---

Primary Outcomes

Description: as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL.

Measure: efficacy of vemurafenib

Time: 3 months

Secondary Outcomes

Description: Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0.

Measure: Toxicity (safety and tolerability)

Time: 2 years

Description: Peripheral blood and/or bone marrow aspirate samples from pretreatment and post-treatment at specified time points will be assessed by Western Blot or by phospho-flow for the downstream targets of BRAF (MEK, pMEK, ERK, pERK) to assess the ontarget effect of the Vemurafenib.

Measure: To assess the pharmacodynamics

Time: 2 years

Description: Reactivation of MAPK pathways: Increased expression of the other RAF isoforms CRAF and ARAF), and MAPK (MAPK8 or COT) will be analyzed by Western Blot and/or real-time PCR39,40. Secondary BRAF mutations (all 18 BRAF exons) and RAS mutations40 will be analyzed by bidirectional Sanger sequencing and by Raindance multiplex PCR and Illumina next generation sequencing, respectively. Activation of RTKs (i.e. PDGFRβ and IGF-IR) will be assessed by Western Blot. Cell Biosciences NanoPro 1000 technology will be used to examine quantitative signaling on the entire MAPK, PI3K and JAK-STAT pathways41.

Measure: evaluate biomarkers

Time: 2 years

179 A Phase II Clinical Trial of Vemurafenib With Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Patients With Metastatic Melanoma

The purpose of this study is to find out more about the effects of an investigational combination of medicines, which includes special immune cells (T-cells). A T-cell is a type of lymphocyte, or white blood cell. Lymphocytes are a kind of white blood cell that protect the body from viral infections, help other cells fight bacterial and fungal infections, produce antibodies, fight cancers, and coordinate the activities of other cells in the immune system.

NCT01659151
Conditions
  1. Metastatic Melanoma
Interventions
  1. Drug: High Dose Interleukin-2 (IL-2)
  2. Procedure: ACT with TIL Infusion
  3. Drug: Vemurafenib
  4. Drug: Lymphodepletion
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- Residual measurable disease after resection of target lesion(s) for TIL growth - Tumor must have a B-RAF V600E, D or K mutation by pyrosequencing, Cobas assay, or equivalent (43) - Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1. ECOG performance status of 0-1 will be inferred if the patient's level of energy is ≥ 50% of baseline. --- V600E ---

Primary Outcomes

Description: Overall response (OR) is defined as the patient being alive at week 6, confirmed at week 12 and tumor size evaluated at both times using the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 to be a complete response (CR) or partial response (PR). Evaluations will be made by CT scan approximately 6 weeks after the cell infusion, then confirmed by CT scanning approximately 12 weeks after the cell infusion, and by clinical evaluation during the first 12 weeks. The complete response rate, complete and partial response rate (CPR) will be summarized using both a point estimate and its 95% exact confidence interval based on the binomial distribution.

Measure: Overall Response (OR)

Time: 12 months

Description: The drop-out rate will be summarized using both a point estimate and its 95% exact confidence interval based on the binomial distribution. For the secondary endpoint, drop-out rate, the power will be 0.66 and 0.91 at the end of stage 1 and 2, respectively, for detecting a desired drop-out rate of ≤ 20% against an expected baseline drop-out rate of ≥ 40% (based on our experience, that of the National Cancer Institute, and that seen at MD Anderson Cancer Center) using a one-sided binomial test at alpha error of 0.05.

Measure: Drop Out Rate

Time: Up to 12 months

Secondary Outcomes

Description: Progression-free survival (PFS), defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Confidence intervals for the median and survival rates at different time points will be constructed if needed and appropriate. This secondary endpoint will be reported descriptively.

Measure: Number of Participants with Progression Free Survival (PFS)

Time: 12 months

180 A Phase I Trial of Single Agent Trametinib (GSK1120212) in Advanced Cancer Patients With Hepatic Dysfunction

This phase I trial studies the side effects and best dose of trametinib in treating patients with cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) with or without liver (hepatic) dysfunction. Trametinib may stop the growth of tumor cells by blocking proteins needed for cell growth. When these proteins are blocked, the growth of cancer cells may be stopped and the cancer cells will then die. Hepatic dysfunction is frequently found in patients with advanced cancer and usually prevents patients from receiving standard treatments or from participating in clinical trials. Patients may also need dose adjustments or absorb drugs differently. Trametinib may be a better treatment for patients with advanced cancers and hepatic dysfunction.

NCT02070549
Conditions
  1. Advanced Malignant Solid Neoplasm
  2. Metastatic Malignant Neoplasm in the Liver
  3. Metastatic Malignant Solid Neoplasm
  4. Unresectable Solid Neoplasm
Interventions
  1. Drug: Trametinib
MeSH:Neoplasms
HPO:Neoplasm

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients must have a histologically or cytologically confirmed solid malignancy that is metastatic or unresectable for which standard curative or palliative treatments do not exist or are no longer effective - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients must have completed any prior chemotherapy, targeted therapy, radiotherapy (unless palliative doses which must be discussed with study principal investigator), surgery, anti-angiogenic therapy or interferon >= 28 days before study entry - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - No distinction should be made between liver dysfunction due to metastases and liver dysfunction due to other causes - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Patients with active hemolysis should be excluded. --- V600E ---

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients must have a histologically or cytologically confirmed solid malignancy that is metastatic or unresectable for which standard curative or palliative treatments do not exist or are no longer effective - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients must have completed any prior chemotherapy, targeted therapy, radiotherapy (unless palliative doses which must be discussed with study principal investigator), surgery, anti-angiogenic therapy or interferon >= 28 days before study entry - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - No distinction should be made between liver dysfunction due to metastases and liver dysfunction due to other causes - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Patients with active hemolysis should be excluded. --- V600E --- --- V600E ---

Hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - History of interstitial lung disease or pneumonitis - Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrollment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib and during the study; patients previously treated with v-raf murine sarcoma (RAF) and/or mitogen-activated protein kinase (MEK) inhibitors are excluded from the study; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (Note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Patients with intra-cardiac defibrillators - Known cardiac metastases - Active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible) - Patients with known human immunodeficiency virus (HIV) infection are eligible if not on antiviral agents and cluster of differentiation (CD)4 counts are adequate (>= 500) - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Animal reproductive studies have not been conducted with trametinib; therefore, the study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Inclusion Criteria: - Patients must have a histologically or cytologically confirmed solid malignancy that is metastatic or unresectable for which standard curative or palliative treatments do not exist or are no longer effective - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients must have completed any prior chemotherapy, targeted therapy, radiotherapy (unless palliative doses which must be discussed with study principal investigator), surgery, anti-angiogenic therapy or interferon >= 28 days before study entry - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - No distinction should be made between liver dysfunction due to metastases and liver dysfunction due to other causes - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Patients with active hemolysis should be excluded. --- V600E ---

Hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - History of interstitial lung disease or pneumonitis - Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrollment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib and during the study; patients previously treated with v-raf murine sarcoma (RAF) and/or mitogen-activated protein kinase (MEK) inhibitors are excluded from the study; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (Note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Patients with intra-cardiac defibrillators - Known cardiac metastases - Active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible) - Patients with known human immunodeficiency virus (HIV) infection are eligible if not on antiviral agents and cluster of differentiation (CD)4 counts are adequate (>= 500) - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Animal reproductive studies have not been conducted with trametinib; therefore, the study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Inclusion Criteria: - Patients must have a histologically or cytologically confirmed solid malignancy that is metastatic or unresectable for which standard curative or palliative treatments do not exist or are no longer effective - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients must have completed any prior chemotherapy, targeted therapy, radiotherapy (unless palliative doses which must be discussed with study principal investigator), surgery, anti-angiogenic therapy or interferon >= 28 days before study entry - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - No distinction should be made between liver dysfunction due to metastases and liver dysfunction due to other causes - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Patients with active hemolysis should be excluded. --- V600E --- --- V600E ---

Primary Outcomes

Description: Dose escalation and determination of the maximum tolerated dose will be carried out separately for each cohort or stratum. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Maximum tolerated dose of trametinib

Time: 28 days

Description: Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018). Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Dose-limiting toxicity

Time: 28 days

Description: Attempts to model associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.

Measure: Pharmacokinetic profile of trametinib

Time: Baseline and 0.5, 1, 2, 3, 4, 6, 10, and 24 hours on days 15 and 16 of cycle 1

Secondary Outcomes

Description: Will document in patients with varying degrees of hepatic dysfunction.

Measure: Non-dose-limiting toxicities associated with the administration of trametinib

Time: Up to 4 weeks post treatment

Description: Will be assessed using the Response Evaluation Criteria in Solid Tumors criteria 1.1. Summary statistics, such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics.

Measure: Objective response to treatment

Time: Up to 4 weeks post treatment

Description: Will be assessed by utilizing genomic sequencing technologies. Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and/or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships.

Measure: Predictive biomarkers for individual cancer patients

Time: Up to 4 weeks post treatment

181 A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination With Trametinib and Dabrafenib in Subjects With Advanced Melanoma

This is a 5-part dose-finding and preliminary efficacy study of pembrolizumab (Pembro) + dabrafenib (D) + trametinib (T) for participants with advanced melanoma and solid tumors. Parts 1 and 2 are open-label to find and confirm the maximum tolerated dose (MTD)/maximum administered dose (MAD) for Pembro+D+T. The primary hypothesis (Parts 1 and 2) is that Pembro+D+T is sufficiently well-tolerated to permit clinical investigation. Part 3 is a double-blind study of Pembro+D+T versus placebo+D+T. The primary study hypothesis (Part 3 only) is that the Pembro+D+T improves progression-free survival (PFS) compared with placebo+D+T. Part 4 is nonrandomized and open-label and is designed to evaluate the safety and tolerability and identify the MTD or MAD of Pembro+T in participants who have v-raf murine sarcoma viral oncogene homolog B1 [BRAF] mutation-negative (without V600 E or K) melanoma or solid tumors [irrespective of BRAF status]. The primary hypothesis (Part 4) is that Pembro+T is sufficiently well-tolerated to permit clinical investigation. Part 5 will confirm the dose(s) identified in Part 4 in participants BRAF wild type [without V600E or K] melanoma or solid tumors [irrespective of BRAF status] and will further evaluate the safety and preliminary efficacy (Objective Response Rate [ORR]) of Pembro+T in participants who have BRAF wild type [without V600E or K] melanoma only. The primary hypotheses (Part 5) are that Pembro+T is sufficiently well-tolerated at the MTD/MAD to permit further clinical investigation and is effective in attaining objective responses based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by Investigator review in participants who have melanoma without BRAF V600 E or K mutations. With Amendment 5 (21-Mar-2019), the Part 5 expansion cohort will not be pursued following the completion of Part 5 dose confirmation. Parts 1 and 2 of the study will also explore the MTD/MAD for open-label Pembro+T (for BRAF mutation-negative participants) concurrently with the Pembro+D+T arm; Pembro+D (for BRAF mutation-positive participants).

NCT02130466
Conditions
  1. Melanoma
  2. Solid Tumors
Interventions
  1. Biological: Pembrolizumab
  2. Drug: Dabrafenib
  3. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Part 5 will confirm the dose(s) identified in Part 4 in participants BRAF wild type [without V600E or K] melanoma or solid tumors [irrespective of BRAF status] and will further evaluate the safety and preliminary efficacy (Objective Response Rate [ORR]) of Pembro+T in participants who have BRAF wild type [without V600E or K] melanoma only. --- V600E ---

Part 5 will confirm the dose(s) identified in Part 4 in participants BRAF wild type [without V600E or K] melanoma or solid tumors [irrespective of BRAF status] and will further evaluate the safety and preliminary efficacy (Objective Response Rate [ORR]) of Pembro+T in participants who have BRAF wild type [without V600E or K] melanoma only. --- V600E --- --- V600E ---

Primary Outcomes

Measure: Parts 1, 2, 4 and 5: Number of Participants with Dose-limiting Toxicities (DLTs)

Time: Up to 6 weeks (Cycle 1)

Measure: Part 2: Objective Response Rate (ORR) in Participants Without BRAF V600 E or K Mutations

Time: Up to approximately 4 years

Measure: Part 3: Progression-Free Survival (PFS) in Participants With BRAF V600 E or K Mutations

Time: Up to approximately 4 years

Secondary Outcomes

Measure: Part 1: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations

Time: Up to approximately 4 years

Measure: Part 2: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations

Time: Up to approximately 4 years

Measure: Part 3: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations

Time: Up to approximately 4 years

Measure: Part 3: Duration of Response (DOR) in Participants With BRAF V600 E or K Mutations

Time: Up to approximately 4 years

Measure: Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations

Time: Up to approximately 4 years

182 A Phase 1 Expansion Cohort Evaluating the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Unresectable Melanoma

This phase I clinical trial studies the side effects of selinexor in treating patients with melanoma that cannot be removed by surgery. Drugs used in chemotherapy, such as selinexor, may stop the growth of tumor cells, by stopping them from dividing.

NCT02120222
Conditions
  1. Recurrent Melanoma
Interventions
  1. Drug: selinexor
  2. Other: Correlative studies
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

interleukin 2) and a BRAF and/or MEK inhibitor (if tumor contains the V600E or V600K mutation) for 628 metastatic disease. --- V600E ---

Primary Outcomes

Description: Types of toxicities, incidences and severity will be summarized by descriptive statistics such as frequencies/proportions.

Measure: Incidence of adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03

Time: 28 days

Secondary Outcomes

Measure: CBR (complete response, partial response, stable disease or stable disease) using Response Evaluation Criteria in Solid Tumors

Time: Up to 1 year

Description: Kaplan-Meier method will be used to assess the PFS.

Measure: PFS

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause or last contact, assessed up to 1 year

Description: Markers with continuous numerical data will be analyzed using linear mixed effects models (LMEMs). Binary markers (presence vs. absence) will be summarized by proportions and the confidence intervals will be calculated. Marker changes by mutation groups in plots will be presented. To correlate the marker changes with response, mainly summary statistics and plots will be used given the potentially small subgroups.

Measure: Change in tumor markers by immunohistochemistry

Time: Baseline to up to 1 year

183 A Phase II Trial to Determine Local Control and Neurocognitive Preservation After Initial Treatment With Stereotactic Radiosurgery (SRS) for Patients With >3 Melanoma Brain Metastases

This phase II trial studies how well stereotactic radiosurgery works in treating patients with melanoma that has spread to more than 3 places in the brain. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue.

NCT01644591
Conditions
  1. Clinical Stage IV Cutaneous Melanoma AJCC v8
  2. Metastatic Malignant Neoplasm in the Brain
  3. Metastatic Melanoma
  4. Pathologic Stage IV Cutaneous Melanoma AJCC v8
Interventions
  1. Other: Quality-of-Life Assessment
  2. Other: Questionnaire Administration
  3. Radiation: Stereotactic Radiosurgery
MeSH:Melanoma Neoplasms Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm Neoplasm of the skin

V. To assess the pre-treatment factors of age, Karnofsky performance scale (KPS), extra-cranial disease, BRAF-V600E mutation status in the predictive determination of local and distal control and neurocognitive outcome in each treatment arm. --- V600E ---

Primary Outcomes

Description: Time to local failure will be estimated using the product-limit estimator of Kaplan and Meier, and log-rank test will be used for comparison of local failure rate in patients treated with stereotactic radiosurgery (SRS) to null hypothesis with respect to the time to local failure. Patients who are lost to follow-up or who die from distant disease before having local failure will be censored. Local control rates at 4 months may be estimated with 95% confidence intervals using Kaplan-Meier method.

Measure: Time to progression

Time: Up to 12 months

Description: The baseline Listening Vocabulary Levels Test-Revised (HVLT-R) score will be compared to the HVLT-R score in patients surviving 4 months. Preservation of function is defined as improvement of HVLT-R score or decline by 4 points or less. Failure is defined as decline by 5 or more points. Time to neurocognitive decline will be estimated using the product-limit estimator of Kaplan and Meier, and log-rank test will be used for comparison of neurocognitive decline rate in patients treated with SRS to null hypothesis with respect to the time to neurocognitive decline. Patients who are lost to follow-up or who die before having neurocognitive decline will be censored. Rates of neurocognitive decline at 4 months may be estimated with 95% confidence intervals using Kaplan-Meier method.

Measure: Time to neurocognitive failure

Time: Up to 12 months

Secondary Outcomes

Description: Will be estimated using the product-limit estimator of Kaplan and Meier. Cox proportional hazards regression will be used to model overall survival as a function of age, Karnofsky performance status, extra-cranial disease, and BRAF mutation status. Will model time to local failure, time to distal failure, and time to neurocognitive decline using competing risk regression when death without events is considered as a competing risk.

Measure: Overall survival

Time: Up to 12 months

Description: Will use descriptive statistics and boxplots to summarize and illustrate the neurocognitive function score at each assessment time. Will similarly summarize and illustrate the change from baseline in neurocognitive function score. Will also fit the neurocognitive data with a general linear model including the baseline score as covariates to assess differences in neurocognitive scores over time (to 4 months) for those patients that are alive and progression-free at 4 months. We will also model the data with mixed effects regression including baseline HVLT-R, time, number of lesions, extra-cranial disease, and a patient specific random effect. Will use logistic regression methods to model the logit of the probability of neurocognitive decline as function of ApoE (i.e., Apo E2, Apo E3, Apo E4) genotyping, inflammatory markers, hormone growth factors.

Measure: Neurocognitive function score

Time: Up to 12 months

Description: Will use descriptive statistics to summarize the number of cycles of systemic chemotherapy given following radiation treatment for each treatment arm.

Measure: Number of cycles of systemic chemotherapy given following radiation treatment

Time: Up to 12 months

184 Pharmacodynamic Study of Vemurafenib in the Neoadjuvant Setting in Patients With Locally Advanced Thyroid Cancer

The goal of this clinical research study is to learn about how vemurafenib may affect certain biomarkers in patients with PTC. Biomarkers are in the blood/tissue and may be related to your reaction to the study drug. The safety of this drug will also be studied. Vemurafenib is designed to block the BRAF gene mutation. This mutation causes cancer and cancer growth. By blocking this mutation, the drug may kill the cancer cells with the mutation and/or stop the tumor from growing.

NCT01709292
Conditions
  1. Thyroid Cancer
Interventions
  1. Drug: Vemurafenib (All Groups)
  2. Drug: Vemurafenib (Post Surgery) - Group A + C
  3. Other: Post Surgery - Group B
MeSH:Thyroid Neoplasms Thyroid Diseases
HPO:Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

4. BRAF V600E mutation detected in the primary tumor or the recurrent/persistent tumor. 5. Total bilirubin V600E ---

Primary Outcomes

Description: ERK phosphorylation and tumor size measured at baseline before first dose of Vemurafenib and again after 56 days of Vemurafenib. We will test whether correlation between percent change in ERK phosphorylation and percent change in tumor size is different from 0 with a t-test.

Measure: Percent Change in ERK (Extracellular-Signal-Regulated Kinase) Phosphorylation and Tumor Size

Time: 56 days

Secondary Outcomes

Description: Objective response rate defined as proportion of patients who have had a partial response (PR) or complete response (CR) after initiation of therapy with Vemurafenib, using RECIST 1.1. All patients who complete baseline and day 56 scans evaluable for this endpoint.

Measure: Objective Response Rate

Time: 56 days

185 Biomarkers of Response and Resistance to Sequential B-RAF and MEK Targeted Therapy in a Pre-Surgical Model of Advanced, Operable Melanoma

This phase II trial studies how well giving dabrafenib alone and in combination with trametinib before surgery works in treating patients with advanced melanoma that can be removed by surgery. Studying samples of tumor tissue in the laboratory from patients receiving dabrafenib and trametinib may help doctors learn more about the effects of these drugs on cells and help identify biomarkers that determine which patients will respond to these drugs best.

NCT01701037
Conditions
  1. Recurrent Melanoma
  2. Stage IIB Melanoma (Locally Advanced)
  3. Stage IIC Melanoma (Locally Advanced)
  4. Stage IIIA Melanoma
  5. Stage IIIB Melanoma
  6. Stage IIIC Melanoma
  7. Stage IV Melanoma (Limited, Resectable)
Interventions
  1. Drug: dabrafenib
  2. Drug: trametinib
  3. Other: laboratory biomarker analysis
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Measured by the percent of tumor necrosis on hematoxylin and eosin stains; RNA gel electrophoresis, percent of adequate tissue for immunohistochemical stains in tissue microarray and cyTOF analysis.. Inclusion Criteria: - Signed written informed consent - Patients with locally-or regionally advanced melanoma being considered for resection of the lesion(s) for local-regional control and potential cure - Patients with limited, resectable metastatic disease (three or fewer lesions) are eligible if surgical resection is considered to be the best therapeutic option - Patients with AJCC clinical stage IIb-IV disease at initial diagnosis, or patients with melanoma of any stage with advanced local or regional recurrence, with or without limited resectable metastatic disease, would be eligible - B-RAF V-600 mutation positive by snapshot molecular analysis - Individuals with B-RAF V-600 mutations other than V600E are eligible - Measurable disease, i.e. presenting with at least one measurable lesion per Response Evaluation Criteria in Solid tumors (RECIST) 1.1 - All prior treatment related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) =< Grade 1 at the time of enrollment - Adequate baseline organ function defined by the criteria below: - Absolute Neutrophil Count (ANC) >= 1.5 X 10^9/L - Platelet Count >= 60 X 10^9/L - Hemoglobin >= 9 g/dl - Creatinine =< 2 mg/dl - Aspartate aminotransferase (AST) =< 100 U/L - Alanine aminotransferase (ALT) =< 100 U/L - Alkaline Phosphatase =< 380 U/L - Total Bilirubin =< 2.0 mg/dl - Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception during the study and for 7 days following the last dose of study treatment - Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 1 day prior to administration of the first dose of study treatment until 7 days after the last dose of study treatment Exclusion Criteria: - ECOG Performance Status > 2 - Lactating female - Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Any serious medical condition that would render the patient unable to undergo surgical resection or would limit life expectancy to less than 1 year - Any prohibited medication - Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment - A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK-2118436 (dabrafenib) or GSK-1120212 (trametinib) or excipient that contraindicates their participation - Patients with a history of severe cardiovascular disease as defined: - Symptomatic or uncontrolled cardiac arrhythmias - Treatment refractory hypertension, defined as a systolic blood pressure > 160mm Hg and/or diastolic > 100 mmHg which cannot be controlled by antihypertensive therapy. --- V600E ---

Inclusion Criteria: - Signed written informed consent - Patients with locally-or regionally advanced melanoma being considered for resection of the lesion(s) for local-regional control and potential cure - Patients with limited, resectable metastatic disease (three or fewer lesions) are eligible if surgical resection is considered to be the best therapeutic option - Patients with AJCC clinical stage IIb-IV disease at initial diagnosis, or patients with melanoma of any stage with advanced local or regional recurrence, with or without limited resectable metastatic disease, would be eligible - B-RAF V-600 mutation positive by snapshot molecular analysis - Individuals with B-RAF V-600 mutations other than V600E are eligible - Measurable disease, i.e. presenting with at least one measurable lesion per Response Evaluation Criteria in Solid tumors (RECIST) 1.1 - All prior treatment related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) =< Grade 1 at the time of enrollment - Adequate baseline organ function defined by the criteria below: - Absolute Neutrophil Count (ANC) >= 1.5 X 10^9/L - Platelet Count >= 60 X 10^9/L - Hemoglobin >= 9 g/dl - Creatinine =< 2 mg/dl - Aspartate aminotransferase (AST) =< 100 U/L - Alanine aminotransferase (ALT) =< 100 U/L - Alkaline Phosphatase =< 380 U/L - Total Bilirubin =< 2.0 mg/dl - Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception during the study and for 7 days following the last dose of study treatment - Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 1 day prior to administration of the first dose of study treatment until 7 days after the last dose of study treatment Exclusion Criteria: - ECOG Performance Status > 2 - Lactating female - Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Any serious medical condition that would render the patient unable to undergo surgical resection or would limit life expectancy to less than 1 year - Any prohibited medication - Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment - A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK-2118436 (dabrafenib) or GSK-1120212 (trametinib) or excipient that contraindicates their participation - Patients with a history of severe cardiovascular disease as defined: - Symptomatic or uncontrolled cardiac arrhythmias - Treatment refractory hypertension, defined as a systolic blood pressure > 160mm Hg and/or diastolic > 100 mmHg which cannot be controlled by antihypertensive therapy. --- V600E ---

Primary Outcomes

Description: Tumor response is defined as greater than 30% reduction from baseline in tumor volume by RECIST criteria. To determine whether a patient is responded at day 14, the patient must have the tumor volume evaluated at both baseline and day 14. The tumor response rate is calculated as the proportion of patients responded among all evaluated patients.

Measure: Clinical Tumor Response Rate (Response is Based on Greater Than 30% Reduction From Baseline in Tumor Volume by RECIST Criteria) at Day 14.

Time: day 14

Secondary Outcomes

Description: Tumor volume reduction is calculated as the tumor volume change relative to the baseline measurement (percent). Change in tumor volume reduction from day 14 to day 28 is calculated as the difference of tumor volume reduction at day 28 and day 14. The median and Inter-Quartile Range are reported.

Measure: Change in Tumor Volume Reduction in Participants With Intrinsic Resistance to B-RAF Targeted Therapy From Day 14 to Day 28.

Time: Day 14 and day 28

Description: The intensity of the adverse event will be graded according to Version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (June 14, 2010): Grade 1 - Mild Grade 2 - Moderate Grade 3 - Severe or medically significant Grade 4 - Life-threatening Grade 5 - Death related to adverse event

Measure: Number of Patients With Worst Grade Toxicities by Grade According to National Cancer Institute (NCI) CTCAE Version 4.0

Time: Up to 3 months

Description: Median number of pills taken

Measure: Investigational Agent Taken

Time: Up to 3 months

Description: Biopsies will be assessed whether or not tissue is acquired at specified time points. Tissue is obtained through core, punch, incisional or excisional biopsy or surgical resection, based upon the clinical situation. Standard operating procedures for biopsies, sample preparation and analysis have been defined.

Measure: Percent of Patients Completing Second and Third (Surgical) Biopsies

Time: Up to 3 months

Description: Measured by the percent of tumor necrosis on hematoxylin and eosin stains; RNA gel electrophoresis, percent of adequate tissue for immunohistochemical stains in tissue microarray and cyTOF analysis.

Measure: Percentage of Biopsies With Adequate Tissue for Biomarker Analysis

Time: Up to 3 months

186 Transfer of Genetically Engineered Lymphocytes in Melanoma Patients: A Phase 1 Dose Escalation Study

This is a phase one trial to determine if genetically engineered lymphocytes can be safely delivered to patients with metastatic melanoma.

NCT01586403
Conditions
  1. Melanoma
Interventions
  1. Biological: Dose 1
  2. Biological: Dose 2
  3. Biological: Dose 3
  4. Biological: Dose 4
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Patients with V600E mutations are eligible if they have failed Vemurafenib therapy or have been offered Vemurafenib therapy and refused. --- V600E ---

- Patients whose BRAF V600E mutation status is unknown, have the BRAF V600E mutation and are responding to Vemurafenib therapy, or have the BRAF V600E mutation and have not been offered the option of receiving Vemurafenib therapy for the treatment of their melanoma. --- V600E ---

- Patients whose BRAF V600E mutation status is unknown, have the BRAF V600E mutation and are responding to Vemurafenib therapy, or have the BRAF V600E mutation and have not been offered the option of receiving Vemurafenib therapy for the treatment of their melanoma. --- V600E --- --- V600E ---

- Patients whose BRAF V600E mutation status is unknown, have the BRAF V600E mutation and are responding to Vemurafenib therapy, or have the BRAF V600E mutation and have not been offered the option of receiving Vemurafenib therapy for the treatment of their melanoma. --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: Establish the recommended phase two dose of autologous T cell receptor transduced T cells when administered with low dose IL-2 to stage IV melanoma patients

Measure: Find dose of autologous T cell receptor

Time: 4 weeks

187 A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma

This is a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to dabrafenib administered with a trametinib placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 340 subjects will be randomized 1:1 (combination therapy: dabrafenib monotherapy). Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). The primary endpoint is investigator-assessed, progression-free survival for subjects receiving the combination therapy compared with those receiving dabrafenib monotherapy. Subjects will be followed for overall survival; crossover will not be permitted.

NCT01584648
Conditions
  1. Melanoma
Interventions
  1. Drug: dabrafenib
  2. Drug: dabrafenib plus trametinib placebo
  3. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma. --- V600E ---

Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. --- V600E ---

Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). --- V600E ---

Plasma concentrations of dabrafenib (GSK2118436) and its metabolites (GSK2285403, GSK2298683, and GSK2167542) were determined using the currently approved analytical methodology.. Inclusion Criteria: - Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). --- V600E ---

(Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.) - The subject has received major surgery or certain tyes of cancer therapy with 21 days of starting treatment - Current use of prohibited medication listed in the protocol - Left ventricular ejection fraction less than the lower limit of normal - Uncontrolled blood pressurl - History or current evidence of retinal vein occlusion or central serous retinopathy - Brain metastases unless previously treated with surgery or stereotactic radiosurgery and the disease has been stable for at least 12 weeks - The subject is pregnant or nursing Inclusion Criteria: - Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). --- V600E ---

Primary Outcomes

Description: Progression-free survival (PFS) is defined as the time (in months) from the date of randomization to the first documented occurrence of PD or death. Investigator PFS was summarized per response evaluation criteria in solid tumors (RECIST, version 1.1) which is a set of published criteria defining when cancer patients improve (respond), stay the same (stable) or worsen (progress). PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. For participants who had not progressed or died at the time of the analysis, censoring was performed at the last adequate disease assessment.

Measure: Progression-Free Survival (PFS) as Assessed by the Investigator

Time: From randomization until the earliest date of disease progression (PD) or death due to any cause (average of 9 study months)

Secondary Outcomes

Description: OS is defined as the interval of time (in months) between the date of randomization and the date of death due to any cause. For participants who did not die, time of death was censored at the date of last contact.

Measure: Overall Survival (OS)

Time: From randomization until death due to any cause (average of 9 study months)

Description: A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm).

Measure: Number of Participants With a Confirmed Response (Complete Response or Partial Response)

Time: From randomization until the first documented complete response or partial response (average of 9 study months)

Description: Duration of response is defined as the time (in months) from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm) until disease progression (PD). PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator.

Measure: Duration of Response for Participants With a Confirmed Response (Complete Response or Partial Response)

Time: From the time of the first documented response (CR or PR) until disease progression (average of 9 study months)

Description: An AE is defined as any untoward medical occurrence in a par., temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Protocol specific SAEs included: ALT≥3XULN and total bilirubin ≥2XULN (35% direct) or ALT ≥3XULN and INR >1.5 (if INR is measured); any new malignancy with a histology different from the primary tumor; left ventricular ejection fraction that met stopping criteria; central serous retinopathy or retinal vein occlusion; pyrexia accompanied by ≥grade 3 hypotension, or hypotension that is clinically significant as judged by the investigator, dehydration requiring IV fluids, or severe rigor/chills. Refer to the general AE/SAE module for a list of AEs and SAEs.

Measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

Time: From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (average of 9 study months)

Description: Clinical chemistry data were summarized according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe or disabling; Grade 4, Life-threatening; Grade 5, Death related to AE. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Clinical chemistry tests where the toxicity grade is defined by NCI-CTCAE includes albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, calcium, glucose, potassium, sodium, creatinine and phosphate. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. Only those participants with laboratory values for worst-case on-therapy are presented. Worst-case on-therapy included both scheduled and unscheduled visits.

Measure: Number of Participants With a Worst-case On-therapy Grade Change From Baseline to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters

Time: From Baseline up to Week 64

Description: Hematology data were summarized according to NCI-CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe, or disabling; Grade 4, Life-threatening; Grade 5, Death related to AE. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Hematology tests where the toxicity grade is defined by NCI-CTCAE includes hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. Only those participants with laboratory values for worst-case on-therapy are presented. Worst-case on-therapy included both scheduled and unscheduled visits.

Measure: Number of Participants With a Worst-case On-therapy Grade Change From Baseline to Grade 3 and 4 for the Indicated Hematology Parameters

Time: From Baseline up to Week 64

Description: Hematology tests where the toxicity grade is not defined by NCI-CTCAE includes basophils, eosinophils and monocytes. Change from Baseline is categorized as a decrease to low, change to normal or no change, increase to high in reference to the normal range. Only those participants with laboratory values for worst-case on-therapy are presented. For the worst-case on-therapy, participants were counted twice if the participant lab value decreased to low and increased to high during the on-therapy period.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline With Respect to the Normal Range for the Indicated Hematology Parameters

Time: From Baseline up to Week 64

Description: Clinical chemistry tests where the toxicity grade is not defined by NCI-CTCAE includes chloride, creatinine clearence, lactate dehydrogenase, urea, protein and carbon dioxide. Change from Baseline is categorized as decrease to low, change to normal or no change, increase to high in reference to the normal range. Only those participants with laboratory values for worst-case on-therapy are presented. For the worst-case on-therapy, participants were counted twice if the participant lab value decreased to low and increased to high during the on-therapy period.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline With Respect to the Normal Range for the Indicated Clinical Chemistry Parameters

Time: From Baseline up to Week 64

Description: Change from Baseline in heart rate is categorized as decrease to <60 beats per minute (bpm), change to normal or no change, and increase to >100 bpm. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant heart rate value decreased to <60 bpm and increased to >100 bpm post-Baseline. Only those participants with heart rate values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline in Heart Rate

Time: From Baseline up to Week 64

Description: Change from Baseline in systolic blood pressure (SBP) is categorized as: Grade 0 (<120 millimeters of mercury [mmHg]), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), and Grade 3 (>=160 mmHg). Change from Baseline in diastolic blood pressure (DBP) is categorized as: Grade 0 (<80 mmHg), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), and Grade 3 (>=100 mmHg). An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of grade 0. Only those participants with blood pressure values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3

Time: From Baseline up to Week 64

Description: Change from Baseline in temperature is categorized as a decrease to <=35 degrees celsius (C), change to normal or no change as 35-38 degrees C, and increase to >=38 degrees C. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant temperature value decreased to <=35 degrees C and increased to >=38 degrees C post-Baseline. Only those participants with temperature values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline in Temperature

Time: From Baseline up to Week 64

Description: The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. Bazett's QTc is categorized as: Grade 0 (<450 milliseconds [msec]), Grade 1 (450-480 msec), Grade 2 (481-500 msec), and Grade 3 (>=501 msec). An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of grade 0. Only those participants with Bazett's QTc values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worse-case On-therapy Change From Baseline in the Bazett's QTc to Grade 2 or Grade 3

Time: From Baseline up to Week 60

Description: Absolute change from Baseline in LVEF were summarized at each scheduled assessment time and in the worst-case post Baseline. Only the post Baseline assessments that used the same method (ECHO or Multi Gated Acquisition Scan [MUGA]) as the Baseline assessments were used to derive the change from Baseline. The change from Baseline was categorized as any increase; no change; and any decrease and as 0-10 decrease, 10 - 19 decrease, >= 20 decrease, >=10 decrease and >= lower limit of normal (LLN), >=10 decrease and 10 decrease and = 20 decrease and >= LLN, >= 20 decrease and Measure: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram

Time: From Baseline up to Week 60

Description: Participants were evaluated for the event of squamous cell carcinoma including Keratoacanthoma.

Measure: Number of Participants With Incidence of Squamous Cell Carcinoma

Time: From Baseline up to end of study (average of 9 study months)

Description: Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24.

Measure: Plasma Concentrations of Trametinib

Time: Week 8: pre-dose, 1-3 hours and 4-6 hours post dose; Week 16 pre-dose and Week 24 pre-dose

Description: Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of dabrafenib (GSK2118436) and its metabolites (GSK2285403, GSK2298683, and GSK2167542) were determined using the currently approved analytical methodology.

Measure: Plasma Concentrations of Dabrafenib and Its Metabolites

Time: Week 8: pre-dose, 1-3 hours and 4-6 hours post dose; Week 16 pre-dose and Week 24 pre-dose

188 An Open-label, Dose Escalation, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetic Profile of GSK2118436 in Japanese Subjects With BRAF V600 Mutation Positive Solid Tumors

BRF116056 is the first clinical experience with GSK2118436, a BRAF inhibitor, in Japan. This study will be designed to assess safety, tolerability, single and repeat dose PK profile and preliminary efficacy of GSK2118436 in Japanese subjects with BRAF V600 mutation positive solid tumors using continuous daily dosing schedule.

NCT01582997
Conditions
  1. Cancer
Interventions
  1. Drug: GSK2118436

- Subjects must have BRAF V600E or K mutant positive tumors. --- V600E ---

Primary Outcomes

Description: Adverse Events will be graded by the investigator according to the NCI-CTCAE (version 4.0)

Measure: Number of participants with adverse events as a measure of safety and tolerability

Time: First 28 days for Dose-limiting toxicity, Adverse Events for 1 year

Secondary Outcomes

Measure: Pharmacokinetics (PK) parameters of GSK2118436 and its metabolites including blood concentration, Cmax and AUC

Time: For 1 year

Measure: Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Time: For 1 year

Measure: Serum levels of cytokines

Time: For 1 year

Measure: Expression levels of pERK and Ki67 in tumor tissues if possible

Time: For 1 year

Measure: Gene mutation in tumor tissues, including BRAF and KRAS

Time: For 1 year

189 Diagnosing Thyroid Cancer Using a Blood Test

Thyroid cancer is a relatively rare disease but its incidence is increasing in many countries.. Early and accurate diagnosis leading to earlier treatment and intervention is recognised as a major factor in determining a good outcomes. This study will investigate new ways of diagnosing thyroid cancer from blood samples using proteomic and genetic markers. The study will take samples from patients with differentiated thyroid cancer and measure relative quantities of 1000s of proteins within the blood. These measures will be explored to see if, when used in combination they can accurately diagnose thyroid cancer. If successful this technique could be extended to routine screening and could replace more invasive tests currently used. Participants will be required to supply a small sample of blood, answer questions on their medical history and also consent for their medical records to be examined. A lifestyle questionnaire will also be supplied to each participant. In the case where a diagnosis is predicted for a condition the participant was not aware of the medical team will discuss the best interests of the patient with their GP and if required refer them to a suitable specialist. The study will run for 24 months and will routinely process around 15 and 20 participants with a history of thyroid cancer per month. All patient details will be kept confidential and only non identifiable information will leave the clinic. The work will be published and if successful will be validated on another site, commercialised and made available for routine clinical use.

NCT01586520
Conditions
  1. Differentiated Thyroid Cancer
MeSH:Thyroid Neoplasms Thyroid Diseases
HPO:Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Among the described markers point mutations (BRAF V600E, NRAS codon 61, HRAS codon 61), gene rearrangements (RET / PTC1, RET / PTC3, PAX8 / PPARgamma) and other polymorphisms have been found to be useful (Nikiforova and Nikiforov, 2009, Ohori et al, 2010). --- V600E ---

Primary Outcomes

Description: The primary objective of the study is to derive molecular (proteomic) diagnostic signatures that that can distinguish patients with recurrent / residual thyroid cancer from those with no residual disease.

Measure: Proteomic markers of differentiated thyroid cancer

Time: 24 months

Secondary Outcomes

Description: The secondary objective is to identify genetic markers of thyroid cancer status (recurrent / residual disease versus no disease) from peripheral blood samples. Information from the proteomics component of the study are expected to identify multiple potential protein markers. Genes encoding these differentially expressed proteins will be sequenced and will guide our team as to which genetic markers in peripheral blood may be targeted in order to improve the diagnostic power of molecular testing.

Measure: Genetic markers of diffferentiated thyroid cancer

Time: 24 months

190 An Open-Label, Multicenter, Phase II Study Of Continuous Oral Zelboraf (Vemurafenib) in Patients With Locally-Advanced, Unresectable, Stage IIIc Or Metastatic Melanoma and Activating Exon 15 BRAF Mutations Other Than V600E

This is an open-label, multicenter, single-agent, phase II study of continuous oral Zelboraf (vemurafenib) in participants with locally-advanced, unresectable, stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E.

NCT01586195
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

An Open-Label, Multicenter, Phase II Study Of Continuous Oral Zelboraf (Vemurafenib) in Patients With Locally-Advanced, Unresectable, Stage IIIc Or Metastatic Melanoma and Activating Exon 15 BRAF Mutations Other Than V600E. --- V600E ---

Study Of Zelboraf (Vemurafenib) in Patients With Locally-Advanced, Unresectable, Stage IIIc Or Metastatic Melanoma and Activating Exon 15 BRAF Mutations Other Than V600E This is an open-label, multicenter, single-agent, phase II study of continuous oral Zelboraf (vemurafenib) in participants with locally-advanced, unresectable, stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. --- V600E ---

Study Of Zelboraf (Vemurafenib) in Patients With Locally-Advanced, Unresectable, Stage IIIc Or Metastatic Melanoma and Activating Exon 15 BRAF Mutations Other Than V600E This is an open-label, multicenter, single-agent, phase II study of continuous oral Zelboraf (vemurafenib) in participants with locally-advanced, unresectable, stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. --- V600E --- --- V600E ---

An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 - Histologically-confirmed metastatic melanoma (unresectable Stage IIIc or IV) with an activating BRAF mutation other than V600E, as detected by DNA sequencing of exon 15 performed at a centralized laboratory - Measurable disease (as defined by RECIST, v1.1) - Adequate recovery from most recent systemic or local treatment for cancer - Adequate organ function within 28 days prior to initiation of treatment - For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of vemurafenib - For men with female partners of childbearing potential, agreement to use a latex condom and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of vemurafenib - Negative serum pregnancy test within 7 days of commencement of treatment in premenopausal women. --- V600E ---

Women who are either surgically sterile or have been post-menopausal for at least 1 year are eligible to participate in this study - Agreement not to donate blood or blood products during the study and for at least 6 months after discontinuation of vemurafenib; for male participants, agreement not to donate sperm during the study and for at least 6 months after discontinuation of vemurafenib - Signed informed consent form (prior to study entry and before performing any study-related procedures) Exclusion Criteria: - Invasive malignancy other than melanoma at the time of enrollment and within 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years - Pregnant or breast-feeding - Inability to swallow pills - Concurrent anti-tumor therapy (e.g., chemotherapy, other targeted therapy, radiation therapy, including participation in an experimental drug study) - Radiation therapy 450 ms at baseline - Ongoing cardiac dysrhythmia >/= Grade 2 - Unwillingness to practice effective birth control - Inability to comply with other requirements of the protocol Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 - Histologically-confirmed metastatic melanoma (unresectable Stage IIIc or IV) with an activating BRAF mutation other than V600E, as detected by DNA sequencing of exon 15 performed at a centralized laboratory - Measurable disease (as defined by RECIST, v1.1) - Adequate recovery from most recent systemic or local treatment for cancer - Adequate organ function within 28 days prior to initiation of treatment - For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of vemurafenib - For men with female partners of childbearing potential, agreement to use a latex condom and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of vemurafenib - Negative serum pregnancy test within 7 days of commencement of treatment in premenopausal women. --- V600E ---

Primary Outcomes

Description: BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants whose best overall response was a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson.

Measure: Best Objective Response Rate (BORR)

Time: Up to 42 months

Secondary Outcomes

Description: In participants with a confirmed CR or PR, time to BORR was defined as the interval between the date of first treatment and the date of first documentation of confirmed CR or PR (whichever occurred first). BORR was assessed by the investigators according to RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. Participants without confirmed CR or PR were censored at the date of last tumor assessment. The time to response was summarized using univariate statistics.

Measure: Time to BORR

Time: From start of treatment up to first documentation of confirmed CR or PR (up to 42 months)

Description: In participants with a confirmed CR or PR, duration of response was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Duration of response was summarized using Kaplan-Meier method.

Measure: Duration of Response

Time: From date of earliest qualifying response up to date of disease progression or death (up to 42 months)

Description: PFS was assessed by the investigators according to RECIST v1.1 and defined as the time interval between the date of the first treatment dose and the date of disease progression or death due to any cause, whichever occurred first. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. PFS was summarized using Kaplan-Meier method.

Measure: Progression-free Survival (PFS)

Time: From start of treatment up to first documentation of disease progression or death (up to 42 months)

Description: OS was defined as the time from the date of first treatment to the date of death due to any cause. OS was summarized using Kaplan-Meier method.

Measure: Overall Survival (OS)

Time: Date of first treatment to date of death due to any cause (up to 42 months)

Measure: Percentage of Participants With 6-Month Survival

Time: Baseline to Month 6

Measure: Percentage of Participants With 12-Month Survival

Time: Baseline to Month 12

Description: An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.

Measure: Number of Participants With an Adverse Event (AE)

Time: Up to 42 months

191 A Phase 2 Study of Dabrafenib and Trametinib in Combination With PDR001 in Patients With BRAFV600E Metastatic Colorectal Cancer

This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation. The names of the study drugs involved in this study are: - Dabrafenib - Trametinib - PDR001

NCT03668431
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
  3. Drug: PDR001
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Dabrafenib + Trametinib + PDR001 In Colorectal Cancer This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation. --- V600E ---

Using multiplexed immune IF and RNAseq, assess the change in immune microenvironment between pre-treatment and day 15 on-treatment biopsies Using serial cfDNA analyses, monitor response and define mechanisms of resistance to this therapy.. Inclusion Criteria: - Participants must have histologically or cytologically confirmed metastatic colorectal cancer and a documented BRAF V600E mutation by a CLIA-certified laboratory test and must be wild-type for KRAS and NRAS. --- V600E ---

Inclusion Criteria: - Participants must have histologically or cytologically confirmed metastatic colorectal cancer and a documented BRAF V600E mutation by a CLIA-certified laboratory test and must be wild-type for KRAS and NRAS. --- V600E ---

- This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation. --- V600E ---

Primary Outcomes

Description: The participants best overall response will be assessed using RECIST 1.1 criteria Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Overall Response Rate

Time: From the start of the treatment until disease progression/recurrence, up to approximately 5 years

Description: Adverse Events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE 4)

Measure: Number of participants with grade 3, 4 and 5 adverse events

Time: From the start of treatment until 30 days after the last dose of a study drug, up to approximately 5 years

Secondary Outcomes

Description: Progression free survival is measured from the date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. Progression will be assessed using RECIST 1.1 Criteria. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Measure: Progression Free Survival

Time: From the date of randomization until disease progression or death due to any cause, up to approximately 5 years

Description: The number of participants that achieve either a Complete Response (CR), Partial Response (PR), or Stable Disease (SD) per RECIST 1.1 Criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Disease Control Rate

Time: From the start of the treatment until disease progression/recurrence, up to approximately 5 years

Description: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation). Response is assessed using RECIST 1.1 Criteria.

Measure: Duration of Response

Time: From the first documented response until the time of disease progression, up to approximately 5 years

Description: Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.

Measure: Overall Survival

Time: From the date of randomization until the time of death, up to approximately 10 years

Description: Using multiplexed immune IF and RNAseq, assess the change in immune microenvironment between pre-treatment and day 15 on-treatment biopsies Using serial cfDNA analyses, monitor response and define mechanisms of resistance to this therapy.

Measure: Mechanisms of response and resistance to dabrafenib, trametinib, and PDR001

Time: Pre treatment and day 15

192 A Randomized Phase III Clinical Trial to Evaluate the Feasibility and Clinical Relevance of Liquid Biopsy in Patients With Suspicious Metastatic Lung Cancer

Lung cancer is diagnosed at metastatic stage in 60% of the cases. For these patients, first-line treatment is based on histology and molecular characterization of non-squamous non-small cell lung cancer (NSCLC). Thus, quality and quantity of tumor tissue are crucial to determine the appropriate treatment (targeted therapies, chemotherapy and immunotherapy). However, in routine practice, tissue quality and quantity can be limited (25%), resulting in the need for tumor rebiopsy for molecular analysis. Therefore, lung cancer patients often experience substantial delays before treatment initiation that may be associated with worse patient experience of subsequent cancer care and poorer clinical outcomes. "Liquid biopsies" (LB) are used to detect genomic alterations in cell-free circulating DNA (cfDNA). Since very recently, they are routinely used in reference centers for the detection of EGFR-mutations when tissue is not sufficient for molecular characterization. Importantly, the feasibility and clinical relevance of systematic liquid biopsies in routine practice has never been evaluated in patients with suspicious advanced lung cancer. Investigators hypothesize that using systematic LB in patients with clinical suspicion of metastatic lung cancer may reduce time-to-treatment initiation and avoid tissue rebiopsy. Investigators performed a retrospective study including 250 NSCLC patients treated in a tertiary Cancer Center and in the University Hospital of Lyon, France. The mean time-to-appropriate frontline treatment initiation (TTI) was 42+/-22.5 days. With the use of LB at the time of first consultation, the investigators believe it is possible to reduce the mean TTI down to 33 days (21% reduction in TTI) in the overall population with suspicious metastatic lung cancer, including a 50% and 40% reduction in TTI for EGFR/ALK/ROS1/BRAF V600E subgroups and KRAS/LKB1/ERBB2/c-MET/BRAF non V600E subgroups, respectively. Investigators therefore designed a "real-life" randomized study to evaluate the feasibility and clinical relevance of LB to decrease the TTI, which may in turn improve patients' outcome. Genomic analyses of circulating cfDNA will be performed using a robust and highly sensitive technology (InVision®), that profiles the presence of genomic aberrations in a panel of 35 genes including mutations, insertion/deletions and rearrangements, including all actionable alterations required to initiate the appropriate first-line therapy (EGFR-, ALK-, ROS1 and BRAF V600E).

NCT03721120
Conditions
  1. Metastatic Lung Cancer
Interventions
  1. Diagnostic Test: InvisionFirst® molecular panel
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

With the use of LB at the time of first consultation, the investigators believe it is possible to reduce the mean TTI down to 33 days (21% reduction in TTI) in the overall population with suspicious metastatic lung cancer, including a 50% and 40% reduction in TTI for EGFR/ALK/ROS1/BRAF V600E subgroups and KRAS/LKB1/ERBB2/c-MET/BRAF non V600E subgroups, respectively. --- V600E ---

With the use of LB at the time of first consultation, the investigators believe it is possible to reduce the mean TTI down to 33 days (21% reduction in TTI) in the overall population with suspicious metastatic lung cancer, including a 50% and 40% reduction in TTI for EGFR/ALK/ROS1/BRAF V600E subgroups and KRAS/LKB1/ERBB2/c-MET/BRAF non V600E subgroups, respectively. --- V600E --- --- V600E ---

Genomic analyses of circulating cfDNA will be performed using a robust and highly sensitive technology (InVision®), that profiles the presence of genomic aberrations in a panel of 35 genes including mutations, insertion/deletions and rearrangements, including all actionable alterations required to initiate the appropriate first-line therapy (EGFR-, ALK-, ROS1 and BRAF V600E). --- V600E ---

Appropriate treatment is defined as follow: Based on contributive results on tissue OR liquid biopsy: EGFR- or BRAF V600E-mutations, ALK- or ROS1- rearrangements: specific targeted therapies None of the four previous alterations: investigator's choice (chemotherapy and/or immunotherapy or targeted therapies based on pathology results, PD-L1 expression and access to therapies in the context of Temporary Used Authorization or clinical trials) In case of non-contributive results on tissue AND liquid biopsy: any treatment initiated by investigator (chemotherapy or immunotherapy based on pathology results and PD-L1 level of expression).. Rate of treatment initiated before molecular results. --- V600E ---

Primary Outcomes

Description: It is defined as the time between the date of randomization and the date of appropriate-treatment initiation (whatever the start date occurs before or after the biopsy results). As all the patients will receive an appropriate-treatment, no censored data are expected, thus the TTI will be analyzed as a continuous outcome. Appropriate treatment is defined as follow: Based on contributive results on tissue OR liquid biopsy: EGFR- or BRAF V600E-mutations, ALK- or ROS1- rearrangements: specific targeted therapies None of the four previous alterations: investigator's choice (chemotherapy and/or immunotherapy or targeted therapies based on pathology results, PD-L1 expression and access to therapies in the context of Temporary Used Authorization or clinical trials) In case of non-contributive results on tissue AND liquid biopsy: any treatment initiated by investigator (chemotherapy or immunotherapy based on pathology results and PD-L1 level of expression).

Measure: Time-to-appropriate Treatment Initiation (TTI)

Time: From date of randomisation to start date of appropriate treatment , assessed up to 12 months

Secondary Outcomes

Description: Defined as the proportion of patients with a treatment initiated without any available molecular results (tissue and liquid biopsy)

Measure: Rate of treatment initiated before molecular results

Time: From date of randomisation to 12 months

Description: Defined as the time from randomization to date of availability of informative molecular pathology results (positive or negative).

Measure: Time to availability of informative molecular pathology results

Time: From date of randomisation to date of molecular results, assessed up to 12 months

Description: Defined as the time from randomization to the date of the first documented clinical or radiological progression (as per RECIST version 1.1.) or death due to any cause.Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment.

Measure: Progression Free Survival (PFS)

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months

Description: Safety assessed according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version5

Measure: Incidence of diagnostic test-emergent adverse events

Time: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months

Description: 64 questions related to cancer impact on health and daily activities composed this questionnaire. Each item has to be graded from 1 to 4 (1 = not at all, 4= very much). More the score is high, worst the quality of life is.

Measure: The impact of cancer on the patient's quality of life using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (QLQ-C30)

Time: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months

Description: 10 questions related to lung cancer symptoms impact on health and daily activities composed this questionnaire. Each item has to be graded from 1 to 10. More the score is high, worst the quality of life is.

Measure: Evaluation of lung cancer symptoms impact on health and daily activities using the Lung Cancer Symptoms Scale (LCSS) questionnaire

Time: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months

Description: 6 questions related to anxiety and 6 questions related to depression composed this questionnaire. Each item has to be graded from 0 to 3. More the score of anxiety or depression is high, worst the quality of life is.

Measure: Evaluation of anxiety and depression level using Hospital Anxiety and Depression (HAD)Scale

Time: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), and at 8 weeks post treatment initiation

Description: Evaluated by the proportion of discordances (error rates) between tissue and liquid biopsies for the mutational status.

Measure: Concordance between molecular status on tissue and liquid biopsies in the experimental arm

Time: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months

Description: Be defined as the proportion of patients with an initial non-informative tissue biopsy and an informative liquid biopsy allowing appropriate treatment initiation without need for tissue rebiopsy.

Measure: Biopsy avoidance rate in the experimental arm

Time: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months

Description: All costs items related to the stratégies and supported by the payers will be collected prospectively for each patient. Mean total costs will be calculated for the 2 stratégies and be compared between the arms.

Measure: The cost analysis

Time: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months

Description: Preferences will be measured using EuroQoL 5 Dimensions 5 Levels questionnaire. Five attributes will therefore be investigated: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each attributes having five levels (from "able to […]"/"no pain/discomfort/anxiety/depression" to "unable to […]"/ "extremely pain/discomfort/anxiety/depression"). More the patient is unable to doing daily activities and painful/anxious, worst the quality-adjusted life-year (QALYs) is.

Measure: The effectiveness analysis using the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L)

Time: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months

Description: Mean QALYs (based on EQ-5D-5L score) will be calculated for each arm and will be compared between the 2 arms.

Measure: QALYS comparaison between 2 arms

Time: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months

Description: The Liquid biopsy using the InVisionFirst® cost, the evolution of market shares, the data pertaining to the target population, and the costs involved with treating the pathologies will be analysed to to estimate the budget impact on the French National Health Insurance of the generalization of innovative Liquid biopsy using the InVisionFirst® panel strategy.

Measure: The budget impact analysis in experimental arm

Time: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months

Description: Additional mandatory 10 ml DNA STRECK tubes will be collected for patients signing study consent.

Measure: Exploratory objectives : Whole-exome sequencing

Time: At baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks after the treatment initiation, and at the progression if occured within 12 month post-baseline.

Description: Additional mandatory 10 ml RNA STRECK tubes will be collected for patients signing study consent.

Measure: Exploratory objectives : miRNA profiling

Time: At baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks after the treatment initiation, and at the progression if occured within 12 month post-baseline.

193 Cetuximab and Vemurafenib Plus FOLFIRI for BRAF V600E Mutated Advanced Colorectal Cancer (IMPROVEMENT): A Single-arm Study

This clinical trial aims to evaluate the efficacy, safety of FOLFIRI with vemurafenib and cetuximab in Advanced Colorectal Cancer Patients with BRAF V600E mutation.

NCT03727763
Conditions
  1. Colorectal Cancer
Interventions
  1. Drug: Vemurafenib
  2. Drug: Cetuximab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Cetuximab and Vemurafenib Plus FOLFIRI for BRAF V600E Mutated Advanced Colorectal Cancer (IMPROVEMENT): A Single-arm Study. --- V600E ---

Cetuximab and Vemurafenib Plus FOLFIRI for BRAF V600E Mutated Advanced Colorectal Cancer (IMPROVEMENT) This clinical trial aims to evaluate the efficacy, safety of FOLFIRI with vemurafenib and cetuximab in Advanced Colorectal Cancer Patients with BRAF V600E mutation. --- V600E ---

Cetuximab and Vemurafenib Plus FOLFIRI for BRAF V600E Mutated Advanced Colorectal Cancer (IMPROVEMENT) This clinical trial aims to evaluate the efficacy, safety of FOLFIRI with vemurafenib and cetuximab in Advanced Colorectal Cancer Patients with BRAF V600E mutation. --- V600E --- --- V600E ---

Inclusion Criteria: - Patients should be histologically diagnosed with advanced colorectal adenocarcinoma or postoperative recurrence; - Patients with BRAF V600E mutation and extended RAS wild type; - Patients have measurable lesions; - Patients are not available for targeted therapy or patients refuse to receive targeted therapy; - Age should be 18-25 years; - Performance status should be 0-2; Exclusion Criteria: - Patients with RAS mutation type; - Patients with brain metastases; - Patients could not tolerate chemotherapy; - Patients have secondary primary tumor Inclusion Criteria: - Patients should be histologically diagnosed with advanced colorectal adenocarcinoma or postoperative recurrence; - Patients with BRAF V600E mutation and extended RAS wild type; - Patients have measurable lesions; - Patients are not available for targeted therapy or patients refuse to receive targeted therapy; - Age should be 18-25 years; - Performance status should be 0-2; Exclusion Criteria: - Patients with RAS mutation type; - Patients with brain metastases; - Patients could not tolerate chemotherapy; - Patients have secondary primary tumor Colorectal Cancer Colorectal Neoplasms null --- V600E ---

Inclusion Criteria: - Patients should be histologically diagnosed with advanced colorectal adenocarcinoma or postoperative recurrence; - Patients with BRAF V600E mutation and extended RAS wild type; - Patients have measurable lesions; - Patients are not available for targeted therapy or patients refuse to receive targeted therapy; - Age should be 18-25 years; - Performance status should be 0-2; Exclusion Criteria: - Patients with RAS mutation type; - Patients with brain metastases; - Patients could not tolerate chemotherapy; - Patients have secondary primary tumor Inclusion Criteria: - Patients should be histologically diagnosed with advanced colorectal adenocarcinoma or postoperative recurrence; - Patients with BRAF V600E mutation and extended RAS wild type; - Patients have measurable lesions; - Patients are not available for targeted therapy or patients refuse to receive targeted therapy; - Age should be 18-25 years; - Performance status should be 0-2; Exclusion Criteria: - Patients with RAS mutation type; - Patients with brain metastases; - Patients could not tolerate chemotherapy; - Patients have secondary primary tumor Colorectal Cancer Colorectal Neoplasms null --- V600E --- --- V600E ---

Primary Outcomes

Description: Evaluation of tumor burden based on RECIST criteria every 4 cycles(each cycle is 14 days), ORR is the proportion of patients with reduction in tumor burden of a predefined amount, including complete response and partial response.

Measure: Objective Respone Rate(ORR)

Time: up to 55months

Secondary Outcomes

Description: (ETS) rate is defined as 20% reduction in target lesions after the first 6 weeks of treatment (first tumor assessment)

Measure: Early tumor shrinkage (ETS) rate

Time: up to 55months

Other Outcomes

Description: Evaluation of tumor burden based on RECIST criteria every 4 cycles(each cycle is 14 days), and DCR is the proportion of patients with reduction in tumor burden of a predefined amount, including complete response, partial response and stable disease

Measure: Disease Control Rate (DCR)

Time: up to 55months

194 Phase II, Multicentre Clinical Trial to Evaluate the Activity of Encorafenib and Binimetinib Administered Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain

Phase II clinical trial, with two cohorts of patients included in parallel, all with melanoma BRAF mutated and brain metastases without previous local treatment in the brain. Cohort 1 will include patients with asymptomatic brain metastases and cohort 2 will include patients with symptomatic brain metastasis.

NCT03898908
Conditions
  1. Metastatic Melanoma
  2. Brain Metastases
Interventions
  1. Drug: encorafenib
  2. Drug: binimetinib
  3. Radiation: Whole brain radiation therapy
  4. Radiation: Radiosurgery/stereotactic radiosurgery
MeSH:Melanoma Neoplasm Metastasis
HPO:Cutaneous melanoma Melanoma

- Histologically confirmed diagnosis of unresectable metastatic cutaneous melanoma, or unknown primary melanoma with one or more brain metastasis with a diameter of 10 to 50 mm, measured by contrast enhanced MRI. - Presence of a BRAF V600E or V600K mutation, or both, in their tumour tissue. --- V600E ---

Primary Outcomes

Description: iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment in cohort 1. The final statistical analysis of this endpoint is expected to be performed within 3 months after the local treatment of the last patient in cohort 1. This outcome will be assessed on day 56, and every 8 weeks up to 24 months after start of treatment

Measure: Intracranial objective response by RECIST 1.1 before local radiotherapy treatment in cohort 1

Time: 24 months after start of treatment

Secondary Outcomes

Description: ORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment in cohort 1. The final statistical analysis of this endpoint is expected to be performed within 3 months after the local treatment of the last patient in cohort 2. This outcome will be assessed on day 56, and every 8 weeks up to 24 months after start of treatment

Measure: Intracranial objective response by RECIST 1.1 before local radiotherapy treatment in cohort 2

Time: 24 months after start of treatment

Measure: Global intracranial response in both cohorts

Time: 24 months

Measure: Duration of intracranial response in both cohorts

Time: 24 months

Measure: Duration of global response in both cohorts

Time: 24 months

Measure: Intracranial progression-free survival (PFS) by RECIST 1.1 in both cohorts

Time: 24 months

Measure: Global (intracranial and extracranial) progression-free survival in both cohorts

Time: 24 months

Measure: Percentage of patients free of progression (intracraneal and extracraneal)

Time: 24 months

Measure: Overall survival in both cohorts

Time: 24 months

Measure: Percentage of patients alive in both cohorts

Time: 24 months

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 until local treatment in both cohorts

Time: 24 months

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 after local treatment in both cohorts

Time: 24 months

Description: Compared to baseline evaluation evaluated after 8 weeks since the start of treatment

Measure: Change on Quality of life at week 8 in both cohorts based on the EORTC QLQ 30 scale

Time: 8 weeks

Description: Compared to baseline evaluation evaluated after 24 weeks since the start of treatment

Measure: Change on Quality of life at week 24 in both cohorts based on the EORTC QLQ 30 scale

Time: 24 weeks

195 Phase I/II Trial of Encorafenib, Binimetinib, and Nivolumab in Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer

This phase I/II trial studies the side effects and how well encorafenib, binimetinib, and nivolumab work in treating patients with microsatellite stable, BRAFV600E gene-mutated colorectal cancer that has spread to other places in the body (metastatic). Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving encorafenib, binimetinib, and nivolumab may work better in treating patients with colorectal cancer compared to standard treatments.

NCT04044430
Conditions
  1. Metastatic Colon Adenocarcinoma
  2. Metastatic Colorectal Adenocarcinoma
  3. Metastatic Microsatellite Stable Colorectal Carcinoma
  4. Metastatic Rectal Adenocarcinoma
  5. Stage III Colon Cancer
  6. Stage III Colorectal Cancer
  7. Stage III Rectal Cancer
  8. Stage IIIA Colon Cancer
  9. Stage IIIA Colorectal Cancer
  10. Stage IIIA Rectal Cancer
  11. Stage IIIB Colon Cancer
  12. Stage IIIB Colorectal Cancer
  13. Stage IIIB Rectal Cancer
  14. Stage IIIC Colon Cancer
  15. Stage IIIC Colorectal Cancer
  16. Stage IIIC Rectal Cancer
  17. Stage IV Colon Cancer
  18. Stage IV Colorectal Cancer
  19. Stage IV Rectal Cancer
  20. Stage IVA Colon Cancer
  21. Stage IVA Colorectal Cancer
  22. Stage IVA Rectal Cancer
  23. Stage IVB Colon Cancer
  24. Stage IVB Colorectal Cancer
  25. Stage IVB Rectal Cancer
  26. Stage IVC Colon Cancer
  27. Stage IVC Colorectal Cancer
  28. Stage IVC Rectal Cancer
Interventions
  1. Drug: Binimetinib
  2. Drug: Encorafenib
  3. Biological: Nivolumab
  4. Other: Questionnaire Administration
MeSH:Colorectal Neoplasms Adenocarcinoma Rectal Neoplasms Colonic Neoplasms
HPO:Colon cancer Neoplasm of the colon Neoplasm of the large intestine Neoplasm of the rectum

Phase I/II Trial of Encorafenib, Binimetinib, and Nivolumab in Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer. --- V600E ---

Encorafenib, Binimetinib, and Nivolumab in Treating Patients With Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer This phase I/II trial studies the side effects and how well encorafenib, binimetinib, and nivolumab work in treating patients with microsatellite stable, BRAFV600E gene-mutated colorectal cancer that has spread to other places in the body (metastatic). --- V600E ---

Primary Outcomes

Description: Will be measured according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). The point estimate of the objective response rate (ORR) and its 95% confidence interval will be obtained.

Measure: Radiographic Response

Time: Up to 3 years

Description: Will be assessed in the following order of importance: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and not evaluable. The point estimate of the ORR and its 95% confidence interval will be obtained

Measure: Best investigator-assessed response

Time: Up to 3 years

Description: Will be graded according to the Common Terminology Criteria for Adverse Events version 5.0. Safety data will be tabulated.

Measure: Incidence of treatment-related grade 3 or higher adverse events (AEs)

Time: 100 days after last dose

Secondary Outcomes

Description: Will be defined by irRECIST criteria for the evaluable population. Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from start of treatment until death or PD

Measure: Progression-free survival

Time: Up to 3 years

Description: Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from start of treatment until death occurs

Measure: Overall survival

Time: Up to 3 years

Description: Will be defined by irRECIST criteria. Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from start of treatment until time of response.

Measure: Time (in days) to response criteria

Time: Up to 3 years

Description: Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from first partial or CR to time of PD or death for subjects with a response

Measure: Duration of response

Time: Up to 3 years

Description: The proportion of patients with CR, PR, or SD defined by irRECIST criteria in the evaluable population. The point estimate of DCR and its 95% confidence interval will be obtained.

Measure: Disease control rate (DCR)

Time: Up to 3 years

196 A Phase 1b, Multicenter, Two-Part, Open-Label Study of Trastuzumab Deruxtecan (DS-8201a), An Anti-Human Epidermal Growth Factor Receptor-2 (HER2)-Antibody Drug Conjugate (ADC), In Combination With Pembrolizumab, An Anti-PD-1 Antibody, In Subjects With Locally Advanced/Metastatic Breast Or Non-Small Cell Lung Cancer (NSCLC)

This two-part study will include a dose escalation part to determine the recommended dose for expansion of DS8201a and pembrolizumab and a dose expansion part to evaluate efficacy, safety, and tolerability of the combination.

NCT04042701
Conditions
  1. Breast Cancer
  2. Non-small Cell Lung Carcinoma
Interventions
  1. Drug: Trastuzumab deruxtecan (DS-8201a)
  2. Drug: Trastuzumab deruxtecan (DS-8201a)
  3. Drug: Pembrolizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Adequate organ function - Adequate treatment washout period before enrollment Inclusion Criteria Specific to Part 1 - Participants in Part 1 should meet the additional inclusion criteria listed for 1 of the 4 cohorts in Part 2. Inclusion Criteria Specific to Part 2 Inclusion Criteria for Cohort 1 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-positive expression as per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines - Received prior trastuzumab emtansine (T-DM1) therapy with documented progression Inclusion Criteria for Cohort 2 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-low expression (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH-]) - Participants must have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for participants who are hormone receptor positive) Inclusion Criteria for Cohort 3 - Pathologically documented, locally advanced/metastatic NSCLC that has centrally determined HER2-expression (IHC 1+, 2+, or 3+) - Participants who have known epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Inclusion Criteria for Cohort 4 - Pathologically documented, locally advanced/metastatic HER2-mutant NSCLC - Participants who have known EGFR mutation, ALK, BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with available targeted therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Exclusion Criteria: - Prior treatment with pembrolizumab or DS-8201a - Medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 days prior to enrollment - Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) - History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening - Spinal cord compression or clinically active central nervous system metastases - Clinically significant corneal disease - Active, known or suspected autoimmune disease - Condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment - Prior therapy with an anti-PD-1 or anti-PD-L1 agent - Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) - Prior anti-HER2 therapy is not allowed for participants with HER2 low-expressing breast cancer or participants with NSCLC (Cohorts 2, 3, or 4). --- V600E ---

- Adequate organ function - Adequate treatment washout period before enrollment Inclusion Criteria Specific to Part 1 - Participants in Part 1 should meet the additional inclusion criteria listed for 1 of the 4 cohorts in Part 2. Inclusion Criteria Specific to Part 2 Inclusion Criteria for Cohort 1 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-positive expression as per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines - Received prior trastuzumab emtansine (T-DM1) therapy with documented progression Inclusion Criteria for Cohort 2 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-low expression (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH-]) - Participants must have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for participants who are hormone receptor positive) Inclusion Criteria for Cohort 3 - Pathologically documented, locally advanced/metastatic NSCLC that has centrally determined HER2-expression (IHC 1+, 2+, or 3+) - Participants who have known epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Inclusion Criteria for Cohort 4 - Pathologically documented, locally advanced/metastatic HER2-mutant NSCLC - Participants who have known EGFR mutation, ALK, BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with available targeted therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Exclusion Criteria: - Prior treatment with pembrolizumab or DS-8201a - Medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 days prior to enrollment - Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) - History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening - Spinal cord compression or clinically active central nervous system metastases - Clinically significant corneal disease - Active, known or suspected autoimmune disease - Condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment - Prior therapy with an anti-PD-1 or anti-PD-L1 agent - Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) - Prior anti-HER2 therapy is not allowed for participants with HER2 low-expressing breast cancer or participants with NSCLC (Cohorts 2, 3, or 4). --- V600E --- --- V600E ---

Primary Outcomes

Description: Maximum Tolerated Dose (MTD) or recommended dose expansion (RDE) of DS-8201a (Part1) are based on the occurrence of DLTs.

Measure: Dose-limiting toxicities (DLTs), Part 1

Time: Within two 3-week cycles (6 weeks)

Measure: Objective Response Rate (ORR), Confirmed by Independent Central Review, Part 2

Time: Within approximately 30 months

Secondary Outcomes

Measure: Duration of Response (DoR)

Time: Within approximately 30 months

Measure: Disease Control Rate (DCR)

Time: Within approximately 30 months

Measure: Progression-Free Survival (PFS), based on Independent Central Review using RECIST v1.1

Time: Within approximately 30 months

Measure: Time to Response (TTR), based on Independent Central Review using RECIST v1.1

Time: Within approximately 30 months

Measure: Overall survival (OS)

Time: Within approximately 30 months

197 A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, Tolerability, and Antitumor Activity of the Combination in Patients With Select Advanced or Metastatic Solid Tumors

The purpose of this study is to determine the safety and tolerability of TAK-981 in combination with pembrolizumab in participants with select solid tumor indications and to establish the recommended phase 2 dose (RP2D) during Phase 1b of study and to evaluate the preliminary efficacy of TAK-981 at the RP2D in combination with pembrolizumab in participants with select solid tumor indications in Phase 2 of the study.

NCT04381650
Conditions
  1. Advanced or Metastatic Solid Tumors
Interventions
  1. Drug: TAK-981
  2. Drug: Pembrolizumab
MeSH:Neoplasms
HPO:Neoplasm

epidermal growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. --- V600E ---

epidermal growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. --- V600E --- --- V600E ---

Primary Outcomes

Description: An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.

Measure: Phase 1: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs)

Time: Up to 48 months

Description: DLTs are defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v5.0 as: Any Grade 5 AE, Grade 4 hematologic AE, platelet count <10.0 x10^9/L, febrile neutropenia [>=Grade 3 neutropenia (absolute neutrophil count <1.0 ×10^9/L) with fever and/or infection], Grade 3 thrombocytopenia lasting longer than 14 days or accompanied by Grade 2 bleeding or requiring transfusion, Grade 3 immune-related adverse event such as pericarditis, pneumonitis, cardiotoxicity, hepatitis or neurotoxicity, >=Grade 3 nonhematologic toxicity, Grade 2 nonhematologic toxicities related to study drug and dose-limiting, delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematological toxicities or missed >=1 planned dose of TAK-981 or planned dose of pembrolizumab in Cycle 1 due to treatment-related AEs.

Measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: Up to Cycle 1 (each cycle is of 21 days)

Description: An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs will be graded using NCI CTCAE 5.0.

Measure: Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)

Time: Up to 48 months

Description: An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.

Measure: Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs)

Time: Up to 48 months

Description: An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.

Measure: Phase 1: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation

Time: Up to 48 months

Description: Laboratory parameters includes parameters of clinical chemistry, hematology, and urinalysis.

Measure: Phase 1: Number of Participants With Clinically Significant Laboratory Values

Time: Up to 48 months

Description: ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR) (determined by the investigator) during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as disappearance of all target lesions; PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.

Measure: Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1

Time: Up to 48 months

Secondary Outcomes

Measure: Phase 2: Cmax: Maximum Observed Plasma Concentration for TAK-981

Time: Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.

Measure: Phase 2: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981

Time: Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.

Measure: Phase 2: AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981

Time: Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.

Measure: Phase 2: AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981

Time: Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.

Measure: Phase 2: t1/2z: Terminal Disposition Phase Half-life for TAK-981

Time: Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.

Measure: Phase 2: CL: Total Clearance After Intravenous Administration for TAK-981

Time: Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.

Measure: Phase 2: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981

Time: Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.

Description: ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR)(determined by the investigator) during the study according to consensus guideline developed by the RECIST Working Group for the use of modified RECIST, Version 1.1 in cancer immunotherapy trials (iRECIST). CR is defined as disappearance of all target lesions; PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.

Measure: Phase 2: ORR as Defined by the Investigator According to iRECIST Modification

Time: Up to 48 months

Description: DOR is defined as a time from the time of first documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study (up to approximately 48 months). PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Phase 2: Duration of Response (DOR)

Time: Up to 48 months

Description: PFS is defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study (up to approximately 48 months). PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Phase 2: Progression-free Survival (PFS)

Time: Up to 48 months

Description: TTR is defined as time from the date of first study drug administration to the date of first documented PR or better (up to approximately 48 months). PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.

Measure: Phase 2: Time to Response (TTR)

Time: Up to 48 months

Description: TAK-981-SUMO adduct formation in blood will be evaluated.

Measure: Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Blood

Time: Up to 48 months

Description: SUMO pathway inhibition in blood will be evaluated.

Measure: Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose in Blood

Time: Up to 48 months

198 A Phase I Trial of a Recombinant Human hsp110-gp100 Chaperone Complex Vaccine for Advanced Stage IIIB/C or IV Melanoma

This phase I trial studies the side effects and best dose of vaccine therapy in treating patients with stage III-IV melanoma that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Vaccines made from peptides or antigens may help the body build an effective immune response to kill tumor cells.

NCT01744171
Conditions
  1. Recurrent Melanoma
  2. Stage IIIB Skin Melanoma
  3. Stage IIIC Skin Melanoma
  4. Stage IV Skin Melanoma
Interventions
  1. Biological: Recombinant Human Hsp110-gp100 Chaperone Complex Vaccine
  2. Other: Laboratory Biomarker Analysis
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Recombinant hsp110-gp100 chaperone complex vaccine specific cell mediated and humoral immune responses elicited by the chaperone complex vaccine as well as the effect of dose and serial administration on these responses will be assessed through the correlative science studies.. Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Recurrent Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and clinically appropriate dose of human heat shock protein (hsp)110-gp100 chaperone complex melanoma vaccine (recombinant hsp110-gp100 chaperone complex vaccine) to recommend a phase II dose in stage IIIB/C and stage IV metastatic melanoma patients. --- V600E ---

Recombinant hsp110-gp100 chaperone complex vaccine specific cell mediated and humoral immune responses elicited by the chaperone complex vaccine as well as the effect of dose and serial administration on these responses will be assessed through the correlative science studies.. Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Recurrent Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and clinically appropriate dose of human heat shock protein (hsp)110-gp100 chaperone complex melanoma vaccine (recombinant hsp110-gp100 chaperone complex vaccine) to recommend a phase II dose in stage IIIB/C and stage IV metastatic melanoma patients. --- V600E --- --- V600E ---

Recombinant hsp110-gp100 chaperone complex vaccine specific cell mediated and humoral immune responses elicited by the chaperone complex vaccine as well as the effect of dose and serial administration on these responses will be assessed through the correlative science studies.. Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Recurrent Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and clinically appropriate dose of human heat shock protein (hsp)110-gp100 chaperone complex melanoma vaccine (recombinant hsp110-gp100 chaperone complex vaccine) to recommend a phase II dose in stage IIIB/C and stage IV metastatic melanoma patients. --- V600E --- --- V600E --- --- V600E ---

Recombinant hsp110-gp100 chaperone complex vaccine specific cell mediated and humoral immune responses elicited by the chaperone complex vaccine as well as the effect of dose and serial administration on these responses will be assessed through the correlative science studies.. Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Recurrent Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and clinically appropriate dose of human heat shock protein (hsp)110-gp100 chaperone complex melanoma vaccine (recombinant hsp110-gp100 chaperone complex vaccine) to recommend a phase II dose in stage IIIB/C and stage IV metastatic melanoma patients. --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Recombinant hsp110-gp100 chaperone complex vaccine specific cell mediated and humoral immune responses elicited by the chaperone complex vaccine as well as the effect of dose and serial administration on these responses will be assessed through the correlative science studies.. Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Recurrent Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and clinically appropriate dose of human heat shock protein (hsp)110-gp100 chaperone complex melanoma vaccine (recombinant hsp110-gp100 chaperone complex vaccine) to recommend a phase II dose in stage IIIB/C and stage IV metastatic melanoma patients. --- V600E --- --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Recombinant hsp110-gp100 chaperone complex vaccine specific cell mediated and humoral immune responses elicited by the chaperone complex vaccine as well as the effect of dose and serial administration on these responses will be assessed through the correlative science studies.. Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Inclusion Criteria: - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Absolute neutrophil count (ANC) > 1500/uL - Platelets >= 120,000/uL - Total bilirubin =< 1.5 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) - Serum creatinine =< 1.5 mg/dL (if > 1.5 mg/dL, then creatinine clearance should be > 60 mL/min) - Blood urea nitrogen (BUN) =< 1.5 x ULN - Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam - An anticipated overall survival of at least 6 months - Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment - Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure - Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status - Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin [IL]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) - Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen) Exclusion Criteria: - Pregnant or nursing female patients - Unwilling or unable to follow protocol requirements - Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug - Received an investigational agent within 30 days prior to enrollment - Melanoma specific systemic therapy within 30 days of enrollment - A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease - Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded - Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis - Previous history of splenectomy or whole spleen radiation - Systemic immunoglobulin therapy within the last 30 days - Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens - Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years - Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled Recurrent Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and clinically appropriate dose of human heat shock protein (hsp)110-gp100 chaperone complex melanoma vaccine (recombinant hsp110-gp100 chaperone complex vaccine) to recommend a phase II dose in stage IIIB/C and stage IV metastatic melanoma patients. --- V600E --- --- V600E --- --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: DLT is defined as grade 3 or 4 toxicity or grade 3 injection site toxicity, with the exception of grade 3 rigors/chills which will be tolerated for 48-72 hours if attributable to vaccine reaction.

Measure: MTD of recombinant human hsp110-gp100 chaperone complex melanoma vaccine based on the probability of dose-limiting toxicity (DLT), graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4

Time: Up to 30 days after the last vaccine dose

Secondary Outcomes

Description: Recombinant hsp110-gp100 chaperone complex vaccine specific cell mediated and humoral immune responses elicited by the chaperone complex vaccine as well as the effect of dose and serial administration on these responses will be assessed through the correlative science studies.

Measure: Objective tumor response according to RECIST version 1.1

Time: Up to 6 months

199 A Phase I Trial of MEK Inhibitor Trametinib in Combination With Neoadjuvant 5-Fluorouracil Chemoradiation in the Treatment of KRAS, BRAF, and NRAS-MUTANT Rectal Cancers

This phase I trial studies the side effects and best dose of trametinib when given together with fluorouracil and radiation therapy before surgery in treating patients with stage II-III rectal cancer. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving trametinib together with fluorouracil and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed

NCT01740648
Conditions
  1. Recurrent Rectal Cancer
  2. Stage IIA Rectal Cancer
  3. Stage IIB Rectal Cancer
  4. Stage IIC Rectal Cancer
  5. Stage IIIA Rectal Cancer
  6. Stage IIIB Rectal Cancer
  7. Stage IIIC Rectal Cancer
Interventions
  1. Drug: trametinib
  2. Drug: fluorouracil
  3. Radiation: radiation therapy
MeSH:Rectal Neoplasms
HPO:Neoplasm of the rectum

- Presence of V600E BRAF gene mutation, or - Presence of an NRAS mutation at codon 12, 13, or 61 Exclusion Criteria: - History of another malignancy; exception: subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible - Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator - Prior chemotherapy treatment unless > 5 years ago - Prior treatment with a selective inhibitor of v-raf-1 murine leukemia viral oncogene homolog 1 (RAF) or mitogen-activated protein kinase kinase 1 (MEK) - Prior radiation therapy to the abdomen or pelvis - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO) - Current use of a prohibited medication - History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E ---

Primary Outcomes

Measure: Identify the maximally tolerated dose of Trametinib to be used in combination with 5FU and radiation in patients with rectal cancers.

Time: up to 9 weeks

Secondary Outcomes

Description: The observed adverse events and their grade and attribution for each dose level, and patterns reflecting tolerability of the regimen will be summarized through graphical analysis and descriptive summaries.

Measure: Frequency of dose-limiting toxicities, assessed according to the NCI CTCAE version 4

Time: up to 9 weeks

Description: Will be described graphically and quantitatively using the methods of Kaplan and Meier.

Measure: Local failure rate

Time: From the time of study enrollment until the first documented date of local failure, assessed up to 5 years

Description: Will be described graphically and quantitatively using the methods of Kaplan and Meier.

Measure: Progression free survival

Time: From the time of study enrollment until the first documented date of disease progression, assessed up to 5 years

Description: Will be described graphically and quantitatively using the methods of Kaplan and Meier.

Measure: Overall survival

Time: From the time of study enrollment until the time of death, assessed up to 5 years

Description: Assuming that this measure is binomially distributed, the proportion will be estimated and corresponding 95% binomial confidence intervals generated.

Measure: Pathological response rate, defined as extent of tumor in the resected specimen that is classified by tumor, lymph node, metastasis (TNM) staging of the AJCC/International Union Against Cancer (UICC)

Time: Up to 5 years

Description: Assuming that this measure is binomially distributed, the proportion will be estimated and corresponding 95% binomial confidence intervals generated.

Measure: Frequency of patients undergoing sphincter preserving surgery

Time: Up to 5 years

200 Pediatric Neuro-Oncology Consortium (PNOC)-002: Safety, Phase 0, and Pilot Efficacy Study of Vemurafenib, an Oral Inhibitor of BRAFV600E, in Children and Young Adults With Recurrent/Refractory BRAFV600E- or BRAF Ins T Mutant Brain Tumors

This is a multicenter, safety and pharmacokinetic trial to determine the MTD and/or select a recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory gliomas containing the BRAFV600E or BRAF Ins T mutation.

NCT01748149
Conditions
  1. Pediatric Recurrent/Refractory BRAFV600E-mutant Gliomas
Interventions
  1. Drug: Vemurafenib
MeSH:Glioma
HPO:Glioma

Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E (BRAFV600E)-Mutant Gliomas This is a multicenter, safety and pharmacokinetic trial to determine the MTD and/or select a recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory gliomas containing the BRAFV600E or BRAF Ins T mutation. --- V600E ---

Primary Outcomes

Description: To determine if the maximum tolerated dose of vemurafenib established in adults is safe and tolerable in pediatric patients with BRAFV600E-mutant gliomas. (Dose is adjusted for pediatric use. Weighted dose extrapolated from FDA approved standard adult dose)

Measure: Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D)

Time: Up to 4 weeks

Description: To describe the toxicity profile/dose limiting toxicity (DLT) of vemurafenib in children with recurrent or refractory glioma. DLT will be assessed by monitoring for adverse events, scheduled laboratory assessments, vital sign measurements, ECGs, and physical examinations. The severity of the toxicities will be graded according to the NCI CTCAE v 4.0. Adverse events and clinically significant laboratory abnormalities (meeting Grade 3, 4, or 5 criteria according to CTCAE) will be summarized by maximum intensity and relationship to study drug. Safety will be assessed weekly for the first 4 weeks and then every 4 weeks. Descriptive statistics will be utilized to display the data on toxicity seen. Safety will be assessed weekly for the first 4 weeks and then every 4 weeks. Descriptive statistics will be utilized to display the data on toxicity seen.

Measure: Toxicity Profile (dose limiting toxicities)

Time: Up to 4 weeks

Description: Venous blood samples (2 mL) will be collected in sodium heparin to measure concentrations of vemurafenib for each PK blood collection. To characterize the pharmacokinetics of vemurafenib in pediatric patients. Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Mandatory plasma pharmacokinetic studies will be performed in all patients enrolled on the MTD, pre-surgical, and "crushed" pill cohorts of this trial. Because the pharmacokinetics of this agent are unknown in the pediatric population, this information will be essential for evaluating toxicity and disease response and for refining dosing in future clinical trials of vemurafenib.

Measure: Concentrations of vemurafenib in the blood found through pharmacokinetic (PK) samples

Time: Up to 4 weeks

Description: To document antitumor activity of treatment with vemurafenib, as measured by objective responses.Objective response will be assessed using the RECIST Response criteria. The response will be collected on case report forms (CRFs). The study team will include complete responses (CR's), partial responses (PR's) and sustained stable disease (SSD- defined as stable disease on two successive scans). The target response rate is 20%. The number and percent of subjects with each type of response will be summarized and presented in data listings.

Measure: Objective Response

Time: Up to 4 weeks

Secondary Outcomes

Description: Subsequent to the safety cohort, the study team will begin enrollment into a presurgical study. Patients who are candidates for surgical resection at the time of relapse, would be eligible for this component of the trial. The aim will be to measure drug levels (based on the dose chosen in the safety cohort) in tumor, with an additional aim to describe target modulation, with vemurafenib treated tumor compared with corresponding archived tissue from prior surgery. Tumor phospho-extracellular signal-regulated kinase (ERK) levels will be used as a molecular readout for agent activity. Drug levels will be measured by liquid chromatography/Mass spec. The statistical analysis will be descriptive and will be limited to frequency tables and summary statistics.

Measure: Intra-tumoral drug concentration Comparison

Time: Up to 4 weeks

Description: Progression-free survival at 6 months (PFS6) is defined as the proportion of patients alive and progression-free 180 days after Study Day 1. Duration of PFS is defined as the time from Study Day 1 to the earlier of disease progression or death due to any cause. All patients included in the study must be assessed for PFS6, even if there are major protocol treatment deviations or if they are ineligible.

Measure: Progression-free survival

Time: Up to 6 months

Other Outcomes

Description: To examine the levels of Phospho-ERK in patient tumor tissue during vemurafenib therapy then compare those to archived tissue on the same patient.

Measure: Levels of Phospho-ERK Comparison

Time: Up to 4 weeks

201 Phase 1b/2, Multicenter, Open-label Trial to Evaluate the Safety and Efficacy of Talimogene Laherparepvec and Ipilimumab Compared to Ipilimumab Alone in Subjects With Unresected, Stage IIIB-IV Melanoma

Phase 1b of the study will evaluate the safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 is a randomized study that will evaluate the safety and efficacy of talimogene laherparepvec in combination with ipilimumab versus ipilumumab alone.

NCT01740297
Conditions
  1. Melanoma
Interventions
  1. Drug: Talimogene laherparepvec
  2. Drug: Ipilimumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Participants randomized before amendment 2 will be stratified by stage of disease (stage IIIB/C, IVM1a, and stage IVM1b vs IVM1c) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E (a mutation resulting in a substitution of glutamic acid for valine at codon 600) (mutation vs mutation not present). --- V600E ---

Primary Outcomes

Description: A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events version 3.0: treatment-related non-laboratory adverse events (AE) ≥ grade 4 ≥ grade 4 immune-mediated dermatitis ≥ grade 4 immune-mediated endocrinopathy (except autoimmune thyroiditis) ≥ grade 3 immune-mediated enterocolitis ≥ grade 3 immune-mediated hepatitis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset) ≥ grade 3 immune-mediated neuropathy ≥ grade 3 other immune-mediated AEs including hemolytic anemia, angiopathy, myocarditis, pericarditis, temporal arteritis, or vasculitis, autoimmune thyroiditis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset), blepharitis, conjunctivitis, episcleritis, iritis, scleritis, or uveitis, pancreatitis, meningitis, arthritis or polymyalgia rheumatic, nephritis, pneumonitis, psoriasis or leukocytoclastic vasculitis.

Measure: Phase 1b: Number of Participants With Dose-limiting Toxicities

Time: The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).

Description: Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.

Measure: Phase 2: Objective Response Rate

Time: Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Secondary Outcomes

Description: Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.

Measure: Phase 1b: Objective Response Rate

Time: Tumor response was assesed every 12 weeks until disease progression; median follow-up time was 148.4 weeks.

Description: Best overall response was categorized in descending order as a complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or unevaluable (UE) based on investigator assessment according to the modified irRC. CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. PD: Increase in tumor burden ≥ 25% relative to nadir. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization. CR, PR and PD must have been confirmed at 2 consecutive assessment ≥ 4 weeks apart. Assessments occurring after the start of the first subsequent anticancer therapy or removal of a lesion were not included.

Measure: Phase 2: Best Overall Response

Time: Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: Disease control rate (DCR) was defined as the percentage of participants with a best overall response of CR, PR or SD based on investigator assessment according to the modified irRC. CR: Complete disappearance of all lesions and no new lesions; any pathological lymph nodes reduced in short axis to <10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization. CR and PR must have been confirmed at 2 consecutive assessments ≥ 4 weeks apart.

Measure: Phase 2: Disease Control Rate

Time: Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: Durable response rate (DRR) was defined as the percentage of participants with a duration of response (best response of CR or PR) per modified irRC of at least 6 months. Duration of response is the time from the first confirmed CR or PR to confirmed disease progression per the modified irRC or death, whichever occurs earlier.

Measure: Phase 2: Durable Response Rate

Time: Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: Time to confirmed response (TTR) was defined as the time from randomization to the date of the first confirmed CR or PR per modified irRC criteria. Participants who did not have a confirmed CR or PR were censored at their last evaluable tumor assessment date.

Measure: Phase 2: Time to Response

Time: Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: Duration of response was calculated only for participants with an objective response per modified irRC and was defined as the time from first confirmed objective response (CR or PR) to confirmed disease progression per the modified irRC or death, whichever was earlier. Responders who did not have an event of death or disease progression were censored at their last evaluable tumor assessment date.

Measure: Phase 2: Duration of Response

Time: Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death on or before the data cutoff date, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date.

Measure: Phase 2: Progression-free Survival

Time: From randomization until the data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: Resection rate was defined as the percentage of participants who had surgical procedures for melanoma that resulted in a partial reduction or complete eradication of all previously unresectable cutaneous or visceral metastatic disease. Surgical procedures for melanoma with palliative intent (eg, for pain control) in the presence of disease progression were not considered resection.

Measure: Phase 2: Resection Rate

Time: From randomization until the data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive. Participants with a vital status obtained after the data cut-off were censored at the date cut-off date.

Measure: Phase 2: Overall Survival

Time: From randomization until the data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Description: The overall survival estimates at month 24 data were not mature as most participants had not been followed for 24 months at the time of data cutoff.

Measure: Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24

Time: Months 12 and 24; The median (Q1, Q3) follow-up time from randomization to the data cutoff date for the analysis was 80.6 (58.3, 106.3) weeks.

Description: Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening or disabling AE and grade 5 = death related to AE. The investigator assessed whether each AE was possibly related to talimogene laherparepvec (T-VEC) and/or ipilimumab (Imab). Note that one participant in the Phase 2 Ipilimumab Alone group was incorrectly noted as having an AE leading to discontinuation of T-VEC which was discovered and corrected after this analysis was conducted.

Measure: Number of Participants With Adverse Events

Time: From first dose of study treatment until 30 days after the last dose; median duration of treatment was 14.7, 9.1, and 21.1 weeks in each treatment group respectively.

202 A Phase 1 Open-label Study of Safety and Tolerability of MEDI4736 in Subjects With Metastatic or Unresectable Melanoma in Combination With Dabrafenib and Trametinib or With Trametinib Alone

The purpose of this study is to determine the maximum tolerated dose and characterize the safety profile of durvalumab (MEDI4736) in combination with dabrafenib and trametinib or with trametinib alone in participants with metastatic or unresectable melanoma with BRAF-mutation positive or wild-type (WT) BRAF, respectively.

NCT02027961
Conditions
  1. Melanoma
Interventions
  1. Biological: Durvalumab
  2. Drug: Dabrafenib
  3. Drug: Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

The number of participants with positive serum antibodies to durvalumab post dosing are reported.. Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Melanoma Melanoma This is a multicenter, open-label study with a dose escalation phase followed by an expansion phase of durvalumab administered in combination with dabrafenib and trametinib or with trametinib alone in participants with BRAF V600 mutation-positive and WT unresectable or metastatic melanoma, respectively. --- V600E ---

The number of participants with positive serum antibodies to durvalumab post dosing are reported.. Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Melanoma Melanoma This is a multicenter, open-label study with a dose escalation phase followed by an expansion phase of durvalumab administered in combination with dabrafenib and trametinib or with trametinib alone in participants with BRAF V600 mutation-positive and WT unresectable or metastatic melanoma, respectively. --- V600E --- --- V600K --- --- V600E ---

Primary Outcomes

Description: Dose limiting toxicities are defined as any Grade 3 or higher treatment-related (related to any study drug) toxicity that occurs during the DLT evaluation period. Number of participants with DLTs are reported.

Measure: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)

Description: An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

Measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Time: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Description: Number of participants with abnormal vital signs and physical examinations reported as TEAEs are reported.

Measure: Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs

Time: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Description: Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.

Measure: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

Time: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Description: Number of participants with abnormal electrocardiograms (ECGs) and echocardiograms (ECHOs) reported as TEAEs are reported.

Measure: Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs

Time: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Secondary Outcomes

Description: Objective Response is defined as confirmed complete response (CR) or confirmed partial response (PR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). A confirmed CR is defined as two CRs that were separated by at least 28 days. A confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days. A CR is defined as disappearance of all target and non-target lesions, normalization of tumor marker level and any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than 10 mm. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Percentage of Participants With Objective Response (OR)

Time: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

Description: Duration of response: Duration from first documentation of OR to first documented PD or death due to any cause, whichever occurs first. CR: disappearance of all target and non-target lesions, normalization of tumor marker level and any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than 10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of >= 5 mm, taking as reference smallest sum of diameters since treatment started including baseline sum of diameters.

Measure: Duration of Response (DOR)

Time: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

Description: Progression-free Survival is defined as duration from the start of treatment with study drug until the first documented PD or death, whichever comes first. PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of >= 5 mm, taking as reference smallest sum of diameters since treatment started including baseline sum of diameters. For participants who are alive and progression-free at the time of data cut-off for analysis, PFS was to be censored at the last tumor assessment date.

Measure: Progression-free Survival (PFS)

Time: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

Description: Overall survival (OS) is measured from the start of treatment until death. For participants who are alive at the end of study or lost to follow-up, OS was censored on the last date when participants are known to be alive.

Measure: Overall Survival

Time: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

Description: Disease control is defined as confirmed CR or PR, or stable disease (SD) that was maintained for >= 12 weeks based on RECIST v1.1. A confirmed CR is defined as two CRs that were separated by at least 28 days. A confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days. CR: disappearance of all target and non-target lesions, normalization of tumor marker level and any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than 10 mm. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. A SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study.

Measure: Percentage of Participants With Disease Control

Time: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

Description: Maximum observed plasma concentration of durvalumab after first dose is reported.

Measure: Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab

Time: Cohorts A and B: End of infusion on Day 1; Cohort C: End of infusion on Day 29

Description: Maximum observed plasma concentration of durvalumab at steady state is reported.

Measure: Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab

Time: Cohorts A and B: end of infusion on Day 141; Cohort C: end of infusion on Day 169

Description: Trough concentration of durvalumab pre-dose at steady state is reported.

Measure: Trough Concentration at Steady State (Ctrough) of Durvalumab

Time: Cohorts A and B: Pre-dose on Day 141; Cohort C: Pre-dose on Day 169

Description: The number of participants with positive serum antibodies to durvalumab post dosing are reported.

Measure: Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab

Time: Cohorts A and B: Days 1 and 29; Cohort C: Days 29 and 57

203 A Randomized Phase II Study Evaluating the Activity of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma

Mucosal melanoma is rare and associated with extremely poor prognosis.No effective treatment for advanced mucosal melanoma patients.Investigators conducted a randomized phase II study in patients with previously untreated metastatic mucosal melanoma to characterize the efficacy and safety of bevacizumab when combined with carboplatin plus paclitaxel.

NCT02023710
Conditions
  1. Melanoma
Interventions
  1. Drug: Paclitaxel
  2. Drug: Carboplatin
  3. Drug: Bevacizumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

8. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Exclusion Criteria: 1. Mutations in C-KIT or BRAF-V600E, asked for other target treatments 2. Pregnant or lactation women 3. Acute infections without control. --- V600E ---

Primary Outcomes

Description: Progression Free Survival is defined as the time from enrollment to the date of first documented disease progression or death from any cause.

Measure: progress-free survival(PFS)

Time: From randomization up to 144 weeks

Secondary Outcomes

Description: Any events,no matter related to interventions,occur during the period from the enrollment to death or 30 days after withdrawal from the trial

Measure: adverse event(AE)

Time: From randomization up to144 weeks

Description: Overall survival was defined as the time from randomization to death from any cause.

Measure: Overall Survival(OS)

Time: Up to 144 weeks

204 Randomized Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer

This randomized phase II trial studies how well irinotecan hydrochloride and cetuximab with or without vemurafenib works in treating patients with colorectal cancer that has spread to nearby tissue or lymph nodes, that has spread to other places in the body, or cannot be removed by surgery. Irinotecan hydrochloride and vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block the ability of tumor cells to grow and spread. It is not yet known whether irinotecan hydrochloride and cetuximab are more effective with or without vemurafenib in treating colorectal cancer.

NCT02164916
Conditions
  1. Colorectal Cancer
Interventions
  1. Biological: cetuximab
  2. Drug: irinotecan hydrochloride
  3. Drug: vemurafenib
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.. - STEP I INITIAL REGISTRATION: BRAFV600E TESTING: - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is either metastatic, or locally advanced and unresectable - Patients must have BRAFV600E mutant status documented by a Clinical Laboratory Improvements Amendments (CLIA) certified laboratory on a pathology report prior to Step 2 registration; use of an Food and Drug Administration (FDA)-approved test is preferred although other BRAF tests at a CLIA-certified laboratory may also be accepted; if a BRAFV600E mutation is known, then the patient must be registered to Step 2 Randomization immediately following Step 1 Initial Registration; if testing has not been performed locally, BRAFV600E testing must be completed by the central lab prior to Step 2 Randomization; if the specimen does not have a BRAFV600E mutation, the patient is ineligible for Step 2 Randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 90 days prior to Step 1 Initial Registration; eligible patients should be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to Step 1 Initial Registration - Patients must have had one or two prior regimens of systemic chemotherapy for metastatic disease; prior treatment with irinotecan is allowed; a maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment; prior treatment for metastatic disease is not required for patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy - Patients must not have been treated with any of the following prior to Step 2 Randomization: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib; regorafenib is not considered a BRAF inhibitor for the purpose of determining trial eligibility - Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor including, but not limited to, trametinib or selumetinib - Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 14 days prior to Step 1 Initial Registration and all toxicity must be resolved to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to Step 1 Initial Registration - Patients must not have a tumor with a mutation detected in codons 12 or 13 in KRAS; patients must not have a tumor with a known mutation detected in codons 61, 117, or 146 of KRAS or NRAS - SPECIMEN SUBMISSION CRITERIA: - Patients must have tumor (slides or block) available for submission for V600E BRAF testing - Patients must have additional tumor available and be willing to submit tissue and blood samples - SPECIMEN SUBMISSION CRITERIA REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for Step 1 Initial Registration of patients who have not yet submitted specimens for the central BRAFV600E testing, the appropriate consent form is the Step 1 Consent Form; for both Step 1 Initial Registration and Step 2 Randomization of patients whose BRAF mutation status is already known, the appropriate consent form is the Step 2 Consent Form - STEP 2 RANDOMIZATION: - Patients must have BRAFV600E mutation - Patients must have measurable or non-measurable metastatic disease; computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess all disease must have been completed within 28 days prior to Step 2 Randomization; CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) - Patients must have a Zubrod performance status of 0-1 - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,00/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present - Total bilirubin =< 1.5 x IULN - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 2 Randomization OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 2 Randomization - Patients must have an electrocardiogram (ECG) within 14 days prior to Step 2 Randomization - Patients must have corrected QT (QTc) =< 500 msec - Patients must not have a known history of Gilbert's Syndrome or known homozygosity for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele - Patients must not have interstitial pneumonia or extensive symptomatic interstitial fibrosis of the lung - Patients must not have an uncontrolled intercurrent illness including, but not limited to, active bleeding diathesis, uncontrolled infection/disorders, nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy, or psychiatric illness/social situations which would limit compliance with study requirements - Patients must be able to swallow pill/tablet and have no refractory nausea, vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 30 days after study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - STEP 2 RANDOMIZATION REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for all patients, the appropriate consent form for this registration is the Step 2 Consent Form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION: - Patients must have documented disease progression while on Arm 1 of this protocol; the follow-up tumor assessment form documenting disease progression must be submitted to Southwestern Oncology Group (SWOG) prior to Step 3 - Registration to Step 3 Crossover must be within 28 days of discontinuation of Arm 1 protocol treatment; patients going off treatment for any other reason are not eligible - ANC >= 1,500/mcL within 14 days prior to Step 3 registration - Platelets >= 100,00/mcL within 14 days prior to Step 3 registration - Hemoglobin >= 9 g/dL within 14 days prior to Step 3 registration - AST and ALT =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present within 14 days prior to Step 3 registration - Total bilirubin =< 1.5 x IULN within 14 days prior to Step 3 registration - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 3 registration OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 3 registration - STEP I INITIAL REGISTRATION: BRAFV600E TESTING: - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is either metastatic, or locally advanced and unresectable - Patients must have BRAFV600E mutant status documented by a Clinical Laboratory Improvements Amendments (CLIA) certified laboratory on a pathology report prior to Step 2 registration; use of an Food and Drug Administration (FDA)-approved test is preferred although other BRAF tests at a CLIA-certified laboratory may also be accepted; if a BRAFV600E mutation is known, then the patient must be registered to Step 2 Randomization immediately following Step 1 Initial Registration; if testing has not been performed locally, BRAFV600E testing must be completed by the central lab prior to Step 2 Randomization; if the specimen does not have a BRAFV600E mutation, the patient is ineligible for Step 2 Randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 90 days prior to Step 1 Initial Registration; eligible patients should be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to Step 1 Initial Registration - Patients must have had one or two prior regimens of systemic chemotherapy for metastatic disease; prior treatment with irinotecan is allowed; a maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment; prior treatment for metastatic disease is not required for patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy - Patients must not have been treated with any of the following prior to Step 2 Randomization: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib; regorafenib is not considered a BRAF inhibitor for the purpose of determining trial eligibility - Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor including, but not limited to, trametinib or selumetinib - Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 14 days prior to Step 1 Initial Registration and all toxicity must be resolved to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to Step 1 Initial Registration - Patients must not have a tumor with a mutation detected in codons 12 or 13 in KRAS; patients must not have a tumor with a known mutation detected in codons 61, 117, or 146 of KRAS or NRAS - SPECIMEN SUBMISSION CRITERIA: - Patients must have tumor (slides or block) available for submission for V600E BRAF testing - Patients must have additional tumor available and be willing to submit tissue and blood samples - SPECIMEN SUBMISSION CRITERIA REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for Step 1 Initial Registration of patients who have not yet submitted specimens for the central BRAFV600E testing, the appropriate consent form is the Step 1 Consent Form; for both Step 1 Initial Registration and Step 2 Randomization of patients whose BRAF mutation status is already known, the appropriate consent form is the Step 2 Consent Form - STEP 2 RANDOMIZATION: - Patients must have BRAFV600E mutation - Patients must have measurable or non-measurable metastatic disease; computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess all disease must have been completed within 28 days prior to Step 2 Randomization; CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) - Patients must have a Zubrod performance status of 0-1 - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,00/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present - Total bilirubin =< 1.5 x IULN - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 2 Randomization OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 2 Randomization - Patients must have an electrocardiogram (ECG) within 14 days prior to Step 2 Randomization - Patients must have corrected QT (QTc) =< 500 msec - Patients must not have a known history of Gilbert's Syndrome or known homozygosity for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele - Patients must not have interstitial pneumonia or extensive symptomatic interstitial fibrosis of the lung - Patients must not have an uncontrolled intercurrent illness including, but not limited to, active bleeding diathesis, uncontrolled infection/disorders, nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy, or psychiatric illness/social situations which would limit compliance with study requirements - Patients must be able to swallow pill/tablet and have no refractory nausea, vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 30 days after study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - STEP 2 RANDOMIZATION REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for all patients, the appropriate consent form for this registration is the Step 2 Consent Form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION: - Patients must have documented disease progression while on Arm 1 of this protocol; the follow-up tumor assessment form documenting disease progression must be submitted to Southwestern Oncology Group (SWOG) prior to Step 3 - Registration to Step 3 Crossover must be within 28 days of discontinuation of Arm 1 protocol treatment; patients going off treatment for any other reason are not eligible - ANC >= 1,500/mcL within 14 days prior to Step 3 registration - Platelets >= 100,00/mcL within 14 days prior to Step 3 registration - Hemoglobin >= 9 g/dL within 14 days prior to Step 3 registration - AST and ALT =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present within 14 days prior to Step 3 registration - Total bilirubin =< 1.5 x IULN within 14 days prior to Step 3 registration - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 3 registration OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 3 registration Colorectal Cancer Colorectal Neoplasms PRIMARY OBJECTIVES: I. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan (irinotecan hydrochloride), cetuximab, and vemurafenib, compared to a control arm of irinotecan and cetuximab. --- V600E ---

Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.. - STEP I INITIAL REGISTRATION: BRAFV600E TESTING: - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is either metastatic, or locally advanced and unresectable - Patients must have BRAFV600E mutant status documented by a Clinical Laboratory Improvements Amendments (CLIA) certified laboratory on a pathology report prior to Step 2 registration; use of an Food and Drug Administration (FDA)-approved test is preferred although other BRAF tests at a CLIA-certified laboratory may also be accepted; if a BRAFV600E mutation is known, then the patient must be registered to Step 2 Randomization immediately following Step 1 Initial Registration; if testing has not been performed locally, BRAFV600E testing must be completed by the central lab prior to Step 2 Randomization; if the specimen does not have a BRAFV600E mutation, the patient is ineligible for Step 2 Randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 90 days prior to Step 1 Initial Registration; eligible patients should be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to Step 1 Initial Registration - Patients must have had one or two prior regimens of systemic chemotherapy for metastatic disease; prior treatment with irinotecan is allowed; a maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment; prior treatment for metastatic disease is not required for patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy - Patients must not have been treated with any of the following prior to Step 2 Randomization: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib; regorafenib is not considered a BRAF inhibitor for the purpose of determining trial eligibility - Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor including, but not limited to, trametinib or selumetinib - Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 14 days prior to Step 1 Initial Registration and all toxicity must be resolved to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to Step 1 Initial Registration - Patients must not have a tumor with a mutation detected in codons 12 or 13 in KRAS; patients must not have a tumor with a known mutation detected in codons 61, 117, or 146 of KRAS or NRAS - SPECIMEN SUBMISSION CRITERIA: - Patients must have tumor (slides or block) available for submission for V600E BRAF testing - Patients must have additional tumor available and be willing to submit tissue and blood samples - SPECIMEN SUBMISSION CRITERIA REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for Step 1 Initial Registration of patients who have not yet submitted specimens for the central BRAFV600E testing, the appropriate consent form is the Step 1 Consent Form; for both Step 1 Initial Registration and Step 2 Randomization of patients whose BRAF mutation status is already known, the appropriate consent form is the Step 2 Consent Form - STEP 2 RANDOMIZATION: - Patients must have BRAFV600E mutation - Patients must have measurable or non-measurable metastatic disease; computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess all disease must have been completed within 28 days prior to Step 2 Randomization; CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) - Patients must have a Zubrod performance status of 0-1 - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,00/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present - Total bilirubin =< 1.5 x IULN - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 2 Randomization OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 2 Randomization - Patients must have an electrocardiogram (ECG) within 14 days prior to Step 2 Randomization - Patients must have corrected QT (QTc) =< 500 msec - Patients must not have a known history of Gilbert's Syndrome or known homozygosity for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele - Patients must not have interstitial pneumonia or extensive symptomatic interstitial fibrosis of the lung - Patients must not have an uncontrolled intercurrent illness including, but not limited to, active bleeding diathesis, uncontrolled infection/disorders, nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy, or psychiatric illness/social situations which would limit compliance with study requirements - Patients must be able to swallow pill/tablet and have no refractory nausea, vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 30 days after study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - STEP 2 RANDOMIZATION REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for all patients, the appropriate consent form for this registration is the Step 2 Consent Form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION: - Patients must have documented disease progression while on Arm 1 of this protocol; the follow-up tumor assessment form documenting disease progression must be submitted to Southwestern Oncology Group (SWOG) prior to Step 3 - Registration to Step 3 Crossover must be within 28 days of discontinuation of Arm 1 protocol treatment; patients going off treatment for any other reason are not eligible - ANC >= 1,500/mcL within 14 days prior to Step 3 registration - Platelets >= 100,00/mcL within 14 days prior to Step 3 registration - Hemoglobin >= 9 g/dL within 14 days prior to Step 3 registration - AST and ALT =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present within 14 days prior to Step 3 registration - Total bilirubin =< 1.5 x IULN within 14 days prior to Step 3 registration - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 3 registration OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 3 registration - STEP I INITIAL REGISTRATION: BRAFV600E TESTING: - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is either metastatic, or locally advanced and unresectable - Patients must have BRAFV600E mutant status documented by a Clinical Laboratory Improvements Amendments (CLIA) certified laboratory on a pathology report prior to Step 2 registration; use of an Food and Drug Administration (FDA)-approved test is preferred although other BRAF tests at a CLIA-certified laboratory may also be accepted; if a BRAFV600E mutation is known, then the patient must be registered to Step 2 Randomization immediately following Step 1 Initial Registration; if testing has not been performed locally, BRAFV600E testing must be completed by the central lab prior to Step 2 Randomization; if the specimen does not have a BRAFV600E mutation, the patient is ineligible for Step 2 Randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 90 days prior to Step 1 Initial Registration; eligible patients should be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to Step 1 Initial Registration - Patients must have had one or two prior regimens of systemic chemotherapy for metastatic disease; prior treatment with irinotecan is allowed; a maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment; prior treatment for metastatic disease is not required for patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy - Patients must not have been treated with any of the following prior to Step 2 Randomization: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib; regorafenib is not considered a BRAF inhibitor for the purpose of determining trial eligibility - Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor including, but not limited to, trametinib or selumetinib - Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 14 days prior to Step 1 Initial Registration and all toxicity must be resolved to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to Step 1 Initial Registration - Patients must not have a tumor with a mutation detected in codons 12 or 13 in KRAS; patients must not have a tumor with a known mutation detected in codons 61, 117, or 146 of KRAS or NRAS - SPECIMEN SUBMISSION CRITERIA: - Patients must have tumor (slides or block) available for submission for V600E BRAF testing - Patients must have additional tumor available and be willing to submit tissue and blood samples - SPECIMEN SUBMISSION CRITERIA REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for Step 1 Initial Registration of patients who have not yet submitted specimens for the central BRAFV600E testing, the appropriate consent form is the Step 1 Consent Form; for both Step 1 Initial Registration and Step 2 Randomization of patients whose BRAF mutation status is already known, the appropriate consent form is the Step 2 Consent Form - STEP 2 RANDOMIZATION: - Patients must have BRAFV600E mutation - Patients must have measurable or non-measurable metastatic disease; computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess all disease must have been completed within 28 days prior to Step 2 Randomization; CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) - Patients must have a Zubrod performance status of 0-1 - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,00/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present - Total bilirubin =< 1.5 x IULN - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 2 Randomization OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 2 Randomization - Patients must have an electrocardiogram (ECG) within 14 days prior to Step 2 Randomization - Patients must have corrected QT (QTc) =< 500 msec - Patients must not have a known history of Gilbert's Syndrome or known homozygosity for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele - Patients must not have interstitial pneumonia or extensive symptomatic interstitial fibrosis of the lung - Patients must not have an uncontrolled intercurrent illness including, but not limited to, active bleeding diathesis, uncontrolled infection/disorders, nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy, or psychiatric illness/social situations which would limit compliance with study requirements - Patients must be able to swallow pill/tablet and have no refractory nausea, vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 30 days after study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - STEP 2 RANDOMIZATION REGULATORY CRITERIA: - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for all patients, the appropriate consent form for this registration is the Step 2 Consent Form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION: - Patients must have documented disease progression while on Arm 1 of this protocol; the follow-up tumor assessment form documenting disease progression must be submitted to Southwestern Oncology Group (SWOG) prior to Step 3 - Registration to Step 3 Crossover must be within 28 days of discontinuation of Arm 1 protocol treatment; patients going off treatment for any other reason are not eligible - ANC >= 1,500/mcL within 14 days prior to Step 3 registration - Platelets >= 100,00/mcL within 14 days prior to Step 3 registration - Hemoglobin >= 9 g/dL within 14 days prior to Step 3 registration - AST and ALT =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present within 14 days prior to Step 3 registration - Total bilirubin =< 1.5 x IULN within 14 days prior to Step 3 registration - Serum creatinine =< 1.5 x IULN within 14 days prior to Step 3 registration OR - Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 3 registration Colorectal Cancer Colorectal Neoplasms PRIMARY OBJECTIVES: I. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan (irinotecan hydrochloride), cetuximab, and vemurafenib, compared to a control arm of irinotecan and cetuximab. --- V600E --- --- V600E ---

To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected by IHC in the primary tumor. --- V600E ---

To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected by IHC in the primary tumor. --- V600E --- --- V600E ---

Primary Outcomes

Description: From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact. Progression is defined as one or more of the following: 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, as well as an absolute increase of at least 0.5 cm; unequivocal progression of non-measurable disease in the opinion of the treating physician; appearance of any new lesion/site; and/or death due to disease without prior documentation of progression and without symptomatic deterioration.

Measure: Progression-free Survival

Time: Up to 3 years from randomization

Secondary Outcomes

Description: Only adverse events that are possibly, probably or definitely related to study drug are reported.

Measure: Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug

Time: Up to 3 years

Other Outcomes

Description: From date of randomization to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

Measure: Overall Survival

Time: Up to 3 years from randomization

Description: Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

Measure: Overall Response Rate

Time: Up to 3 years from randomization

Description: From date of Step 3 Crossover registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive without report of progression are censored at date of last contact. Progression is defined as one or more of the following: 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, as well as an absolute increase of at least 0.5 cm; unequivocal progression of non-measurable disease in the opinion of the treating physician; appearance of any new lesion/site; and/or death due to disease without prior documentation of progression and without symptomatic deterioration.

Measure: Progression-free Survival in Patients Who Register to Arm 3 (Crossover) After Disease Progression on Arm 1

Time: Up to 3 years from randomization

Description: From date of randomization to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

Measure: Overall Survival in Patients Who Register to Arm 3 (Crossover) After Disease Progression on Arm 1

Time: Up to 3 years from randomization

Description: Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

Measure: Overall Response Rate in Patients Who Register to Arm 3 (Crossover) After Disease Progression on Arm 1

Time: Up to 3 years from randomization

205 A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of MK-3475 in Combination With INCB024360 in Subjects With Selected Cancers (ECHO-202/KEYNOTE-037)

The purpose of this study was to assess the safety, tolerability, and efficacy when combining MK-3475 and INCB024360 in participants with certain cancers. This study was conducted in 2 phases, Phase 1 and Phase 2.

NCT02178722
Conditions
  1. Microsatellite-instability (MSI) High Colorectal Cancer (CRC)
  2. Endometrial Cancer
  3. Head and Neck Cancer
  4. Hepatocellular Carcinoma (HCC)
  5. Gastric Cancer
  6. Lung Cancer
  7. Lymphoma
  8. Renal Cell Carcinoma (RCC)
  9. Ovarian Cancer
  10. Solid Tumors
  11. UC (Urothelial Cancer)
  12. Melanoma
  13. Bladder Cancer
  14. Triple Negative Breast Cancer (TNBC)
Interventions
  1. Drug: MK-3475
  2. Drug: INCB024360
MeSH:Carcinoma Carcinoma, Hepatocellular Carcinoma, Renal Cell Endometrial Neoplasms Triple Negative Breast Neoplasms Microsatellite Instability
HPO:Carcinoma Clear cell renal cell carcinoma Endometrial carcinoma Hepatocellular carcinoma Papillary renal cell carcinoma Renal cell carcinoma

- Phase 2 expansion: Melanoma - Documentation of V600E-activating BRAF mutation status. --- V600E ---

Primary Outcomes

Description: An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after a participant provides informed consent. A TEAE is any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug. Serious adverse event (SAE) is defined as an event that meets 1 of the following criteria: is fatal or life threatening, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, is clinically meaningful (i.e. defined as an event that jeopardizes the participant or requires potential medical or surgical intervention to prevent 1 of the outcomes listed above) or requires inpatient hospitalization or prolongation of existing hospitalization.

Measure: Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events

Time: From study start up to clinical data cut-off date of 26 Nov 2018 (approximately 54 months)

Description: ORR was proportion of participants with best overall response [complete response (CR) or partial response (PR)], per modified Response Evaluation Criteria In Solid Tumors (irRECIST) v1.1 criteria for select solid tumors or modified Lugano Classification for diffuse large B-cell lymphoma (DLBCL).

Measure: Phase 2: Objective Response Rate (ORR)

Time: Assessed every 9 weeks after the first dose of study treatment for the first 2 assessments (Weeks 9 and 18) then every 12 weeks thereafter until data cut-off date of 26 Nov 2018 (approximately 54 months)

Secondary Outcomes

Description: Duration of response is the time from the first overall response contributing to an objective response (complete response or partial response) to the date of death or the date of first overall response of progressive disease (whichever is earliest).

Measure: Phase 2: Duration of Response (DOR)

Time: Assessed every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks

Description: Progression-free survival is defined as number of days from the first day of taking study drug to the earlier of death or disease progression by irRECIST v1.1 for select solid tumors and modified Lugano Classification (Cheson et al 2014) for DLBCL.

Measure: Phase 2: Progression Free Survival (PFS)

Time: Response is measured every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks

Description: The duration of disease control is the time from the treatment start date to the first objective response of PD (by irRECIST v1.1 or Lugano Classification Cheson et al 2014), death, or last tumor assessment date (if PD/death not present), for subjects with best overall response of SD or bette

Measure: Phase 2: Duration of Disease Control

Time: Assessed every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks

Description: Ordinal categorical response score, determined by radiographic disease assessments per irRECIST v1.1. The 5-category ordinal response endpoint is determined at a given timepoint by classifying response into one of the following groups: = Complete response per irRECIST v1.1 = Very good response, defined as > 60% tumor reduction = Minor response, defined as > 30% to ≤ 60% tumor reduction = Stable disease per irRECIST v1.1 = Progressive disease per irRECIST v1.1

Measure: Phase 2: Ordinal Categorical Response Score

Time: Assessed every 9 weeks for duration of study participation which is estimated to be a minimum of 18 weeks

Description: Overall survival is determined from the date of first dose until death due to any cause.

Measure: Phase 2: Overall Survival (OS)

Time: Patients are checked for survival every 12 weeks for duration of study participation which is estimated to be a minimum of 18 weeks

Measure: Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events

Time: Adverse events are assessed every 3 weeks for duration of study participation which is estimated to be 27 months

206 A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare Cancers With Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib

This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. This study is designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with oral Trametinib in subjects with rare BRAF V600E mutated cancers. Subjects will need to have a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status. Only subjects with histologically confirmed advanced disease and no available standard treatment options will be eligible for enrollment. Subjects will undergo screening assessments within 14 days (up to 35 days for ophthalmology exam, echocardiogram or disease assessments) prior to the start of treatment to determine their eligibility for enrollment in the study.

NCT02034110
Conditions
  1. Cancer
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib

A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare Cancers With Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib. --- V600E ---

Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. --- V600E ---

Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers This is a Phase II, open-label, non-randomized, multi-center study of oral Dabrafenib in combination with oral Trametinib in subjects with rare cancers including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor/non-geminomatous germ cell tumor, hairy cell leukemia, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine, with BRAF V600E positive-mutations. --- V600E --- --- V600E ---

This study is designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with oral Trametinib in subjects with rare BRAF V600E mutated cancers. --- V600E ---

Subjects will need to have a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status. --- V600E ---

- Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2. - Must have advanced disease and no standard treatment options as determined by locally/regionally available standards of care and treating physician's discretion - Must have a a BRAF V600E mutation-positive tumor as confirmed by an approved local laboratory or a sponsor designated central reference laboratory. --- V600E ---

All subjects must provide an archived or fresh tumor sample (for solid tumors) or a fresh BM aspirate and peripheral blood sample (for HCL and MM) for confirmation testing of the BRAF V600E mutation by a sponsor designated central reference laboratory using a sponsor designated assay - Able to swallow and retain orally administered medication. --- V600E ---

Primary Outcomes

Description: To determine the ORR as measured radiographically via Response Evaluation Criteria in Solid tumors (RECIST) version 1.1 for solid tumor histologies or established response criteria for specific hematologic malignancies.

Measure: Overall response rate (ORR)

Time: Possibly up to Week 208

Secondary Outcomes

Description: Duration of response is defined as the subset of subjects who show a confirmed clinical response (CR) or partial response (PR), the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.

Measure: Duration of response

Time: From the time of first documented evidence of CR or PR until the first documented sign of disease progression or death (approximately up to Week 208)

Description: PFS is defined as the time from the date of enrollment to the earliest date of progression or death.

Measure: Investigator-assessed Progression-free survival (PFS)

Time: Possibly up to Week 208

Description: OS is defined as the time from the date of enrollment to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: Until death or lost to follow-up (approximately up to Week 208)

Description: Examination will include assessments of the head and neck, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, extremities and genitalia. Height (measured only at Screening) and weight will be measured and recorded. Complete physical examinations will also include thorough rectal and genitourinary (pelvic) examinations to assess secondary malignancies.

Measure: Change from baseline in physical examination findings

Time: Possibly up to Week 208

Description: Vital sign measurements will include systolic and diastolic blood pressure, temperature, pulse rate and respiratory rate

Measure: Change from baseline in vital signs

Time: Possibly up to Week 208

Description: AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Measure: Number of subjects with Adverse events (AEs)

Time: Possibly up to Week 208

Description: Laboratory assessments include haematology, clinical chemistry, urinalysis, coagulation and histology-specific tests

Measure: Change from baseline in laboratory values

Time: Possibly up to Week 208

Description: Cardiac assessments include Electrocardiogram (ECG) and Echocardiograms (ECHOs)

Measure: Change from baseline in cardiac assessments

Time: Possibly up to Week 208

207 An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor

The goal of this clinical research study is to learn if the combination of 2 drugs dabrafenib and trametinib can help to control melanoma that has or has not spread to the brain. The safety of this drug combination will also be studied. Dabrafenib is designed to block the mutated BRAF protein. This mutation is only found in moles of the skin and in melanoma cells. By blocking the protein, the drug may slow the growth of or kill cancer cells that have the protein. Trametinib is designed to block certain proteins that cause cancer cells to grow and multiply. This may cause the cancer cells to die.

NCT01619774
Conditions
  1. Melanoma
Interventions
  1. Drug: GSK2118436
  2. Drug: GSK1120212
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

3. BRAF mutation-positive melanoma (i.e., V600E, V600K or V600D) 4. For Cohort A, patients must have easily accessible tumor for a mandatory biopsy. --- V600E ---

Primary Outcomes

Description: Overall response rate defined as percentage of subjects with a confirmed complete response (CR) or a partial response (PR) at any time as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Clinical responses will be evaluated using RECIST 1.1 criteria after every 2 cycles (8 weeks). Complete Response (CR): Disappearance all lesions; pathological lymph nodes reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of lesions, reference smallest sum on study (includes baseline sum if smallest on study); relative increase of 20%, sum must also demonstrate absolute increase of >5 mm; appearance of 1 or > new lesions considered progression). Stable Disease (SD): Neither sufficient shrinkage for PR nor sufficient increase for PD, reference smallest sum diameters while on study.

Measure: Overall Response Rate (ORR)

Time: Evaluation every 8 weeks (2 cycles) up to 12 months

Description: Clinical responses evaluated using RECIST 1.1 criteria after every 2 cycles (8 weeks). Complete Response (CR): Disappearance all lesions; pathological lymph nodes reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of lesions, reference smallest sum on study (includes baseline sum if smallest on study); relative increase of 20%, sum must also demonstrate absolute increase of >5 mm; appearance of 1 or > new lesions considered progression). Stable Disease (SD): Neither sufficient shrinkage for PR nor sufficient increase for PD, reference smallest sum diameters while on study.

Measure: Number of Participants by Response

Time: Evaluation every 8 weeks (2 cycles) up to 12 months

Secondary Outcomes

Description: Duration of response defined for subjects with a confirmed complete response (CR) or partial response (PR), as time from the first documented evidence of a CR or PR until the first documented disease progression or death due to any cause. Progression free survival (PFS) estimated and summarized using the method of Kaplan and Meier.

Measure: Progression-Free Survival (PFS)

Time: Evaluation every 8 weeks (2 cycles) up to 12 months

208 Phase 1/2 Study of PI-3K Inhibition With PX-866 Combined With Vemurafenib (BRAF Inhibitor) in Patients With BRAF-mutant Cancer Including Advanced Melanoma

The purpose of the phase 1 portion of the study is to determine the maximally tolerated dose (MTD) or recommended dose (RD) and the safety/tolerability of PX-866 in combination vemurafenib in patients with any advanced BRAF-mutant cancer. The purpose of the phase 2 portion of the study is to compare progression free survival (PFS), antitumor activity (response rate), disease control rate (DCR), and the safety and tolerability of PX-866 in combination with vemurafenib vs. vemurafenib alone in patients with advanced BRAF-mutant melanoma at the doses recommended from Phase 1.

NCT01616199
Conditions
  1. Advanced BRAF-mutant Cancers
Interventions
  1. Drug: PX-866
  2. Drug: vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Inclusion Criteria: - ≥ 18 years at time of consent - If a sexually active male or a sexually active female of child-bearing potential, agrees to use a highly effective form of contraception (including birth control pills, barrier device, or intrauterine device)from the time of consent 90 days following the last dose of study drug - If female of child-bearing potential, negative pregnancy test - For Phase 1: must have histologically or cytologically-confirmed advanced cancer that is BRAF mutation-positive (V600E or V600K) for which there is no remaining standard therapy with curative potential. --- V600E ---

For Phase 2: must have histologically or cytologically-confirmed BRAF mutation-positive (V600E or V600K) advanced (defined as unresectable Stage IIIC or IV) melanoma that has not been treated with a selective BRAF inhibitor - For Phase 1: must have measurable or non-measurable disease. --- V600E ---

These patients must have undergone appropriate imaging studies and currently be on a stable, lowest possible dose of steroids - History of allergic reactions attributed to compounds of similar chemical or biologic composition to PX-866 or vemurafenib - Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Uncorrectable electrolyte abnormalities or long QT syndrome - Poorly controlled diabetes mellitus - Pregnant, breastfeeding, or planning to become pregnant - Known to be human immunodeficiency virus (HIV)-positive - Inability to swallow pills - Previous treatment with a phosphatidylinositol-3-kinase (PI-3K) inhibitor - Any other significant medical or psychiatric condition that in the opinion of the investigator renders the patient inadequate for participation Inclusion Criteria: - ≥ 18 years at time of consent - If a sexually active male or a sexually active female of child-bearing potential, agrees to use a highly effective form of contraception (including birth control pills, barrier device, or intrauterine device)from the time of consent 90 days following the last dose of study drug - If female of child-bearing potential, negative pregnancy test - For Phase 1: must have histologically or cytologically-confirmed advanced cancer that is BRAF mutation-positive (V600E or V600K) for which there is no remaining standard therapy with curative potential. --- V600E ---

Primary Outcomes

Measure: Incidence and severity of adverse events (phase 1)

Time: 28 days

Measure: Progression-free survival (PFS) (phase 2)

Time: 56 days

Secondary Outcomes

Measure: Plasma concentrations of PX-866 and metabolites (phase 1)

Time: 44 days

Measure: Objective Response Rate (ORR)(phase 2)

Time: 56 days

Measure: Disease Control Rate (DCR)(phase 2)

Time: 56 Days

Measure: Plasma concentrations of vemurafenib (phase 1)

Time: 44 days

209 An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR Antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E Positive Colorectal Cancer and in Subjects With CRC With Secondary Resistance to Prior Anti-EGFR Therapy

This is an open-label, four-part Phase I/II study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody panitumumab in subjects with BRAF-mutation V600E positive colorectal cancer (CRC) and in subjects with CRC with secondary resistance to prior anti-EGFR therapy. Part 1 of the study will consist of dose-escalation cohorts, following a 3 + 3 enrollment scheme. Part 2 of the study will consist of expansion cohorts to investigate safety and clinical activity of dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination with panitumumab. Part 3 of the study will be a randomized Phase II study comparing dosing with dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination with panitumumab as compared to the chemotherapy comparator (a regimen of leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX), leucovorin calcium, fluorouracil, irinotecan hydrochloride (FOLFIRI) or irinotecan with or without panitumumab or bevacizumab). Subjects will be assigned to treatment groups in a randomized fashion to compare safety and clinical activity. Part 4 of the study will investigate the trametinib/panitumumab combination, including dose escalation and subsequent cohort expansion in two patient populations: 1) BRAF-mutation V600E positive CRC and 2) subjects with CRC who developed secondary resistance to prior anti-EGFR therapy. The objective of Part 4 is to identify the recommended Phase 2 dose/regimen for trametinib dosed in combination with panitumumab in dose escalation and to identify an initial signal of clinical activity in expansion cohorts.

NCT01750918
Conditions
  1. Cancer
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
  3. Drug: Panitumumab
  4. Drug: 5-fluorouracil
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR Antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E Positive Colorectal Cancer and in Subjects With CRC With Secondary Resistance to Prior Anti-EGFR Therapy. --- V600E ---

BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC) This is an open-label, four-part Phase I/II study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody panitumumab in subjects with BRAF-mutation V600E positive colorectal cancer (CRC) and in subjects with CRC with secondary resistance to prior anti-EGFR therapy. --- V600E ---

Part 4 of the study will investigate the trametinib/panitumumab combination, including dose escalation and subsequent cohort expansion in two patient populations: 1) BRAF-mutation V600E positive CRC and 2) subjects with CRC who developed secondary resistance to prior anti-EGFR therapy. --- V600E ---

- Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF V600E mutation positive CRC - Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy, defined as patients that derived benefit (disease control based on investigator assessment for >6 months OR partial response [confirmed or unconfirmed] based on RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then subsequently progressed on therapy. --- V600E ---

- Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF V600E mutation positive CRC - Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy, defined as patients that derived benefit (disease control based on investigator assessment for >6 months OR partial response [confirmed or unconfirmed] based on RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then subsequently progressed on therapy. --- V600E --- --- V600E ---

Cancer Colorectal Neoplasms This is an open-label, four-part Phase I/II study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody panitumumab in subjects with BRAF-mutation V600E positive colorectal cancer (CRC) and in subjects with CRC with secondary resistance to prior anti-EGFR therapy. --- V600E ---

Part 4 of the study will investigate the trametinib/panitumumab combination, including dose escalation and subsequent cohort expansion in two patient populations: 1) BRAF-mutation V600E positive CRC and 2) subjects with CRC who developed secondary resistance to prior anti-EGFR therapy. --- V600E ---

Primary Outcomes

Description: Patients will be monitored weekly for changes from baseline in vital signs, electrocardiograms (ECGs), laboratory blood tests and for any adverse effects over the first 28 days of dosing. In the continuation period, patients will be monitored every 4 weeks for changes from baseline in vital signs, ECGs, laboratory blood tests and for any adverse effects.

Measure: Part 1, Part 2, Part 4A and Part 4B: Composite safety parameters including adverse events and changes in laboratory values, vital signs and dose interruptions, modifications and discontinuations

Time: one year

Description: Disease response will be recorded on the electronic case report form (eCRF) as CR, PR, according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.1. Tumors will be assessed using investigator read computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, then every 6 weeks until Week 24 on study, then every 8 weeks, and again at follow-up for patients who discontinue study medication for any reason other than progression or death.

Measure: Part 2 and Part 4B: Response rate (Complete Response [CR] + Partial Response [PR]) in subjects in the dosing groups

Time: one year

Description: Defined as the interval between the start of study treatment until progressive disease is objectively documented. Tumors will be assessed using investigator read CT or MRI at baseline, then every 6 weeks until Week 24 on study, then every 8 weeks, and again at follow-up for patients who discontinue study medication for any reason other than progression or death.

Measure: Part 3: Progression -free survival (PFS)

Time: one year

Secondary Outcomes

Description: Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Pharmacokinetic parameters will include maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), and area under the concentration-time curve from zero (pre-dose) 8 hours (AUC[0-8]), pre-dose (trough) concentration at the end of the dosing interval (Ctau) of trametinib and dabrafenib. Pre-dose (Ctau) and Cmax concentrations of panitumumab

Measure: Part 1: Plasma pharmacokinetics (PK) profile of dabrafenib, trametinib and panitumumab in combination dosing

Time: up to and including Week 20

Measure: Part 1: Response rate (CR +PR) of dabrafenib dosed orally in combination with panitumumab

Time: one year

Measure: Part 1 and Part 2: Progression free survival of subjects treated with dabrafenib dosed orally in combination with panitumumab

Time: one year

Measure: Part 1 and Part 2: Duration of response of dabrafenib dosed orally in combination with panitumumab

Time: one year

Measure: Part 1: Response rate (CR +PR) of trametinib dosed orally in combination with dabrafenib and panitumumab

Time: one year

Measure: Part 1 and Part 2: Progression free survival subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab

Time: one year

Measure: Part 1 and Part 2: Duration of response of trametinib dosed orally in combination with dabrafenib and panitumumab

Time: one year

Description: Pharmacodynamic (PD) response in colorectal tumors following 2 weeks of combination treatments

Measure: Part 1, Part 2, Part 4A and Part 4B: Change in levels of proteins/ Ribonucleic acid (RNA) in pre- and post-dose tumor tissue

Time: One year (At the time of disease progression)

Description: Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be on Weeks 4 on study. Pharmacokinetic parameters will include oral clearance (CL/F), oral volume of distribution (V/F), and absorption rate constant (Ka)

Measure: Part 2: Plasma pharmacokinetics profile of of dabrafenib and trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)

Time: up to and including Week 20

Description: Defined as the interval between the start of study treatment until date of death due to any cause.

Measure: Part 2: Overall survival (OS) of subjects treated with dabrafenib dosed orally in combination with panitumumab

Time: one year

Measure: Part 2: OS of subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab

Time: one year

Measure: Part 3: Response rate (CR +PR) of dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy

Time: one year

Measure: Part 3: Duration of response to dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy

Time: one year

Measure: Part 3: OS of subjects treated with dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy

Time: one year

Measure: Part 3: To evaluate and compare the PFS of the trametinib/dabrafenib/panitumumab combination as compared to the dabrafenib/panitumumab combination

Time: one year

Measure: Part 3: Composite safety parameters including adverse events and changes in laboratory values, vital signs and dose interruptions, modifications and discontinuations

Time: one year

Description: Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Pharmacokinetic parameters will include Cmax, tmax, and area under the concentration-time curve from zero (pre-dose) the time of the last quantifiable concentration (AUC[0-t]), pre-dose (trough) Ctau of trametinib. Pre-dose (Ctau) and Cmax concentrations of panitumumab

Measure: Part 4A: Plasma pharmacokinetics profile of trametinib and panitumumab after combination therapy

Time: up to and including Week 20

Measure: Part 4A: Response rate (CR +PR) of panitumumab/trametinib combination therapy in patient populations

Time: one year

Measure: Part 4A and Part 4B: Progression free survival of panitumumab/trametinib combination therapy in patient populations

Time: one year

Measure: Part 4A and Part 4B: Duration of response of panitumumab/trametinib combination therapy in patient populations

Time: one year

Description: Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Pharmacokinetic parameters will include oral clearance (CL/F), oral volume of distribution (V/F), and absorption rate constant (Ka)

Measure: Part 4B Plasma pharmacokinetics profile of trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)

Time: up to and including Week 20

Measure: Part 4B Overall survival of response with trametinib dosed in combination with panitumumab

Time: one year

210 COMBAT 1: A Phase II Trial of Combined BRAF-Targeted Therapy and Immunotherapy for Melanoma

This research study is a Phase II clinical trial of an investigational combination of drugs (vemurafenib and aldesleukin) to learn whether the combination works in treating a specific cancer. While both vemurafenib and aldesleukin are approved by the FDA for the treatment of metastatic melanoma, the FDA has not yet approved the combination of vemurafenib and aldesleukin. Researchers have found that a large number of melanoma cells have mutations in the BRAF gene. It has been shown that vemurafenib blocks the effects of these mutations in the BRAF gene, and, as a result, may help to prevent cancer growth. Aldesleukin, also referred to as IL-2, is an immunotherapy drug administered via IV infusion that increases the growth of key cells within the immune system that are responsible for targeting cancer cells. Activating more of these key cells, called T-lymphocytes and natural-killer cells, leads to increased cancer cell death. The BRAF gene is located on a larger pathway called the MAPK pathway. Studies have shown that when a BRAF inhibitor, like vemurafenib is used to block the MAPK pathway, melanocytes, or cancer cells express more proteins on their surfaces, making them easier for T-lymphocytes and natural killer cells to recognize and kill them. This suggests that combining BRAF-targeted therapy with aldesleukin, which activates more of these white blood cells, can lead to an increase in the death of cancer cells. In this research study, the investigators are looking to see whether the combination of vemurafenib (a BRAF-inhibitor) combined with aldesleukin(an immunotherapy drug) work together to produce a better health outcome in people with metastatic melanoma.

NCT01754376
Conditions
  1. Melanoma
Interventions
  1. Drug: Aldesleukin
  2. Drug: Vemurafenib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

To assess the efficacy (as measured by progression-free survival (PFS)) of patients with metastatic melanoma with V600E mutation treated with the combination of vemurafenib and aldesleukin. --- V600E ---

The CD8/Treg ratio was calculated.. Inclusion Criteria: - Histologically confirmed metastatic or unresectable melanoma with V600E mutation - Measurable disease - May have received prior immunotherapy (excluding interleukin 2) - Life expectancy greater than 3 months - Recovered from effects of previous surgery and/or traumatic injury - Must agree to use effective contraception Exclusion Criteria: - Pregnant or breastfeeding - Psychological, familial or other conditions that could hamper compliance with protocol - Receiving other study agents - History of carcinomatous meningitis - Known active brain metastases - Have received a BRAF inhibitor - Uncontrolled intercurrent illness - HIV positive on antiretroviral therapy - History of a different malignancy within past 5 years (except cervical cancer in situ or basal/squamous cell carcinoma of the skin) - Active hepatitis B or C - Have received allogenic bone marrow transplant or organ transplant Inclusion Criteria: - Histologically confirmed metastatic or unresectable melanoma with V600E mutation - Measurable disease - May have received prior immunotherapy (excluding interleukin 2) - Life expectancy greater than 3 months - Recovered from effects of previous surgery and/or traumatic injury - Must agree to use effective contraception Exclusion Criteria: - Pregnant or breastfeeding - Psychological, familial or other conditions that could hamper compliance with protocol - Receiving other study agents - History of carcinomatous meningitis - Known active brain metastases - Have received a BRAF inhibitor - Uncontrolled intercurrent illness - HIV positive on antiretroviral therapy - History of a different malignancy within past 5 years (except cervical cancer in situ or basal/squamous cell carcinoma of the skin) - Active hepatitis B or C - Have received allogenic bone marrow transplant or organ transplant Melanoma Melanoma Subjects will take oral vemurafenib twice a day for 2 weeks. --- V600E ---

The CD8/Treg ratio was calculated.. Inclusion Criteria: - Histologically confirmed metastatic or unresectable melanoma with V600E mutation - Measurable disease - May have received prior immunotherapy (excluding interleukin 2) - Life expectancy greater than 3 months - Recovered from effects of previous surgery and/or traumatic injury - Must agree to use effective contraception Exclusion Criteria: - Pregnant or breastfeeding - Psychological, familial or other conditions that could hamper compliance with protocol - Receiving other study agents - History of carcinomatous meningitis - Known active brain metastases - Have received a BRAF inhibitor - Uncontrolled intercurrent illness - HIV positive on antiretroviral therapy - History of a different malignancy within past 5 years (except cervical cancer in situ or basal/squamous cell carcinoma of the skin) - Active hepatitis B or C - Have received allogenic bone marrow transplant or organ transplant Inclusion Criteria: - Histologically confirmed metastatic or unresectable melanoma with V600E mutation - Measurable disease - May have received prior immunotherapy (excluding interleukin 2) - Life expectancy greater than 3 months - Recovered from effects of previous surgery and/or traumatic injury - Must agree to use effective contraception Exclusion Criteria: - Pregnant or breastfeeding - Psychological, familial or other conditions that could hamper compliance with protocol - Receiving other study agents - History of carcinomatous meningitis - Known active brain metastases - Have received a BRAF inhibitor - Uncontrolled intercurrent illness - HIV positive on antiretroviral therapy - History of a different malignancy within past 5 years (except cervical cancer in situ or basal/squamous cell carcinoma of the skin) - Active hepatitis B or C - Have received allogenic bone marrow transplant or organ transplant Melanoma Melanoma Subjects will take oral vemurafenib twice a day for 2 weeks. --- V600E --- --- V600E ---

Primary Outcomes

Description: To assess the efficacy (as measured by progression-free survival (PFS)) of patients with metastatic melanoma with V600E mutation treated with the combination of vemurafenib and aldesleukin. Progression free survival is defined as the time between the first dose of study drug and the first occurrence of progression of disease or death from any cause. Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), as at least a 20% increase in the sum of the diameters of target lesions or the appearance of one or more new lesions.

Measure: Progression Free Survival

Time: 3 years

Secondary Outcomes

Description: To determine the overall response rate (as defined as the rate of objective response (Complete Response (CR) or Partial Response (PR)) lasting continuously for 12 or more months, and beginning at any point within 12 months of initiating therapy) in patients treated with aldesleukin and vemurafenib. In this limited cohort, response rate was calculated as the proportion of patients with partial (PR) or complete response (CR) divided by the total number of patients treated. Per Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), 'Complete Response' is the disappearance of all target lesions and 'Partial Response' is at least a 30% decrease in the sum of the diameters of target lesions, as measured via CT (computed tomography). Overally Response (OR) = CR + PR.

Measure: Overall Response Rate

Time: 2 years

Description: To determine the overall survival in patients treated with aldesleukin and vemurafenib. Overall survival is defined as the time between the first administration of study drug and death due to any cause.

Measure: Overall Survival

Time: 2 years

Description: To determine the toxicity and safety of concurrent administration of aldesleukin and vemurafenib by assessing adverse events experienced by participants.

Measure: Number of Participants Experiencing Grade 3 (Severe) Adverse Events

Time: 2 years

Description: To assess whether the number of doses of aldesleukin that can be safely administered is affected by the co-administration of vemurafenib. The total number of planned doses of aldesleukin was 28 in each of course 1 and course 2. A participant receiving all 28 doses in course 1 would be considered as receiving 100 percent of doses.

Measure: Mean Percentage of Aldesleukin Doses Received Per Participant

Time: Approximately 9 months from start of treatment

Description: Tumor samples were collected pre-treatment, after 1-2 weeks on vemurafenib alone and after administration of aldesleukin (high-dose interleukin 2, HD-IL2). Multi-parameter flow cytometry was performed to measure the frequency of regulatory T cells and of CD8+ T cells. The CD8/Treg ratio was calculated.

Measure: Ratio of CD8+ T Cells to Regulatory T Cells

Time: Up to 8 weeks from start of treatment

211 BrafPanc: A Phase II Trial of Binimetinib in Combination With Encorafenib in Patients With Pancreatic Malignancies and a Somatic BRAFV600E Mutation

This phase II trial studies the side effects and how well the combination of binimetinib and encorafenib work in treating patients with pancreatic cancer with a somatic BRAF V600E mutation. Binimetinib and encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving binimetinib and encorafenib may work better compared to the usual treatment in treating patients with pancreatic cancer and a somatic BRAF V600E mutation.

NCT04390243
Conditions
  1. Locally Advanced Pancreatic Carcinoma
  2. Metastatic Pancreatic Carcinoma
  3. Recurrent Pancreatic Carcinoma
  4. Stage III Pancreatic Cancer AJCC v8
  5. Stage IV Pancreatic Cancer AJCC v8
Interventions
  1. Drug: Binimetinib
  2. Drug: Encorafenib
MeSH:Carcinoma Pancreatic Neoplasms
HPO:Carcinoma Neoplasm of the pancreas

Binimetinib and Encorafenib for the Treatment of Pancreatic Cancer in Patients With a Somatic BRAF V600E Mutation This phase II trial studies the side effects and how well the combination of binimetinib and encorafenib work in treating patients with pancreatic cancer with a somatic BRAF V600E mutation. --- V600E ---

Binimetinib and Encorafenib for the Treatment of Pancreatic Cancer in Patients With a Somatic BRAF V600E Mutation This phase II trial studies the side effects and how well the combination of binimetinib and encorafenib work in treating patients with pancreatic cancer with a somatic BRAF V600E mutation. --- V600E --- --- V600E ---

Giving binimetinib and encorafenib may work better compared to the usual treatment in treating patients with pancreatic cancer and a somatic BRAF V600E mutation. --- V600E ---

The rate of patients experiencing a grade 3+ adverse event will be reported.. Inclusion Criteria: - PRE-REGISTRATION: - Histological confirmation of a pancreatic malignancy as confirmed by the local pathology lab - Patients whose disease has progressed on (or who were intolerant of) at least one line of therapy for metastatic disease - Patients whose disease has recurred with metastatic disease =< 12 weeks of completion of neoadjuvant or adjuvant systemic chemotherapy; or patients with locally advanced disease whose disease progressed to metastatic disease on, or =< 12 weeks after completion of systemic chemotherapy would also be eligible - Provide informed written consent =< 28 days prior to pre-registration - Central electronic/paper confirmation of the presence of a BRAF V600E mutation. --- V600E ---

Results from a Clinical Laboratory Improvement Act (CLIA)/College of American Pathologists (CAP) certified testing lab (commercial or institutional) that confirm the presence of a BRAF V600E mutation in the patient's tumor must be submitted for central review - REGISTRATION: NOTE: Registration must occur =< 30 days after pre-registration - Confirmation of the presence of BRAF V600E mutation in the patient's tumor - Measurable disease - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2. (Form is available on the Academic and Community Cancer Research United [ACCRU] web site) - Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 14 days prior to registration) - Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration) - Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration) - Aspartate transaminase (AST) =< 2.5 x ULN; in participants with liver metastases =< 5 x ULN (obtained =< 14 days prior to registration) - Aminotransferase (ALT) =< 2.5 x ULN; in participants with liver metastases =< 5 x ULN (obtained =< 14 days prior to registration) - Calculated creatinine clearance must be >= 45 ml/min using the Cockcroft Gault formula (obtained =< 14 days prior to registration) - Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only - Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study). --- V600E ---

Results from a Clinical Laboratory Improvement Act (CLIA)/College of American Pathologists (CAP) certified testing lab (commercial or institutional) that confirm the presence of a BRAF V600E mutation in the patient's tumor must be submitted for central review - REGISTRATION: NOTE: Registration must occur =< 30 days after pre-registration - Confirmation of the presence of BRAF V600E mutation in the patient's tumor - Measurable disease - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2. (Form is available on the Academic and Community Cancer Research United [ACCRU] web site) - Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 14 days prior to registration) - Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration) - Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration) - Aspartate transaminase (AST) =< 2.5 x ULN; in participants with liver metastases =< 5 x ULN (obtained =< 14 days prior to registration) - Aminotransferase (ALT) =< 2.5 x ULN; in participants with liver metastases =< 5 x ULN (obtained =< 14 days prior to registration) - Calculated creatinine clearance must be >= 45 ml/min using the Cockcroft Gault formula (obtained =< 14 days prior to registration) - Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only - Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study). --- V600E --- --- V600E ---

Note: During the active monitoring phase of a study (i.e., active treatment), participants must be willing to return to the consenting institution for follow-up - Ability to swallow the investigational product tablets and capsules - Willing to provide tissue and blood samples for correlative research purposes Exclusion Criteria: - REGISTRATION: - Patients whose tumor harbors a BRAF non-V600E mutation or a BRAF fusion - Prior therapy with BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib) - Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients - Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: - Pregnant women - Nursing women - Men or women of childbearing potential who are unwilling to employ adequate contraception - NOTE: Female participants of childbearing potential must agree to use methods of contraception that are highly effective or acceptable, and to not donate ova from screening until 30 days after the last dose of study drug - NOTE: Male participants must agree to use methods of contraception that are highly effective or acceptable, and to not donate sperm from screening until 90 days after the last dose of study drug - Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens - Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy. --- V600E ---

- NOTE: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may register Inclusion Criteria: - PRE-REGISTRATION: - Histological confirmation of a pancreatic malignancy as confirmed by the local pathology lab - Patients whose disease has progressed on (or who were intolerant of) at least one line of therapy for metastatic disease - Patients whose disease has recurred with metastatic disease =< 12 weeks of completion of neoadjuvant or adjuvant systemic chemotherapy; or patients with locally advanced disease whose disease progressed to metastatic disease on, or =< 12 weeks after completion of systemic chemotherapy would also be eligible - Provide informed written consent =< 28 days prior to pre-registration - Central electronic/paper confirmation of the presence of a BRAF V600E mutation. --- V600E ---

- NOTE: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may register Locally Advanced Pancreatic Carcinoma Metastatic Pancreatic Carcinoma Recurrent Pancreatic Carcinoma Stage III Pancreatic Cancer AJCC v8 Stage IV Pancreatic Cancer AJCC v8 Carcinoma Pancreatic Neoplasms PRIMARY OBJECTIVE: I. To determine the efficacy of the combination of binimetinib and encorafenib as >= 2nd line of treatment for patients with metastatic pancreatic cancer with BRAF V600E mutation. --- V600E ---

SECONDARY OBJECTIVES: I. To determine in patients treated with the combination of binimetinib and encorafenib as >= 2nd line of treatment for patients with metastatic pancreatic cancer with BRAF V600E mutation: Ia. --- V600E ---

Primary Outcomes

Description: An objective response is defined as a complete or partial response with a confirmation scan not less than 4 weeks after the initial scan. Disease status will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria. The final ORR point estimate and corresponding 95% confidence interval will be reported.

Measure: Objective response rate (ORR)

Time: At 24 weeks

Secondary Outcomes

Description: Progression-free survival is defined as the time from registration to clinical or radiographic disease progression or death, whichever occurs first, as defined by RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. The median PFS and corresponding 95% confidence interval will be reported.

Measure: Progression-free survival (PFS)

Time: From registration to the first of either disease progression or death from any cause, assessed up to 5 years

Description: Overall survival (OS) is defined as the time from registration to death from any cause. OS will be estimated using the Kaplan-Meier method. The median overall survival and corresponding 95% confidence interval will be reported.

Measure: Overall survival

Time: From registration to death from any cause, assessed up to 5 years

Description: Duration of response is defined as the duration of time from first documentation of an objective response to the earliest date disease progression is documented or death from any cause. Duration of response will be estimated using the Kaplan-Meier method. The median duration of response and corresponding 95% confidence interval will be reported.

Measure: Duration of response

Time: From first documentation of an objective response to the earliest date disease progression is documented or death from any cause, assessed up to 5 years

Description: Time to response is defined as the duration of time from registration to the first documentation of an objective response. Time to response will be estimated using the Kaplan-Meier method. The median time to response and corresponding 95% confidence interval will be reported.

Measure: Time to response

Time: From registration to the first documentation of an objective response, assessed up to 5 years

Description: Adverse Events as defined by National Institute of Health (NIH) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. All patients who have initiated treatment will be considered evaluable for adverse event analyses. The rate of patients experiencing a grade 3+ adverse event will be reported.

Measure: Incidence of adverse events

Time: Up to 5 years

212 An International Phase 1/2 Study of GRT-C901/GRT-R902, a Neoantigen Cancer Vaccine, in Combination With Immune Checkpoint Blockade for Patients With Advanced Solid Tumors

The purpose of this study is to evaluate the safety, dose, immunogenicity and early clinical activity of GRT-C901 and GRT-R902, a personalized neoantigen cancer vaccine, in combination with nivolumab and ipilimumab, in patients with metastatic non-small cell lung cancer, microsatellite stable colorectal cancer, gastroesophageal adenocarcinoma, and metastatic urothelial cancer.

NCT03639714
Conditions
  1. Non Small Cell Lung Cancer
  2. Colorectal Cancer
  3. Gastroesophageal Adenocarcinoma
  4. Urothelial Carcinoma
Interventions
  1. Biological: GRT-C901
  2. Biological: GRT-R902
  3. Biological: nivolumab
  4. Biological: ipilimumab
MeSH:Adenocarcinoma Carcinoma, Transitional Cell

For CRC, patients with a known BRAF V600E mutation or patients with peritoneal carcinomatosis and for GEA, patients with peritoneal carcinomatosis as their only evidence of disease - Patients with known central nervous system (CNS) metastases and/or carcinomatous meningitis - Known exposure to chimpanzee adenovirus or any history of anaphylaxis in reaction to a vaccination or allergy or hypersensitivity to study drug components - Bleeding disorder (eg., factor deficiency, coagulopathy) or history of significant bruising or bleeding following IM injections or blood draws Complete inclusion and exclusion criteria are listed in the clinical study protocol. --- V600E ---

Primary Outcomes

Measure: Incidence of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)

Time: Initiation of study treatment through 100 days post-last dose (up to approximately 27 months)

Measure: Objective Response Rate (ORR) in Phase 2 using RECIST v1.1

Time: Initiation of study treatment until disease progression (up to approximately 27 months)

Measure: Identify the recommended Phase 2 dose (RP2D) of GRT-C901 and GRT-R902

Time: Up to approximately 6 months

Secondary Outcomes

Measure: Measure the immune response to neoantigens encoded by GRT-C901 and GRT-R902

Time: Baseline to end of treatment (up to approximately 12 months)

Measure: Objective Response Rate (ORR) in Phase 1 using RECIST v1.1

Time: Initiation of study treatment until disease progression (up to approximately 4 years)

Measure: Duration of response (DOR) using RECIST v1.1

Time: Initiation of study treatment until disease progression (up to approximately 4 years)

Measure: Clinical benefit rate (using RECIST v1.1)

Time: Initiation of study treatment until disease progression (up to approximately 4 years)

Measure: Progression-free survival (PFS)

Time: Up to approximately 4 years

Measure: Overall survival (OS)

Time: Up to approximately 4 years

Measure: Percentage of patients for whom vaccine is successfully manufactured and timeframe for vaccine manufacturing

Time: Study enrollment to initiation of study treatment (up to approximately 6 months)

213 An Adaptive Phase III, Multicenter, Randomized, Open-Label, Controlled Study of M7824 (Bintrafusp Alfa) Versus Pembrolizumab as a First-line Treatment in Patients With PD-L1 Expressing Advanced Non-small Cell Lung Cancer

The purpose of the study is to evaluate the efficacy and safety of bintrafusp alfa (M7824) compared with pembrolizumab in participants with advanced NSCLC with high PD-L1-tumor expression, with no epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation. The Phase III adaptive design allows for the option to recruit up to 584 patients based on pre-specified rules.

NCT03631706
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: M7824
  2. Drug: Pembrolizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

For radiation toxicity or prior major surgeries, participants should have recovered from side effects and/or complications - Have measurable disease based on RECIST 1.1 - Have a life expectancy of at least 3 months - Availability of tumor tissue (less than 6 months old) before the first dose is mandatory to determine PD-L1 expression level prior to enrollment - PD-L1 high status as determined by central testing - Other protocol defined inclusion criteria could apply Exclusion Criteria: - Participants with nonsquamous NSCLC histologies whose tumor harbors any of the following molecular alterations and targeted therapy is locally approved: epidermal growth factor receptor (EGFR) sensitizing (activating) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 rearrangement, or BRAF V600E mutation - Has received major surgery within 4 weeks prior to the first dose of study intervention; received thoracic radiation therapy of greater than 30 units of gray (Gy) within 6 months prior to the first dose of study - Known severe hypersensitivity to investigational products (M7824 or pembrolizumab), or any components in their formulations - Previous malignant disease (other than the target malignancy to be investigated in this study) within the last 3 years - Other protocol defined exclusion criteria could apply Inclusion Criteria: - Histologically confirmed diagnosis of advanced NSCLC - Have not received prior systemic therapy treatment for their advanced/Stage four NSCLC. --- V600E ---

For radiation toxicity or prior major surgeries, participants should have recovered from side effects and/or complications - Have measurable disease based on RECIST 1.1 - Have a life expectancy of at least 3 months - Availability of tumor tissue (less than 6 months old) before the first dose is mandatory to determine PD-L1 expression level prior to enrollment - PD-L1 high status as determined by central testing - Other protocol defined inclusion criteria could apply Exclusion Criteria: - Participants with nonsquamous NSCLC histologies whose tumor harbors any of the following molecular alterations and targeted therapy is locally approved: epidermal growth factor receptor (EGFR) sensitizing (activating) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 rearrangement, or BRAF V600E mutation - Has received major surgery within 4 weeks prior to the first dose of study intervention; received thoracic radiation therapy of greater than 30 units of gray (Gy) within 6 months prior to the first dose of study - Known severe hypersensitivity to investigational products (M7824 or pembrolizumab), or any components in their formulations - Previous malignant disease (other than the target malignancy to be investigated in this study) within the last 3 years - Other protocol defined exclusion criteria could apply Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- V600E ---

Primary Outcomes

Measure: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) assessed by Independent Review Committee (IRC)

Time: Time from randomization to planned final assessment at approximately up to 60 months

Measure: Overall survival (OS)

Time: Randomization to approximately up to 60 months

Secondary Outcomes

Measure: Occurrences of Treatment-emergent Adverse Events (TEAEs) and Treatment-related AEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0

Time: Randomization up to the last safety follow-up visit at approximately up to 60 months

Measure: Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee

Time: Time from randomization to planned final assessment expected at up to 60 months

Measure: Duration of Response Assessed from Complete Response (CR) or Partial Response (PR) according to RECIST 1.1 Assessed by Independent Review Committee

Time: Time from CR or PR to planned assessment, expected at approximately up to 60 months

Measure: Concentration of M7284 at the end of Infusion (Ceoi)

Time: Pre-dose, 30 minutes post-dose at Week 1, 3, 5, 7 and 6 weekly during treatment up to safety follow-up visit (28 days after last dose, assessed up to approximately 60 months)

Measure: Concentration of M7284 at the end of the Dosing Interval (C trough)

Time: Pre-dose, 30 minutes post-dose at Week 1, 3, 5, 7 and 6 weekly during treatment up to safety follow-up visit (28 days after last dose, assessed up to approximately 60 months)

Measure: Immunogenicity as measured by Anti-drug Antibodies Concentration

Time: Randomization up to safety follow-up visit (28 days post last-dose of study drug administration, assessed up to approximately 60 months)

214 A Randomized Phase II Study of Regorafenib Followed by Anti-EGFR Monoclonal Antibody Therapy Versus the Reverse Sequencing for Metastatic Colorectal Cancer Patients Previously Treated With Fluoropyrimidine, Oxaliplatin and Irinotecan (REVERCE II)

This phase II trial how well regorafenib and anti-EGFR therapy (cetuximab or panitumumab) works for the treatment of patients with colorectal cancer that cannot be removed by surgery (unresectable), has spread to nearby tissue or lymph nodes (locally advanced), or has spread to other places in the body (metastatic). Regorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab or panitumumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. The purpose of this research study is to compare the effects, good and/or bad, of taking regorafenib follow by cetuximab or panitumumab, to those that receive cetuximab or panitumumab before regorafenib.

NCT04117945
Conditions
  1. BRAF V600E Negative
  2. KRAS Gene Mutation Negative
  3. Locally Advanced Unresectable Colorectal Adenocarcinoma
  4. Metastatic Colorectal Adenocarcinoma
  5. NRAS Gene Mutation Negative
  6. Stage III Colorectal Cancer AJCC v8
  7. Stage IIIA Colorectal Cancer AJCC v8
  8. Stage IIIB Colorectal Cancer AJCC v8
  9. Stage IIIC Colorectal Cancer AJCC v8
  10. Stage IV Co
  11. Stage IV Colorectal Cancer AJCC v8
  12. Stage IVA Colorectal Cancer AJCC v8
  13. Stage IVB Colorectal Cancer AJCC v8
  14. Stage IVC Colorectal Cancer AJCC v8
Interventions
  1. Biological: Cetuximab
  2. Drug: Irinotecan
  3. Biological: Panitumumab
  4. Drug: Regorafenib
MeSH:Colorectal Neoplasms Adenocarcinoma
HPO:Neoplasm of the large intestine

opinion, makes the subject unsuitable for trial participation BRAF V600E Negative KRAS Gene Mutation Negative Locally Advanced Unresectable Colorectal Adenocarcinoma Metastatic Colorectal Adenocarcinoma NRAS Gene Mutation Negative Stage III Colorectal Cancer AJCC v8 Stage IIIA Colorectal Cancer AJCC v8 Stage IIIB Colorectal Cancer AJCC v8 Stage IIIC Colorectal Cancer AJCC v8 Stage IV Co Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Colorectal Neoplasms Adenocarcinoma PRIMARY OBJECTIVE: I. To compare the overall survival between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib. --- V600E ---

Primary Outcomes

Description: The median OS and 95% confidence intervals in each arm will be reported.

Measure: Overall survival (OS)

Time: Up to 3 years

Secondary Outcomes

Description: The median first PFS and 95% confidence intervals in each arm will be reported.

Measure: First progression-free survival (PFS)

Time: Up to 3 years

Description: The median second PFS and 95% confidence intervals in each arm will be reported.

Measure: Second PFS

Time: Up to 3 years

Description: The median PFS while on sequential treatment and 95% confidence intervals in each arm will be reported.

Measure: Sequential treatment PFS

Time: Up to 3 years

Description: Point estimates and the corresponding 95% confidence intervals for the true success proportions in each arm will be reported.

Measure: Objective response rate

Time: Up to 3 years

Description: Point estimates and the corresponding 95% confidence intervals for the true success proportions will be reported.

Measure: Sequential treatment objective response rate

Time: Up to 3 years

Description: The number of patients who experience a grade 3 or higher adverse event (Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0), regardless of attribution, will be reported by arm.

Measure: Incidence of adverse events

Time: Up to 3 years

215 Noninvasive vs. Invasive Lung Evaluation

Tumor derived cell free DNA (cfDNA) is increasingly used in the clinic to obtain genotype information about lung cancer, but its concordance with concurrent tumor-derived sequenced data is not known. The purpose of the trial is to determine the non-inferiority of cfDNA-based vs. tumor tissue-based genotyping as it pertains to the detection of National Comprehensive Cancer Network (NCCN)-recommended biomarkers in first line, treatment naive, non-squamous Non-Small Cell Lung Cancer (NSCLC).

NCT03615443
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Diagnostic Test: Guardant360
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

This will be assessed for the overall population and for the subpopulation of subjects who are identified by either tissue or cfDNA as having actionable EGFR activating mutations, ALK fusions, ROS1 fusions, and BRAF V600E mutations and who are subsequently treated with tyrosine kinase inhibitors.. Turnaround Time for cfDNA vs. Tissue Results. --- V600E ---

Primary Outcomes

Description: The proportion of subjects for whom a genetic alteration is found in at least one of seven genes (EGFR, ALK, ROS1, BRAF, MET, ERBB2, RET) by testing tumor tissue will be compared to the proportion of subjects for whom a genetic alteration is found in at least one of the same genes by testing cfDNA.

Measure: Demonstrate the non-inferiority of cfDNA-based vs. tumor tissue-based genotyping

Time: 34 months

Secondary Outcomes

Description: The proportion of subjects with complete or partial tumor response as determined by the investigator. This will be assessed for the overall population and for the subpopulation of subjects who are identified by either tissue or cfDNA as having actionable EGFR activating mutations, ALK fusions, ROS1 fusions, and BRAF V600E mutations and who are subsequently treated with tyrosine kinase inhibitors.

Measure: Objective Response Rate (ORR)

Time: 34 months

Description: The time (in days) from the date of request for genetic testing to the report date for cfDNA and for tumor tissue.

Measure: Turnaround Time for cfDNA vs. Tissue Results

Time: 34 months

Description: The number of days from the date of study enrollment until the date that systemic or localized treatment is initiated.

Measure: Time to Treatment Initiation

Time: 34 months

Description: The proportion of subjects deemed to have quantity not sufficient for tumor tissue testing of any of seven genes (EGFR, ALK, ROS1, BRAF, MET, ERBB2, RET) due to any of the following reasons: 1) insufficient tumor specimen for the genotyping tests to be performed, or 2) tumor cellularity below lab-dictated minimal requirements, or 3) no results available within 45 days of enrollment.

Measure: Quantity Not Sufficient Rate of Tissue for Complete NCCN Biomarker Testing

Time: 34 months

Description: The proportion of subjects with tumor tissue testing results not available for all seven genes (EGFR, ALK, ROS1, BRAF, MET, ERBB2, RET) and with no alterations detected among the genes that were tested.

Measure: Tissue Incomplete Rate of Tissue for NCCN Biomarker Testing

Time: 34 months

Description: The proportion of subjects for whom cfDNA could not be detected in blood.

Measure: Tumor Not Detected Rate of cfDNA in Blood

Time: 34 months

Description: This objective applies to genes included in the Guardant360 panel other than EGFR, ALK, ROS1, BRAF, MET, ERBB2, RET and to subjects for whom both cfDNA and tumor tissue testing results are available. Diagnostic accuracy will include calculations for sensitivity, specificity, positive predictive value, and negative predictive value comparing tissue to cfDNA results and vice versa.

Measure: Sensitivity, Specificity, and Diagnostic Accuracy of Non-NCCN Biomarkers on the Guardant360 Panel

Time: 34 months

Description: Among subjects with tumor genetic alterations in EGFR, ALK, ROS1, BRAF, MET, ERBB2, or RET, the proportion with new (compared to baseline) genetic alterations in cfDNA at the time of disease progression following treatment with a therapy targeting the specific genetic alteration.

Measure: Rate of Discovery of Genomically Mediated, Acquired Resistance to Targeted Therapies in the Biomarker-Positive Subsets

Time: 34 months

Other Outcomes

Description: Among subjects with tumor tissue quantity not sufficient for genetic testing, the proportion that had cfDNA detected.

Measure: Liquid Biopsy Rescue Rate of QNS Tissue Samples

Time: 34 months

216 A Randomized, Controlled Trial Examining the Use of The "Serious Illness Conversation Guide" (SICG) in Patients With Advanced Gastro-Intestinal Cancers

The purpose of the study is to determine whether standardized implementation of a scripted template for discussing important issues that arise near the end of life improves the care of those who have advanced cancer.

NCT04077372
Conditions
  1. Gastrointestinal Cancer
  2. Colorectal Cancer
  3. Pancreatic Adenocarcinoma
  4. Gastric Cancer
  5. Esophageal Cancer
  6. Cholangiocarcinoma
  7. Hepatocellular Carcinoma
  8. Neuroendocrine Tumors
  9. GIST, Malignant
Interventions
  1. Behavioral: Serious Illness Conversation Guide (SICG)
  2. Behavioral: Quality of Life (QOL) survey
MeSH:Carcinoma, Hepatocellular Neuroendocrine Tumors Cholangiocarcinoma Gastrointestinal Neoplasms Intestinal Neoplasms
HPO:Cholangiocarcinoma Hepatocellular carcinoma Malignant gastrointestinal tract tumors Neoplasm of the gastrointestinal tract Neuroendocrine neoplasm

- Exception: Patients with metastatic colorectal cancer whose tumors demonstrate a BRAF V600E mutation may be enrolled regardless of prior chemotherapy. --- V600E ---

Primary Outcomes

Description: Difference in proportions of patients who have documented goals of care in medical records, assessed after death, for both arms

Measure: Difference in proportions of patients with documented goals of care

Time: 1 year

Secondary Outcomes

Description: Proportion of patients receiving appropriate care in line with their goals of care toward the end of life, by arm will be assessed.

Measure: Difference in proportions of patients with appropriate care toward end of life

Time: 1 year

Description: Comparison of survey QOL measures by section for control and intervention arms will be done by Functional Assessment of Cancer Therapy (FACT-G) , version 4 scale. It is a 28-item validated QoL questionnaire in patients receiving cancer treatment. All subscales are summed together to arrive at a total score. A higher point value is considered a better quality of life score

Measure: Comparison of QOL survey measures by section

Time: 1 year

Description: Comparison of survey QOL measures overall for control and intervention arms will be done by Functional Assessment of Cancer Therapy (FACT-G) , version 4 scale. It is a 28-item validated QoL questionnaire in patients receiving cancer treatment. All subscales are summed together to arrive at a total score. A higher point value is considered a better quality of life score

Measure: Overall comparison of QOL survey

Time: 1 year

217 A Phase 2 Study to Assess the Safety and Efficacy of Cobimetinib in Refractory Langerhans Cell Histiocytosis, LCH-Associated Neurodegenerative Disease, and Other Histiocytic Disorders.

This is a research study of a drug called cobimetinib in children and adults diagnosed with Langerhans cell histiocytosis (LCH), and other histiocytic disorders that has returned or does not respond to treatment. Cobimetinib blocks activation of a protein called Mitogen-activated protein kinase (MEK) that is part of incorrect growth signals in histiocytosis cells. Four different groups of patients will be enrolled.

NCT04079179
Conditions
  1. Langerhan's Cell Histiocytosis
  2. Juvenile Xanthogranuloma
  3. Erdheim-Chester Disease
  4. Rosai Dorfman Disease
  5. Neuro-Degenerative Disease
  6. Histiocytic Sarcoma
  7. Histiocytic Disorders, Malignant
Interventions
  1. Drug: Cobimetinib
MeSH:Histiocytic Sarcoma Histiocytic Disorders, Malignant Histiocytosis, Langerhans-Cell Neurodegenerative Diseases Histiocytosis Erdheim-Chester Disease Xanthogranuloma, Juvenile Histiocytosis, Sinus
HPO:Histiocytosis Neurodegeneration

BRAF-V600E) . --- V600E ---

The purpose of this research study is to learn whether cobimetinib is safe and effective in subjects diagnosed with LCH, LCH-ND, RDD, JXG and ECD which may have a specfic mutation called BRAF-V600E. --- V600E ---

BRAF-V600E is a specific change in a gene that may cause cancer cells to grow and spread by sending constant signals to the MEK protein. --- V600E ---

Primary Outcomes

Description: Proportion of participants with (complete response, partial response, stable disease, progressive disease) by 1 year of therapy with Cobimetinib. It is assumed that at each protocol-specified timepoint, a response assessment occurs. Status calculation will occur at each timepoint for patients who have measurable disease at baseline per the criteria defined in the protocol.

Measure: Overall Response Rates using modified RECiST criteria

Time: 12 months

Secondary Outcomes

Description: Progression Free Survival defined as the length of time during and after the treatment of a disease, that a patient lives with the disease but it does not get worse.

Measure: Progression Free Survival

Time: 12 months

Description: Assessment of the nature and severity of adverse events in patients treated with Cobimetinib for histiocytic disorders.

Measure: Nature and Severity of Adverse Events

Time: 12 months

Other Outcomes

Description: Response assessment using modified RECIST criteria for target lesions with specific mutations (e.g. BRAF-V600E) . Best response rate by 1 year of therapy.

Measure: Response assessment (Modified RECIST) of histiocytic lesions with specific mutations

Time: 12 months

218 Exploratory Study of the Molecular Profile of Thyroid Cancer

This is a two part study; part A proposes to collect plasma samples to examine how ctDNA (circulating thyroid DNA) markers correlate with detection of recurrent disease, response to therapy, clinical outcome and pathological data. Part B aims to use tissue obtained from biopsies of primary or recurrent disease to establish cell lines and tumour explants to further investigate the biology of thyroid cancer in the preclinical setting

NCT04133870
Conditions
  1. Thyroid Cancer
MeSH:Thyroid Neoplasms Thyroid Diseases
HPO:Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

To correlate BRAF V600E, RAS, RET/PTC, RET, PAX8/PPARϒ, βcatenin, p53, PTEN and PI3K mutations in ctDNA with Formalin Fixed Paraffin Embedded tumour tissue (FFPE) mutational analysis. --- V600E ---

Primary Outcomes

Description: Part A: blood and tumour tissue will be measured to determine molecular profiling.

Measure: Primary Objective

Time: 3 Years (at the end of study)

Description: Part B: blood and tumour tissue will be assessed to establish cell lines and to determine patient derived xenograft (PDX) models of thyroid cancer

Measure: Primary Objective

Time: 3 years (at end of study)

219 Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma

DONIMI is a phase 1b trial testing the combination of domatinostat + nivolumab or nivolumab monotherapy in IFN-gamma signature high patients and of domatinostat + nivolumab or domatinostat + nivolumab + ipilimumab in IFN-gamma signature low patients with de-novo or recurrent macroscopic stage III cutaneous or unknown primary melanoma. The trial will include 45 stage III cutaneous or unknown primary melanoma patients with RECIST 1.1 measurable de-novo or recurrent disease (short axis lymph node metastasis ≥1.5cm). NanoString IFN-gamma signature high patients will be randomized to be treated pre-surgically for 6 weeks with nivolumab (arm A; 10 patients) or domatinostat + nivolumab (arm B; 10 patients). IFN-gamma signature low patients will be randomized to be treated pre-surgically for 6 weeks with domatinostat + nivolumab (arm C; 10 patients) or domatinostat + nivolumab + ipilimumab (arm D; 15 patients). Patients will be stratified according to center. Post-surgery (starting at week 12), the patients will start with adjuvant nivolumab or pembrolizumab for 52 weeks according to institute's standard. BRAF V600E/K mutation positive patients with no pathologic response after neoadjuvant therapy may also receive adjuvant BRAF + MEK inhibition if commercially available and according to the patient's and the treating physician's decision. Follow-up after the adjuvant therapy will be for 2 years, according to the institutes' standard. Toxicity and pathologic response rates will be descriptive. In case of 2/5 or 4/10 patients not undergoing their lymph node dissection at week 6 +/- 1 week due to treatment related toxicity, this arm will be declared unfeasible.

NCT04133948
Conditions
  1. Malignant Melanoma Stage III
Interventions
  1. Drug: Domatinostat
  2. Drug: Nivolumab
  3. Drug: Ipilimumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

BRAF V600E/K mutation positive patients with no pathologic response after neoadjuvant therapy may also receive adjuvant BRAF + MEK inhibition if commercially available and according to the patient's and the treating physician's decision. --- V600E ---

Primary Outcomes

Description: A treatment arm will be declared as not safe if 8/10 patients develop gr 3-4 adverse events or if 2/10 patients develop longlasting (>6 months) gr 3-4 adverse events.

Measure: Safety of patients as measured by the adherence to the timelines in the study protocol

Time: 6 months

Description: A treatment arm will be declared as not feasible if 2/5 or 4/10 patients cannot adhere to the planned time of surgery (week 6 +/- 1 week) due to treatment related adverse events.

Measure: Feasability of patients as measured by the adherence to the timelines in the study protocol

Time: 6 weeks

Secondary Outcomes

Measure: Pathologic response rates (pPR, near-pCR, and pCR).

Time: At 6 weeks

Measure: Frequency of treatment-related toxicities as measured according to CTCAE 5.0.

Time: At 6 weeks

Measure: Radiologic response rate according to RECIST 1.1 criteria

Time: At 6 weeks

Measure: Relapse Free Survival (RFS)

Time: Up to 3 years after treatment

Measure: RNA signatures associated with pathologic response and RFS for each arm (by RNAseq and NanoString gene expression analysis).

Time: Up to 3 years after treatment

Measure: Changes in immune infiltrates/markers at week 3 and/or 6 compared to baseline by NanoString DSP technology or alternative immunohistochemistry analysis.

Time: At week 3 and/or 6

Measure: Inter-arm comparison of the expansion of tumor-resident T cell clones, as measured by TCR sequencing of the baseline tumor-biopsy and PBMC samples from baseline week 3 and week 6.

Time: At week 3 and/or 6

Measure: Feces microbiome diversity analyses and its correlation with pathologic response and toxicities.

Time: Up to 3 years after treatment

Measure: Quality of life as measured by EORTC QLQ C30

Time: Up to 3 years after treatment

Measure: Quality of life as measured by the the Melanoma Subscale and Melanoma Surgery Subscale of FACT-M

Time: Up to 3 years after treatment

Measure: Quality of life as measured by the Cancer Worry Scale

Time: Up to 3 years after treatment

Measure: Quality of life as measured by HADS questionnaire

Time: Up to 3 years after treatment

Measure: Quality of life as measured by EQ-5D-5L

Time: Up to 3 years after treatment

Measure: Quality of life as measured by the immunotherapy-specific questionnaire

Time: Up to 3 years after treatment

Measure: Quality of life as measured by an assessment of work performance.

Time: Up to 3 years after treatment

220 Part I and Part II A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of KTN3379 in Adult Subjects With Advanced Tumors Alone or With Chemotherapy

Part I will evaluate the pharmacokinetic profile and safety of KTN3379 over several doses with the objective of defining a Phase 2 dose in patients with advanced malignancies. Part II will evaluate the pharmacokinetic profile and safety of KTN3379 in combination with other targeted agents and obtain preliminary evidence of anti tumor activity in specific types of cancer. Patients will continue receiving KTN3379 alone or in combination until disease progression or toxicity that necessitates discontinuation (whichever comes first).

NCT02014909
Conditions
  1. Advanced Cancer
Interventions
  1. Biological: KTN3379

Part II Arm A have head and neck cancer or K-Ras wild type EGFR expressing colon cancer, Arm B, have non small cell lung cancer, Arm C, have BRAF V600E mutated melanoma and Arm D have HER2 positive breast or gastric cancer that has progressed following one or more treatments for advanced or metastatic disease. --- V600E ---

Primary Outcomes

Description: Continued assessment of safety

Measure: Dose limiting toxicities for KTN3379 alone or in combination

Time: Participants will be followed for the duration of treatment, an expected average of 3 cycles/9 weeks

Secondary Outcomes

Measure: Area Under the Concentration-Time Curve (AUC 0 through end of study)

Time: Prior to the initial dose on day 1 through duration of treatment, an expected average of 3 cycles/9 weeks

221 A Phase I, Open-Label Study to Determine the Effect of Repeat Dosing of Trametinib on the Pharmacokinetics and Safety of a Combined Oral Contraceptive (Norethindrone Plus Ethinyl Estradiol) and to Characterize the Pharmacokinetics of Trametinib's Metabolite M5 in Female Subjects With Solid Tumors

This is a Phase I, open-label, non-randomized, sequential, two-period, repeat-dose study to evaluate the effect of trametinib 2 milligram (mg) once daily on the repeat-dose pharmacokinetic (PK) of an oral contraceptive (OC) containing norethindrone (NE) and ethinyl estradiol (EE) (ORTHO-NOVUM® tablets: 1 mg NE + 0.035 mg EE) in female subjects with solid tumors. The study will determine PK interaction between trametinib and the components of combination oral contraceptives that would compromise the effectiveness of the contraceptives. The study will also evaluate the repeat dose PK of trametinib and its metabolite M5 using a validated assay. The study will enroll approximately 24 subjects. Each subject will participate in the study for approximately up to 13 to 15 weeks which will consist of a 30 day screening period, followed by 2 treatment periods (Period 1: 28 days and Period 2: ranging from 12 days to up to 21 days), and a transition visit or post-treatment follow-up visit. In Period 1, subjects will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 21 days (Days 1 through 21), followed by one inert (referred to as placebo) tablet once daily at approximately the same time each day for 7 days (Days 22 through 28). In addition, subjects will take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for a total of 17 days (Days 12 through 28). In Period 2, subjects will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 11 days (Days 1 through 11). In addition, subjects will continue taking trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11). ORTHO-NOVUM® is a registered trademark of Ortho Pharmaceutical Corporation.

NCT02292732
Conditions
  1. Cancer
Interventions
  1. Drug: Trametinib 0.5 mg
  2. Drug: Trametinib 2 mg
  3. Drug: ORTHO-NOVUM® tablet 1/35
  4. Drug: Placebo

ALT with documented liver metastases or tumor infiltration; >2.5xULN but <=5xULN) ; Renal (Creatinine or <=1.5 ULN; Calculated creatinine clearance [calculated by the Cockcroft-Gault formula] >=50 milliliters/minute [mL/min]) ; Cardiac (left ventricular ejection fraction [LVEF] >= lower limit of normal [LLN] by echocardiogram [ECHO] or Multigated acquisition scan [MUGA]) Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: - Had prior exposure to a MEK inhibitor - Has one of the following excluded tumor types as trametinib therapy has been shown to have minimal benefit in these populations: BRAF V600E mutant melanoma and failed prior BRAF inhibitor therapy; Metastatic pancreatic cancer - Has had any major surgery extensive radiotherapy, or anti-cancer therapy (e.g., chemotherapy with delayed toxicity, biologic therapy, or immunotherapy) within 21 days prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrollment. --- V600E ---

Primary Outcomes

Description: Steady state PK parameters will include Area under the concentration-time curve over the dosing interval (AUC[0-tau]), Maximum observed plasma concentration (Cmax), Pre-dose concentration (C0) and Time to Cmax (Tmax)

Measure: Composite of steady state PK parameters of NE and EE

Time: Day 11 and Day 12 of both the treatment periods

Description: Steady state PK parameters will include AUC(0-tau), Cmax, C0 and Tmax

Measure: Composite of steady state PK parameters of NE and EE in combination with trametinib

Time: Day 11 and Day 12 of both the treatment periods

Secondary Outcomes

Description: Steady-state PK parameters will include AUC(0-tau), Cmax, C0, Tmax, and metabolite/parent AUC ratio

Measure: Composite of steady state PK parameters of Plasma trametinib and M5

Time: Day 11 and Day 12 of treatment period 2

Description: Vital signs will include measurement of blood pressure, temperature and pulse rate

Measure: Safety and tolerability as assessed by measuring vital signs

Time: Up to 107 days

Description: Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT interval (QTc) intervals. Electrocardiograms (ECGs) will be performed by qualified site personnel after the subject has rested at least 5 minutes in a semi-recumbent or supine position.

Measure: Safety and tolerability as assessed by measuring electrocardiogram (ECGs)

Time: Up to 107 days

Description: The evaluation of the echocardiographer will include an evaluation for Left ventricular ejection fraction (LVEF) and both right and left-sided valvular lesions

Measure: Safety and tolerability by assessing ECHOs

Time: Up to 107 days

Description: Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters

Measure: Safety and tolerability by assessing clinical laboratory tests

Time: Up to 107 days

Description: AEs will be collected throughout the treatment periods up to follow up

Measure: Safety and tolerability by assessing adverse events (AEs)

Time: Up to 107 days

222 A Phase II Clinical Trial on the Combination of Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients With Advanced BRAF V600 Mutant Melanoma

Patients with BRAF V600 mutant advanced melanoma benefit from treatment with a BRAF-inhibitor (e.g. dabrafenib, vemurafenib) and from combination of a BRAF- and MEK-inhibitor (e.g. dabrafenib and trametinib). Following initial tumor regression, progression is diagnosed in a majority of patients treated with BRAF-inhibitor mono-therapy within the first 12-months of therapy. Various molecular mechanisms that underlie the development of resistance to treatment with a BRAF-inhibitor have been reported. These mechanisms do not include secondary mutations in the BRAF-gene and therefore resistance to BRAF-inhibition could potentially be reversible when selective pressure by BRAF-inhibition is withheld for a sufficient period of time of melanoma progression. This clinical trial protocol addresses the potential renewed anti-tumor activity of combined BRAF- and MEK inhibition with the combination of dabrafenib and trametinib in patients with unresectable AJCC stage III or - IV BRAF V600 mutant melanoma who are documented with progression of disease at least 12 weeks following the last day of dosing of a BRAFinhibitor containing treatment regimen.

NCT02296996
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: Dabrafenib + Trametinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

2. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive. --- V600E ---

Primary Outcomes

Measure: Overall response rate

Time: Participants will be monitored until progression, with an expected average of 6 months

Secondary Outcomes

Measure: Progression-free survival

Time: Participants will be monitored until progression, with an expected average of 6 months

Measure: Overall Survival

Time: 2 years

Description: Detect adverse events

Measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Time: Participants will be monitored until progression, with an expected average of 6 months

Other Outcomes

Description: To explore if tumor specific cfDNA levels can be used as a monitoring tool to detect early progression of disease

Measure: Tumour-specific cfDNA levels

Time: Participants will be monitored until progression, with an expected average of 6 months

223 A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease

Erdheim-Chester Diseases (ECD) is a very rare non-Langerhans cell histiocytosis of unknown origin and pathogenesis. It has been reported mainly in adult males over the age of 40 years, although cases have been reported in females as well. Children are rarely affected. Mutation of the BRAF gene, specifically BRAFV600E, has been recently identified in 50% of Erdheim Chester lesions in a French cohort. This somatic mutation is believed to be the driver mutation in positive cases. The clinical characteristics of ECD range from asymptomatic to multisystemic involvement; longitudinal progression and natural history are becoming better understood. ECD commonly affects the bones, kidneys, retroperitoneal space, skin and brain. If untreated, the disease progresses rapidly, causing fatal outcomes due to severe lung disease, chronic renal failure, cardiomyopathy and other complications. The diagnosis of ECD relies upon imaging studies and specific pathologic findings in biopsies of affected organs, i.e., fibrosis and infiltration of tissues with foamy histiocytes, lymphocytes, and plasma cells. Immunohistochemistry reveals cells positive for CD68 and CD163 and negative for CD1a, with 20% positivity to S-100. There is no standard treatment for ECD, although chemotherapy, radiation, stem cell transplantion, alpha-interferon, anakinra, imatinib and sirolimus have been proposed. The recent discovery of the BRAFV600E mutation in several ECD patients has opened a new area for treatment options. Vemurafenib, an FDA approved BRAF inhibitor for the treatment of patients with metastatic or unresectable melanoma with the V600E mutation, binds to this form of mutated BRAF causing protein inactivation. The use of vemurafenib in patients with ECD has been reported in 3 patients who experienced remission of the disease, and is currently being studied in the U.S. and Europe as monotherapy. Tumor/disease resistance to vemurafenib has occurred in melanoma and other cancers, although it has not been reported in patients with ECD. In this protocol, we propose to clinically evaluate ECD patients with the BRAFV600E mutation and administer combination therapy with dabrafenib, a BRAFV600E inhibitor, and trametinib, an inhibitor of MEK, downstream of BRAF. Screening for possible contraindications will be made prior to the administration of the first dose. With this trial, we will determine the safety, tolerability, and efficacy of dabrafenib and trametinib in patients with ECD who harbor the BRAFV600E mutation. Dabrafenib 150mg will be given twice daily p.o.; trametinib 2mg will be given once daily p.o. Patients will be seen 1 week, 1 month, 2 months, 4 months, and 6 months, 8 months, 10 months and 12 months to complete a oneyear trial.

NCT02281760
Conditions
  1. BRAF V600E Mutation
Interventions
  1. Drug: Dabrafenib Mesylate
  2. Drug: Trametinib Dimethyl Sulfoxide
MeSH:Erdheim-Chester Disease

A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease. --- V600E ---

Dabrafenib and Trametinib in People With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease Erdheim-Chester Diseases (ECD) is a very rare non-Langerhans cell histiocytosis of unknown origin and pathogenesis. --- V600E ---

Vemurafenib, an FDA approved BRAF inhibitor for the treatment of patients with metastatic or unresectable melanoma with the V600E mutation, binds to this form of mutated BRAF causing protein inactivation. --- V600E ---

Affected tissue must harbor the BRAF V600E or V600K mutation. --- V600E ---

BRAF V600E Mutation Erdheim-Chester Disease Erdheim-Chester Diseases (ECD) is a very rare non-Langerhans cell histiocytosis of unknown origin and pathogenesis. --- V600E ---

Primary Outcomes

Measure: To study the efficacy and safety

Time: 7 times in 12 months

Measure: To determine the clinical response rate

Time: 7 times in 12 months

Measure: To determine progression and survival

Time: 7 times in 12 months

Measure: To determine anitumor effect

Time: 7 times in 12 months

Secondary Outcomes

Measure: To monitor organ function on therapy

Time: 7 times in 12 months

Measure: To monitor inflammation on therapy

Time: 7 times in 12 months

Measure: To measure quality of life on therapy

Time: 7 times in 12 months

224 A Phase I/II Trial of Dabrafenib, Trametinib and Metformin Administered to Unresectable Stage IIIC and Stage IV BRAF V600E + Melanoma Patients

The main purpose is to evaluate the clinical response, safety and survival of the FDA approved drugs Dabrafenib, Trametinib in combination with Metformin. Investigators hypothesize that the combination of an FDA approved non toxic dose of oral Metformin with the B-Raf inhibitor, Dabrafenib and the MEK inhibitor, Trametinib will yield little toxicity and improve clinical outcomes in terms of objective response rates and survival in metastatic melanoma patients.

NCT02143050
Conditions
  1. Melanoma
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
  3. Drug: Metformin
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Phase I/II Trial of Dabrafenib, Trametinib and Metformin Administered to Unresectable Stage IIIC and Stage IV BRAF V600E + Melanoma Patients. --- V600E ---

Primary Outcomes

Description: During phase I, six patients will be enrolled and monitored for toxicities. If drug related deaths occur or more than two drug related CTCAE grade 4 toxicities occur the trial will be suspended. Phase II will estimate the efficacy of the drugs, enrolling 20 patients during stage 1 with an upper limit of 39 for the 2nd stage.

Measure: Observation of two CTCAE drug related grade 4 toxicities in six patients.

Time: Duration of phase I portion, approxiately 6 months

Description: Phase II will study the efficacy of the drugs enrolling 20 patients during stage I with an upper limit of 39 for the 2nd stage.

Measure: Clinical Response Rate

Time: 6 years

Secondary Outcomes

Description: Patients will be contacted every 3 months following treatment administration for up to three years to obtain survival data.

Measure: To estimate the overall survival rates.

Time: Approximately 3 years

Description: To identify demographic, disease and treatment related effects on overall survival.

Measure: To explore the effect of other covariates on overall survival

Time: 3 years

225 Phase 1 Study of the BRAF Inhibitor Dabrafenib +/- MEK Inhibitor Trametinib in Combination With Ipilimumab for Unresectable or Metastatic Melanoma

This is an open-label, multi-center, dose-finding Phase 1 study that will enroll subjects at least 18 years old with unresectable or metastatic melanoma and BRAF V600 mutations. The primary objective of the study is to describe the safety for the doublet therapy (dabrafenib and ipilimumab) and the triplet therapy (dabrafenib/trametinib and ipilimumab). Preliminary efficacy data will also be collected. Subjects will be assigned to receive either the doublet combination (dabrafenib and ipilimumab) or the triplet combination (dabrafenib, trametinib, and ipilimumab). Subjects will be enrolled to dose-finding cohorts in the doublet combination (dabrafenib + ipilimumab) in a sequential 3+3 fashion. Following establishment of a dose for the doublet combination, an expansion cohort will be opened. At the same time, enrollment to dose finding cohorts for the triplet combination (dabrafenib + trametinib + ipilimumab) will begin in a sequential 6+6 fashion. Enrollment into triplet cohorts will take priority when both the doublet expansion arm and the triplet dose-finding arm are open for enrollment at the same time. Approximately 9-24 subjects will be enrolled to the dose finding portion of the study. Approximately 30 subjects will be enrolled to doublet expansion cohort and 30 subjects will be enrolled in the triplet expansion cohort. A two-week run-in period without ipilimumab will be followed by 4 intravenous doses of ipilimumab at the recommended dose and schedule. Oral daily dosing of dabrafenib or dabrafenib + trametinib will continue from the two-week run-in, through combination with ipilimumab, and post-ipilimumab until no longer of clinical benefit, in the opinion of the treating physician, or until unacceptable AE or death

NCT01767454
Conditions
  1. Solid Tumours
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
  3. Drug: Ipilimumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Study of Dabrafenib +/- Trametinib in Combination With Ipilimumab for V600E/K Mutation Positive Metastatic or Unresectable Melanoma This is an open-label, multi-center, dose-finding Phase 1 study that will enroll subjects at least 18 years old with unresectable or metastatic melanoma and BRAF V600 mutations. --- V600E ---

PK samples have a +/-30 minute window for collection.. Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E ---

Patients with active autoimmune disease or a history of autoimmune disease other than those mentioned above must be approved by the GSK medical monitor - Active pneumonitis or interstitial lung disease - Lactating female - History of another malignancy (Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible) - Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Any prohibited medication - Administration of an investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment(s) in this study - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Unwillingness or inability to follow the procedures outlined in the protocol Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E ---

Primary Outcomes

Description: AEs will be collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment

Measure: Number of subjects with Adverse Events (AEs) to assess the safety of dabrafenib +/- trametinib when administered in combination with ipilimumab

Time: Follow-up up to 6 months after last subject last dose

Description: Hematology, clinical chemistry, and urinalysis parameters to be tested. Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate. A complete physical examination will be performed at screening and every 12 months thereafter, as well as whenever clinically indicated.A brief physical examination will be performed every 3 or 4 weeks

Measure: Changes in laboratory values, vital signs, and physical examinations as a measure of safety of dabrafenib +/- trametinib when administered in combination with ipilimumab

Time: Follow-up up to 6 months after last subject last dose

Secondary Outcomes

Description: All subjects will be evaluated for dose-limiting toxicity (DLT) from the first dose of ipilimumab until 1 week after the third dose of ipilimumab to determine a recommended dose for dabrafenib +/- trametinib when administered in combination with ipilimumab

Measure: Number of subjects with AEs and changes in laboratory values, vital signs, and physical examinations to determine a recommended dose for dabrafenib +/- trametinib when administered in combination with ipilimumab

Time: Up to approximately Week 9 in doublet and triplet arm

Description: Overall Response will be determined using Modified immune-related response criteria (irRC)

Measure: Overall response rate

Time: Follow-up up to 6 months after last subject last dose

Description: Four blood samples will be collected on the day of first dose of ipilimumab (Cycle 1) - Study Day 15. One blood sample will be obtained on the day of the second and third dose of ipilimumab (Cycles 2 and 3) - Study Days 36 and 57. Subjects will be instructed to withhold their morning dose until after they arrive at the clinic. Ipilimumab infusion should start as soon as possible after oral dosing of dabrafenib/trametinib. PK samples have a +/-30 minute window for collection.

Measure: Concentrations of trametinib, dabrafenib and its metabolites (GSK2285403, GSK2298683, and GSK2167542) in the triplet arm and dabrafenib and its metabolites in the doublet arm

Time: Day 15 (pre-dose,1, 2, and 4 hours post-dose); Day 36 and Day 57 (pre-dose only) for doublet and triplet arms

226 Allogeneic Vaccine Modified to Express HLA A2/4-1BB Ligand for High Risk or Low Residual Disease Melanoma Patients - Phase I/II Study.

This study is designed for patients who had malignant melanoma and, following tumor removal, are now free of disease, or have only very minor residual disease, and are at a very high risk of disease recurrence. These patients will be treated with the A2/4-1BBL melanoma vaccine, a compatible melanoma cell line that has been engineered to express a molecule termed 4-1BBL, which enhances the chances of the cell line to be recognized by the patient's immune system, and to induce its stimulation. The hypothesis that drives the study states that the immune response against the cell line will also be effective against the residual tumor that may still be present in the body.

NCT01898039
Conditions
  1. Malignant Melanoma
Interventions
  1. Biological: A2/4-1BBL melanoma vaccine
  2. Procedure: DNP sensititzation
  3. Drug: Cyclophosphamide
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

5. Non-resectable metastatic melanoma of low burden disease and normal LDH who have undergone at least two treatment lines, including chemotherapy (DTIC, temodal, taxanes, platinum compounds), anti-CTLA-4 (ipilimumab) and B-RAF inhibitor if harboring the V600E BRAF mutation in their tumor. --- V600E ---

Primary Outcomes

Measure: grade 2-4 adverse events according to CTCEA criteria

Time: Day 1

Description: Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response.

Measure: monitoring anti-tumor immune response

Time: Day 0

Measure: grade 2-4 adverse events according to CTCEA criteria

Time: Day 28

Measure: grade 2-4 adverse events according to CTCEA criteria

Time: Day 56

Measure: grade 2-4 adverse events according to CTCEA criteria

Time: month 3

Measure: grade 2-4 adverse events according to CTCEA criteria

Time: month 4

Measure: grade 2-4 adverse events according to CTCEA criteria

Time: month 5

Measure: grade 2-4 adverse events according to CTCEA criteria

Time: month 6

Description: Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response

Measure: monitoring anti-tumor immune response

Time: Day 28

Description: Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response

Measure: monitoring anti-tumor immune response

Time: Day 56

Description: Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response

Measure: monitoring anti-tumor immune response

Time: month 3

Description: Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response

Measure: monitoring anti-tumor immune response

Time: month 4

Description: Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response

Measure: monitoring anti-tumor immune response

Time: month 5

Description: Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response

Measure: monitoring anti-tumor immune response

Time: month 6

Secondary Outcomes

Measure: overall survival and disease free survival

Time: D1, Mo6, Mo10, Mo14, Mo18, Mo20, Mo24 and every 4 months till year 5

227 A Phase I Trial of Vemurafenib and Hydroxychloroquine in Patients With Advanced BRAF Mutant Melanoma

This is a Phase I study combining vemurafenib and hydroxychloroquine in the treatment of BRAF V600E+ metastatic melanoma.

NCT01897116
Conditions
  1. Melanoma
Interventions
  1. Drug: Hydroxychloroquine (HCQ)
  2. Drug: Vemurafenib (VEM)
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- Patients must have histologically confirmed diagnosis of Stege IV metastic melanoma positive for BRAF V600E mutation by either the COBAS test or other CLIA approved assay. --- V600E ---

Primary Outcomes

Measure: Number of Adverse Events

Time: 8 weeks

228 MoTriColor: A Phase II Study of Vinorelbine in Advanced BRAF-like Colon Cancer

Vecchione et al showed that suppression of RANBP2 results in mitotic defects only in BRAF-like colon cancer (CC) cells, which leads to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. Vinorelbine mimics RANPB2 silencing in BRAF-like and BRAFV600E CC cell lines. These preclinical data represent a strong rationale to also explore the anti-tumor activity of vinorelbine in patients with advanced BRAF-like (both BRAFm and BRAF wild type) CC. Tumors having this gene signature are referred to as "BRAF-like" and have a similar poor prognosis irrespective of the presence of BRAF(V600E) mutation. Since vinorelbine is standard of care in advanced breast and NSCLC, there is ample experience with the dose and schedule as well as with the safety profile and supportive measures required to prevent side-effects.

NCT03482362
Conditions
  1. Colon Cancer
Interventions
  1. Drug: Vinorelbine Tartrate
MeSH:Colonic Neoplasms
HPO:Colon cancer Neoplasm of the colon

Tumors having this gene signature are referred to as "BRAF-like" and have a similar poor prognosis irrespective of the presence of BRAF(V600E) mutation. --- V600E ---

Primary Outcomes

Description: This means that by vinorelbine treatment the rate of progression drops to 25%.

Measure: Doubling of progression free survival

Time: 15 months

Secondary Outcomes

Measure: Incidence and severity of adverse events

Time: 15 months

Measure: Overall response rate

Time: 15 months

Measure: Duration of response

Time: 15 months

Measure: Time to response

Time: 15 months

Measure: Overall survival

Time: 15 months

Description: The molecular status will be measured by NGS and IHC in tumor tissue.

Measure: Baseline molecular status (mutation/ expression) in tumor tissue of potential predictive markers of tumor response

Time: 15 months

Description: The molecular status will be measured by NGS and IHC in tumor tissue.

Measure: Gene alterations/expression profiles (i.e. baseline, relapse) in tumor tissue upon progression

Time: 15 months

Other Outcomes

Measure: Overall response rate of vinorelbine in patients with KRAS mutant, BRAF wildtype, BRAF-like colon cancer vs. KRAS wildtype, BRAF mutant, BRAF-like colon cancer.

Time: 15 months

229 Avelumab Combined With Cetuximab and Irinotecan for Treatment Refractory Metastatic Colorectal Microsatellite Stable Cancer - A Proof of Concept, Open Label Non-randomized Phase IIa Study. The AVETUXIRI Trial

Cancer immunotherapy with immunostimulatory antibodies targeting the CTLA-4 or PD-1/PD-L1 pathways has demonstrated its efficacy in variable proportions of cancer. For metastatic colorectal cancer (mCRC) it appeared that only the small subgroup of patients with MSI-H tumors (microsatellite instability-high phenotype) had a clinically meaningful response to the anti-PD-1- L1 antibodies. In the majority group of non-MSI-H CRC (90-95% of patients), current research expect that additional means would be able to render the tumor "immunogenic" (like MSI-H CRC) and increase the intratumoral immune infiltrate which is the prerequisite to observe a benefit from PD1-PD-L1 inhibitors. Combinations of immune checkpoint inhibitors and procedures that increase intratumoral immune responses, such as targeted therapy, are actively explored.

NCT03608046
Conditions
  1. Colorectal Neoplasms, Malignant
Interventions
  1. Drug: Avelumab
  2. Drug: Cetuximab Injection
  3. Drug: Irinotecan
MeSH:Colorectal Neoplasms Neoplasms
HPO:Neoplasm Neoplasm of the large intestine

Inclusion Criteria: - Age 18 and over, Performance status: ECOG 0-1 - Histologically proven metastatic colorectal adenocarcinoma, refractory to standard chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan) and anti-EGFR treatment (only for RAS WT tumor) - Measurable disease (RECIST 1.1) - Metastasis accessible for sequential biopsies - Patient consent for metastasis biopsies in the study protocol - BRAF V600E wild-type and MSS tumors - Adequate normal organ and marrow function (see adequate section of the full protocol for definition) - Life expectancy of at least 4 months Exclusion Criteria: - Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy that are not indicated in the study protocol - Systemic autoimmune disease, - Chronic treatment with corticoids or other immunosuppressive treatment - Clinically significant cardiac, lung or general disease despite optimal treatment - Non-progressive disease following irinotecan-based treatment. --- V600E ---

Primary Outcomes

Description: The overall tumor response rate (ORR) defined as the proportion of all included patient with a confirmed best overall tumor response of PR or CR according to irRECIST 1.1 occuring until 19 weeks after study treatment start.

Measure: Tumor response rate

Time: Up to 19 weeks

Secondary Outcomes

Description: Safety will be controlled

Measure: Adverse events

Time: Up to 19 weeks

230 Encorafenib/Binimetinib With or Without Nivolumab for Patients With Metastatic BRAF V600 Mutant Thyroid Cancer

This phase II trial studies how well encorafenib and binimetinib given with or without nivolumab works in treating patients with BRAF V600 mutation positive thyroid cancer that has spread to other places in the body (metastatic) and does not respond to radioiodine treatment (refractory). Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The trial aims to find out if the combination of encorafenib and binimetinib, with and without study nivolumab, is a safe and effective way to treat metastatic radioiodine refractory thyroid cancer.

NCT04061980
Conditions
  1. BRAF NP_004324.2:p.V600M
  2. BRAF V600E Mutation Present
  3. Metastatic Thyroid Gland Carcinoma
  4. Refractory Thyroid Gland Carcinoma
  5. Stage IV Differentiated Thyroid Gland Carcinoma AJCC v8
  6. Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v8
  7. Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v8
Interventions
  1. Drug: Binimetinib
  2. Drug: Encorafenib
  3. Biological: Nivolumab
MeSH:Carcinoma Thyroid Neoplasms Thyroid Diseases
HPO:Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

ability to understand the patient information, give informed consent, comply with the study protocol or complete the study BRAF NP_004324.2:p.V600M BRAF V600E Mutation Present Metastatic Thyroid Gland Carcinoma Refractory Thyroid Gland Carcinoma Stage IV Differentiated Thyroid Gland Carcinoma AJCC v8 Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v8 Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v8 Carcinoma Thyroid Neoplasms Thyroid Diseases PRIMARY OBJECTIVES: I. To assess the overall rate of response among study participants treated with the combination of encorafenib and binimetinib, with or without nivolumab. --- V600E ---

Primary Outcomes

Description: ORR is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria. ORR at 6 months will be assessed using the efficacy evaluable analysis set. A point and 90% exact binomial confidence interval will be provided for each arm.

Measure: Overall response rate (ORR)

Time: From the start of randomization up to 6 months from first dose of study drugs

Secondary Outcomes

Description: The Kaplan-Meier method will be used to estimate PFS and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided for each arm.

Measure: Progression free survival (PFS)

Time: From date of randomization until either tumor progression (per RECIST v1.1) or death, assessed for up to 12 months

Description: The Kaplan-Meier method will be used to estimate OS and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided for each arm.

Measure: Overall survival

Time: From date of randomization until the date of death from any cause, assessed for up to 1 year

Description: The Kaplan-Meier method will be used to estimate DOR, and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided for each arm. DOR will be estimated only among responders (i.e. participants achieving at least once CR or PR). Data visualization tools such as waterfall plots (% change in tumor size) or swimmer plot (DOR) will be used to display the data.

Measure: Duration of response (DOR)

Time: From date of first documented CR or PR up to first documented progression or death due to any cause, assessed for up to 1 year

Description: Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Using the safety evaluable analysis set, the incidence of having grade >= 3 adverse events will be determined for study participants that received at least one dose of their assigned treatment. The point estimate and 95% confidence interval will be reported for each arm.

Measure: Incidence of grade >= 3 toxicities

Time: From the first dose of assigned study intervention until 90 days from the last dose of assigned study intervention

231 An Open-Label, Phase Ib Dose Escalation Trial of Oral Combination Therapy With MSC1936369B and SAR245409 in Subjects With Locally Advanced or Metastatic Solid Tumors

This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.

NCT01390818
Conditions
  1. Locally Advanced Solid Tumor
  2. Metastatic Solid Tumor
  3. Breast Cancer
  4. Non Small Cell Lung Cancer
  5. Melanoma
  6. Colorectal Cancer
Interventions
  1. Drug: MSC1936369B (pimasertib)
  2. Drug: SAR245409 (PI3K and mTOR inhibitor)
  3. Drug: MSC1936369B (pimasertib)
  4. Drug: SAR245409 (PI3K and mTOR inhibitor)
MeSH:Neoplasms
HPO:Neoplasm

In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.. Inclusion Criteria: - Subject with advanced solid tumors for which there is no approved therapy: - Advanced solid tumor with diagnosed alteration in one or more of the following genes (PTEN, BRAF, KRAS, NRAS, PI3KCA, ErbB1, ErbB2, MET, RET, c-KIT, GNAQ, GNA11 and/or - A histologically or cytologically confirmed diagnosis of one of the following solid tumors: pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma and melanoma - Subject with archived tumor tissue available for transfer to the Sponsor - Subject enrolled at lower dose level cohorts and MTD expansion cohorts must have tumor available for biopsy and agree to pre-treatment and on-treatment tumor biopsies - Subject has measurable or evaluable disease by response evaluation criteria in solid tumors (RECIST) v1.1 - Subject is aged greater than or equal to (>=) 18 years - Subjects enrolled in disease specific expansion cohorts must fulfill all the inclusion/exclusion criteria listed above with the following restriction to the Inclusion Criterion number 1: - Relapsed or refractory Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral oncogene homolog (NRAS) mutated metastatic non-small cell lung cancer (NSCLC) with no approved therapies, or - Relapsed or refractory metastatic triple negative breast cancer defined as estrogen, progesterone and HER2 negative carcinoma of the breast with no approved therapies, or - Relapsed or refractory metastatic colorectal cancer (CRC) with dual KRAS and PIK3CA mutation with no approved therapies, or - BRAF V600E/K mutated unresectable or metastatic melanoma after progression on B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors - Other protocol-defined inclusion criteria could apply Exclusion Criteria: - Subject has been previously treated with a PI3K inhibitor or a MEK inhibitor and taken off treatment due to treatment related adverse events - Subject has received: - Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anti-cancer therapy within 28 days of trial drug treatment - Any investigational agent within 28 days of trial drug treatment - Extensive prior radiotherapy on more than 30% bone marrow reserves, or prior bone marrow/stem cell transplantation - Subject has not recovered from toxicity due to prior therapy - Subject has poor organ and marrow function as defined in the protocol - Subject has a history of central nervous system metastases, unless subject has been previously treated for CNS metastases - Subject has a history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease - Subject has a history of recent major surgery or trauma within the last 28 days. --- V600E ---

- Subject has participated in another clinical trial within the past 30 days - Other protocol-defined exclusion criteria could apply Inclusion Criteria: - Subject with advanced solid tumors for which there is no approved therapy: - Advanced solid tumor with diagnosed alteration in one or more of the following genes (PTEN, BRAF, KRAS, NRAS, PI3KCA, ErbB1, ErbB2, MET, RET, c-KIT, GNAQ, GNA11 and/or - A histologically or cytologically confirmed diagnosis of one of the following solid tumors: pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma and melanoma - Subject with archived tumor tissue available for transfer to the Sponsor - Subject enrolled at lower dose level cohorts and MTD expansion cohorts must have tumor available for biopsy and agree to pre-treatment and on-treatment tumor biopsies - Subject has measurable or evaluable disease by response evaluation criteria in solid tumors (RECIST) v1.1 - Subject is aged greater than or equal to (>=) 18 years - Subjects enrolled in disease specific expansion cohorts must fulfill all the inclusion/exclusion criteria listed above with the following restriction to the Inclusion Criterion number 1: - Relapsed or refractory Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral oncogene homolog (NRAS) mutated metastatic non-small cell lung cancer (NSCLC) with no approved therapies, or - Relapsed or refractory metastatic triple negative breast cancer defined as estrogen, progesterone and HER2 negative carcinoma of the breast with no approved therapies, or - Relapsed or refractory metastatic colorectal cancer (CRC) with dual KRAS and PIK3CA mutation with no approved therapies, or - BRAF V600E/K mutated unresectable or metastatic melanoma after progression on B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors - Other protocol-defined inclusion criteria could apply Exclusion Criteria: - Subject has been previously treated with a PI3K inhibitor or a MEK inhibitor and taken off treatment due to treatment related adverse events - Subject has received: - Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anti-cancer therapy within 28 days of trial drug treatment - Any investigational agent within 28 days of trial drug treatment - Extensive prior radiotherapy on more than 30% bone marrow reserves, or prior bone marrow/stem cell transplantation - Subject has not recovered from toxicity due to prior therapy - Subject has poor organ and marrow function as defined in the protocol - Subject has a history of central nervous system metastases, unless subject has been previously treated for CNS metastases - Subject has a history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease - Subject has a history of recent major surgery or trauma within the last 28 days. --- V600E ---

Primary Outcomes

Description: DLT was defined as any of the following toxicities experienced during the first cycle of treatment at any dose level (DL) and judged not to be related to the underlying disease or any concomitant medication by the Investigator and/or the Sponsor: A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation (DE) would have exposed subjects to unacceptable risk. Any Grade greater than or equal to (>=) 3 non-hematological toxicity, except for: Grade 3 diarrhea, nausea and vomiting with a duration less than or equal to (<=) 48 hours despite adequate supportive care and Alopecia. Grade 4 neutropenia of > 5 days duration or febrile neutropenia. Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia. Any treatment interruption > 2 weeks due to AEs not related to the underlying disease or concomitant medication at any dose level and any severe, life-threatening impairing daily functions complication or abnormality.

Measure: Number of Subjects With Dose Limiting Toxicities (DLT)

Time: Day 1 up to Day 16 in cycle 1

Secondary Outcomes

Description: An adverse event (AE) was defined as any untoward medical occurrence in a subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as those AEs that started between first dose of study drug and up to 30 days after last dose.

Measure: Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)

Time: Baseline up to 30 Days after last dose; assessed up to 4 years

Measure: Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Area under the concentration-time curve from time 0 to the last quantifiable concentration.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUC0-t + last observed concentration (Clast)/terminal rate constant (λz), using the Linear up/Log down method. Terminal rate constant (λz).

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts

Measure: Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Measure: Half-Life (t1/2) of MSC1936369B (Pimasertib)

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf.

Measure: Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Apparent volume of distribution during the terminal phase, calculated by CL/f/λz. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.Data was not available for 'Pimasertib (MSC1936369B) 60mg Twice Daily' arm as no subjects were considered evaluable because of limited number of samples collected to characterize the terminal phase rate constant needed for the calculation of Vz/f.

Measure: Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau per Day 1 dosing interval AUCtau.

Measure: Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax/Day 1 Cmax.

Measure: Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Measure: Maximum Observed Plasma Concentration (Cmax) for SAR245409

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: The time to reach maximum plasma concentration (Tmax) of SAR245409 was calculated.

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time (0-24 hours) at which the concentration is at or above the lower limit of quantification. Unit of assessment was hour*nanogram per milliliter (hr*ng/mL).

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Measure: Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUC0-t + last observed concentration (Clast)/terminal rate constant (λz), using the Linear up/Log down method. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts

Measure: Apparent Terminal Half-Life (t1/2) of SAR245409

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the dose with area under the plasma concentration time curve from time zero to infinity (AUC 0-inf)=Dose/AUC 0-inf.

Measure: Total Body Clearance (CL/f) of SAR245409

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Apparent volume of distribution during the terminal phase, calculated by CL/f/λz. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.

Measure: Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau divided by Day 1 dosing interval AUCtau.

Measure: Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax divided by Day 1 Cmax.

Measure: Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15

Time: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Description: pS6 Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for "Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily", "Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily", "Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily" and "Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily" reporting arms.

Measure: pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)

Time: DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); Cycle 1 Day 1 (C1D1) and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose)

Description: pERK Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for "Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily", "Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily", "Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily" and "Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily" reporting arms.

Measure: pERK Concentrations in PBMCs

Time: DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); C1D1 and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose)

Description: CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD= At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)

Time: From the date of randomisation every 6 weeks up to assessed up to 4 years

232 A Phase II, Multi-center, Single Arm, Open Label Study to Assess Efficacy and Safety of Dabrafenib and Trametinib Combination Therapy in Japanese Patients With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer

This is an open-label, multicenter, non-randomized, single arm, phase II study to assess efficacy and safety of the dabrafenib and trametinib combination in Japanese patients with any line, stage IV NSCLC harboring a confirmed BRAF V600E mutation. Patients will receive oral dabrafenib twice daily and oral trametinib once daily combination therapy. Patients may continue study treatment until disease progression, unacceptable adverse events, start of a new anti-cancer therapy, consent withdrawal, death, or end of the study. Patients who have met the criteria for disease progression (PD) according to RECIST v1.1 may continue to receive study treatment if the investigator believes the patient is receiving clinical benefit and the patient is willing to continue on study treatment. After discontinuation of study treatment, all patients will be followed for survival until death, lost to follow-up, withdrawal of consent, or end of study.

NCT02672358
Conditions
  1. Non-Small-Cell Lung Cancer
Interventions
  1. Drug: Dabrafenib
  2. Drug: Trametinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase II, Multi-center, Single Arm, Open Label Study to Assess Efficacy and Safety of Dabrafenib and Trametinib Combination Therapy in Japanese Patients With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. --- V600E ---

Study of Efficacy and Safety of Dabrafenib and Trametinib Combination Therapy in Japanese Patients With BRAF V600E Stage IV NSCLC This is an open-label, multicenter, non-randomized, single arm, phase II study to assess efficacy and safety of the dabrafenib and trametinib combination in Japanese patients with any line, stage IV NSCLC harboring a confirmed BRAF V600E mutation. --- V600E ---

Study of Efficacy and Safety of Dabrafenib and Trametinib Combination Therapy in Japanese Patients With BRAF V600E Stage IV NSCLC This is an open-label, multicenter, non-randomized, single arm, phase II study to assess efficacy and safety of the dabrafenib and trametinib combination in Japanese patients with any line, stage IV NSCLC harboring a confirmed BRAF V600E mutation. --- V600E --- --- V600E ---

OS, defined as the time from the date of first dose until death due to any cause.. Inclusion Criteria: - Histologically- or cytologically-confirmed diagnosis of NSCLC stage IV (according to AJCC Staging 7th Edition) - Presence of a BRAF V600E mutation in lung cancer tissue. --- V600E ---

BRAF V600E mutation tested by local laboratory (e.g. --- V600E ---

Inclusion Criteria: - Histologically- or cytologically-confirmed diagnosis of NSCLC stage IV (according to AJCC Staging 7th Edition) - Presence of a BRAF V600E mutation in lung cancer tissue. --- V600E ---

Primary Outcomes

Description: ORR, defined as the percentage of patients with a confirmed CR or PR by investigator assessment as per RECIST v1.1 criteria

Measure: Overall Response Rate (ORR) by investigator assessment

Time: Approximately 2 years

Secondary Outcomes

Description: DOR, defined for the subset of patients with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression or death due to any cause.

Measure: Duration of response (DOR)

Time: Approximately 2 years

Description: DCR, defined as the proportion of patients with best overall response of CR, PR, or SD.

Measure: Disease control rate (DCR)

Time: Approximately 2 years

Description: PFS, defined as the interval between first dose and the earliest date of disease progression or death due to any cause.

Measure: Progression-free survival (PFS)

Time: Approximately 2 years

Description: OS, defined as the time from the date of first dose until death due to any cause.

Measure: Overall survival (OS)

Time: Approximately 2 years

233 Randomization of Cytarabine Monotherapy Versus Standard-of-Care Vinblastine/Prednisone for Frontline Treatment of Langerhans Cell Histiocytosis (TXCH LCH0115)

Langerhans Cell Histiocytosis (LCH) is a type of cancer that can damage tissue or cause lesions to form in one or more places in the body. Langerhans cell histiocytosis (LCH) is a cancer that begins in LCH cells (a type of dendritic cell which fights infection). Sometimes there are mutations (changes) in LCH cells as they form. These include mutations of the BRAF gene. These changes may make the LCH cells grow and multiply quickly. This causes LCH cells to build up in certain parts of the body, where they can damage tissue or form lesions. For most patients with LCH, standard-of-care vinblastine/prednisone are used as front-line therapy while cytarabine therapy has been used as therapy for patients who develop recurrence. No alternate treatment strategy has been developed for frontline therapy in LCH. The purpose of this research study is to compare previously used vinblastine/prednisone to single therapy with cytarabine for LCH. We will evaluate the utility of an imaging study called a positron emission tomography (PET) scan to more accurately assess areas of LCH involvement not otherwise seen in other imaging studies as well as response to therapy. We also want to identify if genetic and other biomarkers (special proteins in patient's blood and in patient's cancer) relate to the response of patients LCH to study treatment.

NCT02670707
Conditions
  1. Langerhans Cell Histiocytosis
Interventions
  1. Drug: Cytarabine
  2. Drug: Vinblastine/prednisone
MeSH:Histiocytosis, Langerhans-Cell Histiocytosis
HPO:Histiocytosis

Time to eradication of BRAF-V600E cells or other LCH-defining mutation. --- V600E ---

This will be quantified by quantitative real-time PCR.. Number of patients who have 18-FDG PET/CT positivity in identifying high-risk organ (liver, spleen, or bone marrow) involvement and correlation of PET/CT response with presence of disease activity as well as presence of circulating cells with BRAF-V600E.. --- V600E ---

Primary Outcomes

Description: A Kaplan-Meier curve will be used to compare event-free survival between treatment groups. Curves will be compared using the log-rank statistic. Patients will be followed for up to 5 years after one year of therapy. Patients who have not had the event by the 5-year mark will be censored observations. Patients who are lost to follow-up without having an event will be censored at the time of last contact. Statistical significance will be assessed at the 0.05 level. A Cox proportional hazards model will also be used to estimate the Hazards Rate for combined events in the Cytarabine group versus standard therapy. A multiple regression model will also be used to estimate the adjusted HRs for genotype and baseline risk of death (high vs. low).

Measure: Time to determine 1-year event-free survival (EFS) of patients treated with cytarabine monotherapy for LCH, compared directly with that of standard-of-care vinblastine/prednisone (Events include progression of LCH, relapse, or death).

Time: up to 60 months

Secondary Outcomes

Description: Overall disease response at each timepoint will be assigned based on the lesion or organ system with worst response. For disease response not defined by the criteria included in the protocol, guidelines established in the RECIST criteria will be used.

Measure: Durable responses with 2-year and 5-year EFS and OS of the patients treated with cytarabine versus vinblastine/prednisone for LCH.

Time: 2-years and 5-years post treatment

Description: Toxicity will be graded by the NCI Common Toxicity Criteria Version 5.0.

Measure: Number of toxicities (including psychosis, hypertension, neuropathy, fever, headache) in the patients treated with cytarabine versus vinblastine/prednisone for LCH.

Time: up to 60 months after completion of therapy

Description: RECIST criteria will be used for assessing disease response

Measure: Rate at which patients achieve non-active disease on cytarabine versus vinblastine/prednisone therapy.

Time: up to 60 months after completion of therapy

Description: This will be quantified by quantitative real-time PCR.

Measure: Time to eradication of BRAF-V600E cells or other LCH-defining mutation

Time: within 6-24 weeks of therapy initiation

Description: For disease response not defined by the criteria included in the protocol, guidelines established in the RECIST criteria will be used.

Measure: Number of patients who have 18-FDG PET/CT positivity in identifying high-risk organ (liver, spleen, or bone marrow) involvement and correlation of PET/CT response with presence of disease activity as well as presence of circulating cells with BRAF-V600E.

Time: up to 60 months after completion of therapy

Description: This trial will utilize RECIST criteria for assessing disease response, which uses standard oncology response criteria terminology. Using RECIST terminology, we define response criteria for organs that may not have measurable lesions (i.e. bone marrow) but are clearly critical sites of disease. In addition, definitions of response in terms of metabolic activity from PET scans will also be prospectively analyzed based on prior retrospective radiologic reviews.

Measure: RECIST criteria and terminology in conjunction with metabolic PET imaging (where applicable) to assess disease response to therapy.

Time: up to 60 months after completion of therapy

Description: Evaluation of CNS+ site involvement at start of therapy, somatic BRAFV600E mutation status and measurable peripheral/marrow levels, ethnicity, age at onset, and extent of disease in predicting risk of neurodegenerative disease and/or pituitary involvement.

Measure: Number of risk factors for and time to development of diabetes insipidus and neurodegenerative disease.

Time: up to 60 months after completion of therapy

Description: To store serial samples (viable WBCs, plasma, tumor, bone marrow, cerebrospinal fluid) for future correlative biology studies.

Measure: Storage of serial samples

Time: up to 60 months after completion of therapy

234 Colorectal Cancer Metastatic dMMR/MSI-H Immuno-Therapy (COMMIT) Study: A Randomized Phase III Study of mFOLFOX6/Bevacizumab/Atezolizumab Combination Versus Single Agent Atezolizumab in the First-Line Treatment of Patients With Deficient DNA Mismatch Repair (dMMR)/Microsatellite Instability-High (MSI-H) Metastatic Colorectal Cancer

This phase III trial studies how well combination chemotherapy, bevacizumab, and/or atezolizumab work in treating patients with deficient deoxyribonucleic acid (DNA) mismatch repair colorectal cancer that has spread to other places in the body (metastatic). Chemotherapy drugs, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as bevacizumab and atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy, bevacizumab, and atezolizumab may work better in treating patients with colorectal cancer.

NCT02997228
Conditions
  1. Metastatic Colorectal Adenocarcinoma
  2. Stage IV Colorectal Cancer AJCC v7
  3. Stage IVA Colorectal Cancer AJCC v7
  4. Stage IVB Colorectal Cancer AJCC v7
Interventions
  1. Drug: Atezolizumab
  2. Biological: Bevacizumab
  3. Drug: Fluorouracil
  4. Drug: Leucovorin
  5. Drug: Oxaliplatin
  6. Other: Quality-of-Life Assessment
  7. Other: Questionnaire Administration
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

The experimental arms will be compared to the control arm by the log-rank test stratified by BRAF status (V600E mutation or not), metastatic disease: (liver-only, extra-hepatic), and prior adjuvant therapy for colon cancer (yes, no). --- V600E ---

Primary Outcomes

Description: The analysis set is intent-to-treat (ITT). The experimental arms will be compared to the control arm by the log-rank test stratified by BRAF status (V600E mutation or not), metastatic disease: (liver-only, extra-hepatic), and prior adjuvant therapy for colon cancer (yes, no). Hazard ratios and associated confidence intervals from a stratified Cox regression model will also be reported along with estimates of the distributions of time to PFS event by the method of Kaplan and Meier. Sensitivity analyses accounting for 2 or more consecutively missed scheduled tumor imaging scans before progression/death will also be conducted.

Measure: Progression free survival (PFS)

Time: From the time from randomization until first confirmed progression or death from any cause, assessed up to 5 years

Secondary Outcomes

Description: Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.

Measure: Overall survival (OS)

Time: The time from randomization to death from any cause, assessed up to 5 years

Description: Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemotherapy [chemo]) using the ITT population. Observed proportions along with confidence intervals will be presented by treatment.

Measure: Objective response rate (ORR) (complete response [CR] or partial response [PR])

Time: Up to 5 years

Description: Defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The safety profile will be described by tabulating the maximum observed grade of adverse event for each individual adverse event, for each system organ class, and overall using the Safety population.

Measure: Incidence of adverse events

Time: Up to 30 days after last cycle

Measure: Rate of PFS

Time: At 12 months

Description: Assessed by RECIST 1.1. Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo) using the ITT population. Observed proportions along with confidence intervals will be presented by treatment.

Measure: Disease control rate (CR + PR + stable disease [SD])

Time: At 12 months

Description: Assessed by RECIST 1.1. Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.

Measure: Duration of overall response (CR or PR)

Time: From the time of first response to first confirmed progression by the study investigator or death from any cause, assessed up to 5 years

Description: Assessed per RECIST 1.1. Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.

Measure: Duration of SD

Time: From the time of first on-study assessment of SD to first progression by the study investigator or death from any cause, assessed up to 5 years

Other Outcomes

Description: Will use the ITT population. Measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Will be compared between the control arm (Chemo-bevacizumab [Bev]) and the experimental arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.

Measure: Severity of fatigue

Time: At 16 weeks

Description: Will use the ITT population. Measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire (QLQ)-C30 physical functioning scale. Will be compared between the control arm (Chemo-Bev) and the experimental arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.

Measure: Physical functioning

Time: At 16 weeks

Description: Will use the PRO population. The corresponding item (PRO-CTCAE severity, PRO-CTCAE frequency, or QOL scale) will be compared between the control arm (Chemo-Bev) and the experimental arm using a mixed regression model for repeated measures with the response being ordinal for the PRO-CTCAE items and linear for QOL scales. The model will also include the corresponding baseline measurement, time, and stratification variables. Presence of treatment-by-time interaction will be investigated for each model. Each comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.

Measure: Severity and frequency of quality of life (QOL) and patient-reported outcomes (PRO)

Time: Up to 5 years

Description: Will use the ITT population. Will be measured using the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire.

Measure: Health utility scores

Time: Up to 5 years

Description: Will use the ITT population.

Measure: Proportion of patients reporting each response option at each assessment timepoint by treatment arm for item GP5 from the Functional Assessment of Cancer Therapy - General (FACT-G)

Time: Up to 5 years

Description: Will use the ITT population.

Measure: Intratumoral lymphocyte PD-L1+ expression (>= 1 % is positive) by immunohistochemistry (IHC) as a predictive biomarker of efficacy

Time: Up to 5 years

Description: Will use the ITT population.

Measure: Efficacy dependent on the number of somatic mutations

Time: Up to 5 years

Description: Will use the ITT population.

Measure: Efficacy in tumors with MLH1 silencing

Time: Up to 5 years

Description: Will use the ITT population.

Measure: Change in quantification of cell free deoxyribonucleic acid (cfDNA) mutations

Time: Baseline up to 5 years

Description: Will use the ITT population.

Measure: Development of progression or relapse to treatment in cfDNA

Time: Up to 5 years

Description: Will use the ITT population.

Measure: Changes in T-cell repertoire diversity as a predictive biomarker of efficacy

Time: Baseline up to 5 years

Description: Compared to patients with low levels of diversity. Will use the ITT population.

Measure: PFS of patients with high levels of diversity

Time: Up to 5 years

Description: Will use the ITT population.

Measure: Change in T-cell diversity

Time: Baseline to first restaging between immunotherapy arms and the standard of care arm

Description: Will use the ITT population.

Measure: Mechanism of immune resistance to PD-1 blockade in mismatch repair deficient (dMMR)/microsatellite instability-high metastatic colorectal cancer (mCRC) by comparative analysis of tumor samples collected

Time: Baseline up to 5 years

235 A Phase I, Randomized, Open-label, Multi-center, Multiple Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO5185426 Administered as 240 mg Tablets to Previously Treated BRAF V600E Positive Metastatic Melanoma Patients

This open-label study will assess the pharmacokinetics, efficacy and safety of RO5185426 administered as 240mg tablets in previously treated patients with metastatic melanoma. Patients will be randomized to receive one of four dose-levels of RO5185426 [RG7204; PLEXXIKON; PLX4032] orally twice daily on days 1 to 15 (morning dose). Starting on day 22, treatment with RO5185426 may be resumed at a dose of 960 mg twice daily and continued until disease progression. Target sample size is <100 patients.

NCT01107418
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: RO5185426
  2. Drug: RO5185426
  3. Drug: RO5185426
  4. Drug: RO5185426
  5. Drug: RO5185426
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Phase I, Randomized, Open-label, Multi-center, Multiple Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO5185426 Administered as 240 mg Tablets to Previously Treated BRAF V600E Positive Metastatic Melanoma Patients. --- V600E ---

OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.. Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix Malignant Melanoma Melanoma null --- V600E ---

OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.. Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix Inclusion Criteria: - adult patients, >/=18 years of age - histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) - failure of at least one prior standard of care regimen - positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) - ECOG performance status 0 or 1 - adequate hematologic, renal and liver function Exclusion Criteria: - active CNS lesions on CT/MRI within 28 days prior to enrollment - history of spinal cord compression o carcinomatous meningitis - anticipated or ongoing anti-cancer therapies other than those administered in this study - previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - severe cardiovascular disease within 6 months prior to study - previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix Malignant Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15

Measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Description: Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Measure: Apparent Clearance (CL/F) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Description: Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel).

Measure: Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Description: Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.

Measure: Accumulation Ratio of Vemurafenib on Day 15

Time: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15

Secondary Outcomes

Description: Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) were required to demonstrate a reduction to normal (short axis less than [<] 10 millimeters [mm]). PR was defined as a 30 percent (%) decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of confirmed CR or PR are reported.

Measure: Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)

Time: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)

Description: OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.

Measure: Overall Survival (OS)

Time: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)

236 AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE 3 STUDY OF FIRST-LINE ENCORAFENIB PLUS CETUXIMAB WITH OR WITHOUT CHEMOTHERAPY VERSUS STANDARD OF CARE THERAPY WITH A SAFETY LEAD-IN OF ENCORAFENIB AND CETUXIMAB PLUS CHEMOTHERAPY IN PARTICIPANTS WITH METASTATIC BRAF V600E-MUTANT COLORECTAL CANCER

To evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC

NCT04607421
Conditions
  1. Neoplasms
Interventions
  1. Drug: Encorafenib
  2. Drug: Cetuximab
  3. Drug: Oxaliplatin
  4. Drug: Irinotecan
  5. Drug: Leucovorin
  6. Drug: 5-FU
  7. Drug: Capecitabine
  8. Drug: Bevacizumab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE 3 STUDY OF FIRST-LINE ENCORAFENIB PLUS CETUXIMAB WITH OR WITHOUT CHEMOTHERAPY VERSUS STANDARD OF CARE THERAPY WITH A SAFETY LEAD-IN OF ENCORAFENIB AND CETUXIMAB PLUS CHEMOTHERAPY IN PARTICIPANTS WITH METASTATIC BRAF V600E-MUTANT COLORECTAL CANCER. --- V600E ---

BRAF V600E-mutant Colorectal Cancer Study of Encorafenib Taken With Cetuximab Plus or Minus Chemotherapy (BREAKWATER) To evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs). --- V600E ---

BRAF V600E-mutant Colorectal Cancer Study of Encorafenib Taken With Cetuximab Plus or Minus Chemotherapy (BREAKWATER) To evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs). --- V600E --- --- V600E ---

BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment. --- V600E ---

Trough plasma concentrations in all patients in Arm A and Arm B. Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition - Active bacterial or viral infections in 2 weeks prior to starting dosing - Symptomatic brain metastases Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition - Active bacterial or viral infections in 2 weeks prior to starting dosing - Symptomatic brain metastases Neoplasms Colorectal Neoplasms The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. --- V600E ---

Trough plasma concentrations in all patients in Arm A and Arm B. Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition - Active bacterial or viral infections in 2 weeks prior to starting dosing - Symptomatic brain metastases Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition - Active bacterial or viral infections in 2 weeks prior to starting dosing - Symptomatic brain metastases Neoplasms Colorectal Neoplasms The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. --- V600E --- --- V600E ---

Trough plasma concentrations in all patients in Arm A and Arm B. Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition - Active bacterial or viral infections in 2 weeks prior to starting dosing - Symptomatic brain metastases Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition - Active bacterial or viral infections in 2 weeks prior to starting dosing - Symptomatic brain metastases Neoplasms Colorectal Neoplasms The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: Incidence of dose limiting toxicity defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring during the first 28 days of treatment

Measure: Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs)

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Progression free survival, defined as the time from the date of randomization to the earliest documented disease progression or death due to any cause: encorafenib and cetuximab + (Arm A) vs Control Arm (Arm C) and encorafenib and cetuximab + mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs the Control Arm (Arm C)

Measure: Phase 3: Progression free survival, by blinded independent review

Time: Duration of Phase 3, approximately 34 months

Secondary Outcomes

Description: An adverse event is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship as assessed by CTCAE 4.03

Measure: Safety Lead-in: Incidence of adverse events

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.

Measure: Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Measure: Safety Lead-in: Incidence of dose interruptions, dose modifications and discontinuations due to adverse events

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Measure: Safety Lead-in: Overall response rate by investigator

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Measure: Safety Lead-in: Duration of response by Investigator

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Measure: Safety Lead-in:Progression free survival by Investigator

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Measure: Safety Lead-in: Time to response by Investigator

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Measure: Safety Lead-in: Overall survival

Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Description: Overall survival, defined as the time from the date of randomization to death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Overall survival

Time: Duration of Phase 3, approximately 34 months

Description: Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Overall response rate by blinded independent review and by Investigator

Time: Duration of Phase 3, approximately 34 months

Description: Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Duration of response by blinded independent review and by Investigator

Time: Duration of Phase 3, approximately 34 months

Description: Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Time to response by blinded independent review and by Investigator

Time: Duration of Phase 3, approximately 34 months

Description: Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause:: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Progression free survival by Investigator

Time: Duration of Phase 3, approximately 34 months

Description: Progression free survival 2, defined as the time from the date of randomization to the second objective disease progression per RECIST v1.1, or death from any cause, whichever occurs first: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Progression free survival 2 by Investigator

Time: Duration of Phase 3, approximately 34 months

Description: An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Incidence of adverse events

Time: Duration of Phase 3, approximately 34 months

Description: Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)

Measure: Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Time: Duration of Phase 3, approximately 34 months

Description: EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.

Measure: Phase 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)

Time: Duration of Phase 3, approximately 34 months

Description: The EQ-5D-5L is a standardized measure of health utility that provides a single index value for the participant's health status. It is frequently used for economic evaluations of health care and has been shown to be a valid and reliable instrument, and comprises a short descriptive system questionnaire and a visual analogue scale (EQ VAS) that are cognitively undemanding, taking about 2 minutes to complete

Measure: Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire

Time: Duration of Phase 3, approximately 34 months

Description: The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.

Measure: Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)

Time: Duration of Phase 3, approximately 34 months

Description: The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change in symptoms or quality of life since starting treatment.

Measure: Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires

Time: Duration of Phase 3, approximately 34 months

Description: Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue

Measure: Phase 3: Confirm the MSI-status in tumor tissue

Time: Once, pre-treatment

Description: BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment

Measure: Phase 3: Determine the correlation between cfDNA genetic alterations and clinical outcome

Time: Predose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15 and Cycle 7 Day 1. Each cycle is 28 days for all treatments except for oxaliplatin/capecitabine treatment which is 21 days

Measure: Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746, irinotecan and SN-38

Time: Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Measure: Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38

Time: Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days. Each cycle is 28 days

Measure: Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38

Time: Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Measure: Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746 and oxaliplatin

Time: Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Measure: Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746 and oxaliplatin

Time: Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Description: Changes in exposures of irinotecan and its metabolite (SN-38) on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 1 (encorafenib and cetuximab + FOLFIRI) Changes in exposures of oxaliplatin on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 2 (encorafenib and cetuximab + mFOLFOX6)

Measure: Safety Lead-in: Clearance of irinotecan, SN-38 and oxaliplatin

Time: Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Measure: Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746 and oxaliplatin

Time: Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Description: Trough plasma concentrations in all patients in Arm A and Arm B

Measure: Phase 3: Trough concentrations of encorafenib and its metabolite LHY746

Time: Predose on Cycle 1 through Cycle 6. Each cycle is 28 days

237 A Phase 2 Study of Brentuximab Vedotin in Combination With Pembrolizumab in Subjects With Metastatic Solid Malignancies After Progression on Prior PD-1 Inhibitor Treatment

This trial will find out whether brentuximab vedotin and pembrolizumab work together to treat different types of cancer. There will be several different types of cancer studied in the trial. The cancer must have spread to other parts of the body (metastatic) and must have gotten worse (progressed) after being treated with a PD-1 inhibitor treatment. The study will also find out what side effects occur. A side effect is anything the treatment does besides treat cancer. This is a multi-cohort study.

NCT04609566
Conditions
  1. Melanoma
  2. Non-small Cell Lung Cancer
Interventions
  1. Drug: brentuximab vedotin
  2. Drug: pembrolizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Analyses of AEs will be summarized with descriptive statistics.. Inclusion Criteria - Must have relapsed or refractory metastatic squamous or nonsquamous non-small cell lung cancer (NSCLC; EGFR, ALK, ROS1, and BRAF negative) or metastatic cutaneous melanoma (including participants without targetable gene mutations and BRAF-V600E/V600K participants who have failed targeted therapy) - Participants must be currently on PD-1 checkpoint inhibitor therapy (nivolumab or pembrolizumab) or have been on a PD-1 checkpoint inhibitor containing therapy as the last previous line of therapy within 90 days prior to enrollment; PD-1 checkpoint inhibitor therapy should be the immediate prior line of treatment. --- V600E ---

Inclusion Criteria - Must have relapsed or refractory metastatic squamous or nonsquamous non-small cell lung cancer (NSCLC; EGFR, ALK, ROS1, and BRAF negative) or metastatic cutaneous melanoma (including participants without targetable gene mutations and BRAF-V600E/V600K participants who have failed targeted therapy) - Participants must be currently on PD-1 checkpoint inhibitor therapy (nivolumab or pembrolizumab) or have been on a PD-1 checkpoint inhibitor containing therapy as the last previous line of therapy within 90 days prior to enrollment; PD-1 checkpoint inhibitor therapy should be the immediate prior line of treatment. --- V600E ---

Primary Outcomes

Description: Confirmed ORR per RECIST 1.1 is defined as the proportion of participants whose best overall response is a confirmed complete response (CR) or partial response (PR) per RECIST 1.1.

Measure: Confirmed objective response rate (ORR) based on investigator assessment using RECIST 1.1 criteria

Time: Up to approximately 2 years

Secondary Outcomes

Description: DOR per RECIST 1.1 is defined as the time from start of the first documentation of confirmed objective tumor response (CR or PR) per RECIST 1.1 to the first documentation of PD (per RECIST v1.1) or to death due to any cause, whichever comes first.

Measure: Duration of response (DOR) based on investigator assessment using RECIST 1.1 criteria

Time: Up to approximately 3 years

Description: PFS is defined as the time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1)

Measure: Progression-free survival (PFS) based on investigator assessment using RECIST 1.1 criteria

Time: Up to approximately 3 years

Description: ORR per RECIST 1.1 is defined as the proportion of participants whose best overall response is confirmed CR or PR based on iRECIST guidelines

Measure: ORR per iRECIST by investigator assessment

Time: Up to approximately 2 years

Description: DOR per iRECIST is defined as the time from first documentation of confirmed objective response (CR or PR) based on iRECIST guidelines by investigator assessment to the first documentation of confirmed objective tumor progression per iRECIST by investigator assessment, or to death due to any casuse, whichever comes first.

Measure: DOR per iRECIST by investigator assessment

Time: Up to approximately 3 years

Description: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Analyses of AEs will be summarized with descriptive statistics.

Measure: Incidence of adverse events (AEs)

Time: Up to approximately 2 years

238 A Phase 1 Study of MORAb-202 in Subjects With Solid Tumors

The primary objective of this study is to evaluate the tolerability and safety profile of MORAb-202 in participants with solid tumors.

NCT03386942
Conditions
  1. Solid Tumors
Interventions
  1. Drug: MORAb-202
MeSH:Neoplasms
HPO:Neoplasm

- Cohort 1: High grade serous adenocarcinoma - Cohort 2: Other histological types of ovarian carcinoma (excluding mucinous adenocarcinoma) - Cohort 3: NSCLC adenocarcinoma - Cohort 4: NSCLC non-adenocarcinoma - Participants with the following disease characteristics: 1. Ovarian carcinoma (including primary peritoneal carcinoma and fallopian tube carcinoma): - Participants with platinum-resistant disease (defined as progression radiographically within less than [<] 6 months from completion of last platinum therapy) who have received >4 cycles in last platinum-containing chemotherapy for ovarian carcinoma - Participants who have received up to two regimen of chemotherapy after diagnosed as platinum-resistant 2. NSCLC: - Participants that have advanced after previous treatment and those for which no alternative standard therapy exist and those who are not indicated for epidermal growth factor receptor (EGFR), BRAF V600E mutation, anaplastic lymphoma kinase (ALK) or reactive oxygen species (ROS)-targeted therapy (Participants who have progressed after prior such therapy may be eligible) Exclusion Criteria: - Medical history of clinically significant cardiovascular impairment: 1. Congestive heart failure greater than or equal to New York Heart Association Class III. 2. Unstable angina pectoris, myocardial infarction or stroke within 6 months before of the first administration of the study drug. --- V600E ---

Primary Outcomes

Description: The following toxicities developed in Cycle 1 and causal relationship with MORAb-202 cannot be ruled out are regarded as DLTs: 1) febrile neutropenia; 2)Grade 4 neutropenia that persists for more than 7 days or that requires hematopoietic-stimulating agents; 3)Grade 4 thrombocytopenia, or thrombocytopenia that requires platelet transfusion; 4)Grade 4 anemia or anemia that requires blood transfusion; 5)any Grade 3 non-hematological toxicity with the exception of: a)abnormal clinical laboratory values with no clinical significance; b)any events that can be managed and controlled to Grade 2 or less by maximal medical management; c)infusion reactions of Grade 3 or higher are not considered DLTs because they are stochastic and idiosyncratic events, not related to dose; 6)any Grade 4 non-hematologic toxicity; 7)development of any toxicity that is considered to be related to MORAb-202 and where dose at Cycle 2 Day 1 is necessary to postpone for over 14 days for recovery from the toxicities.

Measure: Part 1: Number of participants with dose-limiting toxicities (DLTs)

Time: At the end of Cycle 1 (21 days)

Measure: Part 1 and Part 2: Number of participants with adverse events (AEs), adverse events of interest (AEIs), and serious adverse events (SAEs)

Time: Up to 50 months

Description: Clinical significance will be determined by the Investigator.

Measure: Number of participants with any clinically significant clinical laboratory test value

Time: Up to 50 months

Description: Clinical significance will be determined by the Investigator.

Measure: Number of participants with any clinically significant vital sign value

Time: Up to 50 months

Measure: Change from Baseline in arterial oxygen saturation

Time: Baseline; up to 50 months

Measure: Change from Baseline in body weight

Time: Baseline; up to 50 months

Description: Clinical significance will be determined by the Investigator.

Measure: Number of participants with any clinically significant 12-lead electrocardiogram (ECG) value

Time: Up to 50 months

Measure: Change from Baseline in the performance status (PS) score established by the Eastern Cooperative Oncology Group (ECOG)

Time: Baseline; up to 50 months

Measure: Change from Baseline in serum anti-drug antibody (ADA) titer

Time: Baseline; up to 50 months

Secondary Outcomes

Description: The MTD will be selected as the dose with the smallest difference between the target DLT rate of 25% and an estimate of DLT rate based on the posterior distribution of DLT rate for each dose.

Measure: Part 1: Maximum Tolerated Dose (MTD) of MORAb-202

Time: 21 days following each dose level of MORAb-202 (up to a maximum of 50 months)

Description: Cmax is the maximum serum concentration of MORAb-202 after administration of the drug.

Measure: Part 1 and Part 2: Maximum observed serum concentration (Cmax) of MORAb-202

Time: Predose; end of infusion; 0.5, 1, 2, 4, and 24 hours post infusion on Day 1; on Days 4, 8, and 15; and the discontinuation and last observation visit (up to 50 months)

Measure: Part 1 and Part 2: Maximum serum concentration of total antibody

Time: Predose; end of infusion; 0.5, 1, 2, 4, and 24 hours post infusion on Day 1; on Days 4, 8, and 15; and the discontinuation and last observation visit (up to 50 months)

Measure: Part 1 and Part 2: Plasma concentration of free eribulin

Time: Predose; end of infusion; 0.5, 1, 2, 4, and 24 hours post infusion on Day 1; on Days 4, 8, and 15; and the discontinuation and last observation visit (up to 50 months)

Description: The RD will be determined based on the MTD, efficacy, and safety data in Part 1 and Part 2.

Measure: Recommended dose (RD) of MORAb-202 for future studies

Time: From the date of screening until the last observation visit (up to 50 months)

Description: BOR was based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). BORs are complete response (CR), partial response (PR), stable disease (SD), progression of disease (PD), and not evaluable (NE), where SD has to be achieved at ≥5 weeks after the first dose. CR or PR in Part 1 of this study requires no confirmation of the next response at ≥4 weeks. CR or PR in Part 2 of this study requires confirmation of the next response at ≥4 weeks.

Measure: Part 1 and Part 2: Best overall response (BOR)

Time: From the date of screening until the last observation visit (up to 50 months)

Description: ORR is defined as the percentage of participants with BOR of CR or PR.

Measure: Part 1 and Part 2: Overall response rate (ORR)

Time: From the date of screening until the last observation visit (up to 50 months)

Description: DCR is defined as the percentage of participants with BOR of CR, PR, or SD.

Measure: Part 1 and Part 2: Disease control rate (DCR)

Time: From the date of screening until the last observation visit (up to 50 months)

Description: CBR is defined as the percentage of participants with BOR of CR, PR or durable (SD) (duration of SD ≥ 23 weeks).

Measure: Part 1 and Part 2: Clinical benefit rate (CBR)

Time: From the date of screening until the last observation visit (up to 50 months)

Description: DOR is defined as the time from the first documentation of CR or PR to the first documented date of event (disease progression or death from any cause, whichever occurs first).

Measure: Part 2: Duration of Response (DOR)

Time: From the date of screening until the last observation visit (up to 50 months)

Description: PFS is defined as the time from the date of the first dose of study drug to the first documented date of event (disease progression or death from any cause, whichever occurs first).

Measure: Part 2: Progression-free survival (PFS)

Time: From the date of screening until disease progression or death (up to 50 months)

Description: OS is defined as the time from the date of the first dose to the date of death from any cause. For participants who are alive or unknown, OS is censored as the date of the last known alive date or the date of data cut off, whichever comes first.

Measure: Part 2: Overall Survival (OS)

Time: From the date of screening until the last observation visit (up to 50 months)

239 A Phase I/II Study of LY3022855 With BRAF/MEK Inhibition in Patients With Melanoma

This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation The interventions involved in this study are: - LY3022855 - Vemurafenib - Cobimetinib

NCT03101254
Conditions
  1. Melanoma
Interventions
  1. Drug: LY3022855
  2. Drug: Vemurafenib
  3. Drug: Cobimetinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

LY3022855 With BRAF/MEK Inhibition in Patients With Melanoma This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation The interventions involved in this study are: - LY3022855 - Vemurafenib - Cobimetinib Progression Free Survival. --- V600E ---

Disappearance of all target lesions.. Inclusion Criteria: - For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. --- V600E ---

- For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and cannot have received prior BRAF or MEK inhibitor therapy. --- V600E ---

Inclusion Criteria: - For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. --- V600E ---

Primary Outcomes

Description: Time from initiation of study therapy until documentation of disease progression by RECIST criteria

Measure: Progression Free Survival

Time: 2 years

Secondary Outcomes

Description: Ability to give these three medications in combination without a dose limiting side effect. Assessment of side effects that do occur

Measure: Side effects from therapy

Time: 2 years

Description: Rate of patients with a complete response or partial response as assessed by RECIST criteria

Measure: Overall Response Rate

Time: 2 years

Description: At least a 30% decrease in the sum of the diameters of target lesions.

Measure: Partial Response Rate

Time: 2 years

Description: Disease that is less than a 30% decrease or 20% increase in the sum of the diameters of the target lesions.

Measure: Stable Disease

Time: 2 years

Description: At least a 20% increase in the sum of the diameters of target lesions.

Measure: Progressive Disease

Time: 2 years

Description: Time from initiation of study therapy to death.

Measure: Overall Survival

Time: 2 years

Description: Disappearance of all target lesions.

Measure: Complete response

Time: 2 years

240 A Phase II Study of AMG 510 in Participants With Previously Treated Stage IV or Recurrent KRAS G12C Mutated Non-Squamous Non-Small Cell Lung Cancer (ECOG-ACRIN LUNG-MAP SUB-STUDY)

This phase II Lung-MAP treatment trial studies the effect of AMG 510 in treating non-squamous non-small cell lung cancer that is stage IV or has come back (recurrent) and has a specific mutation in the KRAS gene, known as KRAS G12C. Mutations in this gene may cause the cancer to grow. AMG 510, a targeted treatment against the KRAS G12C mutation, may help stop the growth of tumor cells.

NCT04625647
Conditions
  1. Lung Adenocarcinoma
  2. Lung Non-Small Cell Carcinoma
  3. Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  4. Stage IV Lung Cancer AJCC v8
  5. Stage IVA Lung Cancer AJCC v8
  6. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Sotorasib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma of Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to registration - Participants must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to sub-study registration - Participants with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to sub-study registration - Participants with EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS1 gene rearrangement, or BRAF V600E mutation must have progressed following all standard of care targeted therapy - Participants with spinal cord compression or brain metastases must have received local treatment to these metastases and remained clinically controlled and asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study registration - Participants must have received at least one line of systemic treatment for stage IV or recurrent NSCLC - Participants must have progressed (in the opinion of the treating physician) following the most recent line of systemic therapy for NSCLC - Participants must have recovered (=< grade 1) from side effects of prior therapy. --- T790M --- --- V600E ---

Primary Outcomes

Measure: Response rate (confirmed, complete or partial)

Time: Up to 3 years

Secondary Outcomes

Description: The frequency and grade of individual toxicities attributable to treatment will be estimated.

Measure: Incidence of adverse events

Time: Up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method and about landmark time points will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Binary proportions and associated confidence intervals will be estimated for within cohort objectives. With participants in Cohort 1 and 3 and participants in Cohort 2, binary proportions can be estimated to within 16% and 20% with 95% confidence, respectively.

Measure: Progression free survival

Time: Up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method and about landmark time points will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Binary proportions and associated confidence intervals will be estimated for within cohort objectives. With participants in Cohort 1 and 3 and participants in Cohort 2, binary proportions can be estimated to within 16% and 20% with 95% confidence, respectively.

Measure: Overall survival

Time: Up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method and about landmark time points will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Binary proportions and associated confidence intervals will be estimated for within cohort objectives. With participants in Cohort 1 and 3 and participants in Cohort 2, binary proportions can be estimated to within 16% and 20% with 95% confidence, respectively.

Measure: Duration of response

Time: Up to 3 years

241 A Phase 2 Randomized Double-blind Study of Relatlimab Plus Nivolumab in Combination With Chemotherapy vs. Nivolumab in Combination With Chemotherapy as First Line Treatment for Participants With Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC)

The purpose of this study is to assess the safety profile of nivolumab plus relatlimab in combination with platinum doublet chemotherapy (PDCT) and to determine if nivolumab plus relatlimab in combination with PDCT improves progression free survival (PFS) when compared to nivolumab plus PDCT in participants with previously untreated Stage IV or recurrent non-small cell lung cancer (NSCLC).

NCT04623775
Conditions
  1. Non-small Cell Lunch Cancer
  2. Recurrent Non-small Cell Lung Cancer
  3. Metastatic Non-small Cell Lung Cancer
Interventions
  1. Biological: Nivolumab
  2. Biological: Relatlimab
  3. Drug: Carboplatin
  4. Drug: Cisplatin
  5. Drug: Paclitaxel
  6. Drug: Nab-Paclitaxel
  7. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically confirmed metastatic non-small cell lung cancer (NSCLC) of squamous (SQ) or non-squamous (NSQ) histology with Stage IV A/B (as defined by the 8th International Association for the Study of Lung Cancer Classification) or recurrent disease following multi-modal therapy for locally advanced disease - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of less than or equal to 1 at screening and confirmed prior to randomization - Measurable disease by computed tomography (CT) or magnetic resonance resources (MRI) per response evaluation criteria in solid tumor version 1.1 (RECIST 1.1) criteria - No prior systemic anti-cancer treatment (including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors) given as primary therapy for advanced or metastatic disease Exclusion Criteria: - Participants with EGFR, ALK, ROS-1, or known B-rapidly accelerated fibrosarcoma proto-oncogene (BRAF V600E) mutations that are sensitive to available targeted therapy - Untreated CNS metastases - Leptomeningeal metastases (carcinomatous meningitis) - Concurrent malignancy requiring treatment or history of prior malignancy active within 2 years prior to enrollment (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before registration and the participant has no evidence of disease) - Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-programmed death-ligand 2 (PD-L2), or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Other protocol-defined inclusion/exclusion criteria apply For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com --- V600E ---

Inclusion Criteria: - Histologically confirmed metastatic non-small cell lung cancer (NSCLC) of squamous (SQ) or non-squamous (NSQ) histology with Stage IV A/B (as defined by the 8th International Association for the Study of Lung Cancer Classification) or recurrent disease following multi-modal therapy for locally advanced disease - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of less than or equal to 1 at screening and confirmed prior to randomization - Measurable disease by computed tomography (CT) or magnetic resonance resources (MRI) per response evaluation criteria in solid tumor version 1.1 (RECIST 1.1) criteria - No prior systemic anti-cancer treatment (including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors) given as primary therapy for advanced or metastatic disease Exclusion Criteria: - Participants with EGFR, ALK, ROS-1, or known B-rapidly accelerated fibrosarcoma proto-oncogene (BRAF V600E) mutations that are sensitive to available targeted therapy - Untreated CNS metastases - Leptomeningeal metastases (carcinomatous meningitis) - Concurrent malignancy requiring treatment or history of prior malignancy active within 2 years prior to enrollment (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before registration and the participant has no evidence of disease) - Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-programmed death-ligand 2 (PD-L2), or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Other protocol-defined inclusion/exclusion criteria apply Non-small Cell Lunch Cancer Recurrent Non-small Cell Lung Cancer Metastatic Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- V600E ---

Primary Outcomes

Description: Part 1

Measure: Treatment-related adverse events (TRAEs) leading to discontinuation within 12 weeks after the first dose

Time: Up to 10 months, from first participant's first dose

Description: Part 2

Measure: Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent clinical review (BICR)

Time: 10 months after randomization, up to 21 months

Secondary Outcomes

Description: Part 1

Measure: Incidence of TRAEs leading to discontinuation

Time: Up to 10 months, 30 days from participant's last dose

Description: Part 1

Measure: Incidence of Serious Adverse Events (SAEs)

Time: Up to 10 months, 30 days from participant's last dose

Description: Part 1

Measure: Incidence of select Adverse Events (AEs)

Time: Up to 10 months, 30 days from participant's last dose

Description: Part 2

Measure: PFS per RECIST v1.1 by BICR in biomarker subgroups

Time: Until progression, up to 21 months

Description: Part 2

Measure: Overall response rate (ORR) per RECIST v1.1 by BICR

Time: Up to 21 months

Description: Part 2

Measure: Incidence of Serious Adverse Events (SAEs)

Time: Up to 21 months

Description: Part 2

Measure: Incidence of select Adverse Events (AEs)

Time: Up to 21 months

242 Early Rebiopsy to Identify Mechanisms and Biomarkers of Tumor Cell Survival Following Targeted Therapy in Patients With EGFR, ALK, ROS1 or BRAF Mutations.

A comparison of baseline tumor characteristics in oncogene-driven cancers to tumor characteristics after early response to Tyrosine Kinase Inhibitor (TKI) targeted treatment will allow identification of early adaptive mechanisms of cell survival. This will facilitate targeting and termination of these survival/ resistance pathways before they develop with rational combinations of therapeutic agents to improve outcomes.

NCT03042221
Conditions
  1. Non-Small Cell Carcinoma of Lung, TNM Stage 4
  2. Non-Small Cell Lung Cancer
  3. EGFR Gene Mutation
  4. ALK Gene Mutation
  5. ROSE Cluster 1
  6. BRAF V600E
MeSH:Carcinoma, Non-Small-Cell Lung Lung Neoplasms
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Carry a diagnosis of stage IV lung adenocarcinoma with an activating mutation determined to respond to an estimated glomerular filtration rate (EGFR) TKI, alkaline phosphatase (ALK) or ROS Proto-Oncogene 1 (ROS1) fusion or BRAF V600E. --- V600E ---

Non-Small Cell Carcinoma of Lung, TNM Stage 4 Non-Small Cell Lung Cancer EGFR Gene Mutation ALK Gene Mutation ROSE Cluster 1 BRAF V600E Carcinoma, Non-Small-Cell Lung Lung Neoplasms null --- V600E ---

Primary Outcomes

Description: change from baseline of tumor gene expression profile at 2 weeks. Global gene expression data will be collected using RNAseq

Measure: gene expression changes

Time: baseline and 2 weeks (+/- 1 week) for each patient.

Description: change from baseline of protein gene expression profile at 2 weeks as measured by multiplex protein assay (proteins to be assayed include: e-cadherin, vimentin, fibronectin, CD4, CD8, CD14, CD16, CD206, PDL1, and CSF1R)

Measure: protein expression change

Time: baseline and 2 weeks (+/- 1 week) for each patient.

Secondary Outcomes

Description: Correlation between the depths of tumor response (by RECIST v1.1) (percentage decrease in tumor size) with the presence of an EMT signature.

Measure: Depth of Response

Time: Study startup through 36 months

Other Outcomes

Description: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0

Measure: Evaluation of Adverse Events

Time: Study startup through 36 months

Description: Success rate of early rebiopsy in obtaining tumor samples that have evaluable material for RNA Seq and other analyses

Measure: Success rate of Repeat Biopsy

Time: Study startup through 36 months

Description: Length of PFS as per RECIST 1.1

Measure: Progression Free Survival

Time: Study startup through 36 months

243 Phase II Trial of Single-agent Cobimetinib for Adults With Histiocytic Disorders

The purpose of this study is to find out what effects, good or bad, Cobimetinib has in patients with histiocytosis. Cobimetinib is an investigational oral medication that blocks MEK1.

NCT02649972
Conditions
  1. Histiocytic Disorders
Interventions
  1. Drug: Cobimetinib
MeSH:Disease

- One of the following: - Documentation of BRAF V600E mutation and inability to access of BRAF inhibitor or prior treatment with a BRAF inhibitor discontinued due intolerable side effects or toxicity prior to progression, -OR- - Documentation of wild-type BRAF V600 mutational status - Patients with BRAF-mutated ECD/LCH who have had disease progression on BRAF inhibitor therapy would be eligible but would require tissue biopsy (or available tissue) for genotyping before participating. --- V600E ---

Primary Outcomes

Description: by PET Response Criterial (PRC), with a dichotomous BOR of CR or PR versus neither of those. Assuming we use this binary endpoint of response, defined as best overall response of CR or PR versus not using the PET Response Criteria (PRC), a sample size of 18 patients provides 90% power to test the hypothesis that the response rate is promising (defined as 35% or higher) against a non-promising rate of 10% or lower.

Measure: best overall response

Time: 1 year

244 Νew Molecular Biomarkers for the Prevention and Early Detection of Precancerous or Cancerous Colorectal Lesions During Screening for Colorectal Cancer

The investigators designed a prospective study to evaluate the predictive ability of detection of mutations in genes involved in carcinogenesis of the colon (eg hMLH1, K-Ras, B-Raf, ccfDNA) in a sample of Greek population presents for conducting colonoscopy in the context of screening under international CRC prevention instructions. This investigation will be carried out in individuals in normal risk in order to study specific mutations (in blood and tissue) to draw reliable conclusions about whether we can detect (with greater sensitivity and specificity) patients with precancerous lesions or CRC with a simple blood test thereby reducing the cost and side effects of repeated endoscopic procedures.

NCT02596113
Conditions
  1. Colorectal Cancer
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

From all these three populations, samples would be collected from peripheral blood (plasma) and colon tissue biopsy (normal or abnormal, respectively) in order to find a possible common mutations of some genes involved in the pathogenesis of the CRC in these 3 groups [e.g. in KRAS12, 13, 61, BRAF (V600E), ccfDNA some point mutations in hMLH1]. --- V600E ---

Primary Outcomes

Measure: Genes' mutations rate in patients who are submitted screening colonoscopy and they presented with no endoscopic findings

Time: 1 month

Measure: Genes' mutations rate in patients who are submitted screening colonoscopy and they presented with adenomatous polyp bigger than 1 cm

Time: 1 month

Measure: Genes' mutations rate in patients who are submitted screening colonoscopy and they presented with cancerous lesion

Time: 1 month

245 An Open-Label, 2-Cohort, Multicenter, Phase 2 Study of E7080 (Lenvatinib) in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

The purpose of this study is to assess the objective response rate of lenvatinib in previously treated participants with American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV melanoma and disease progression.

NCT01136967
Conditions
  1. Unresectable Stage III
  2. Stage IV Melanoma
Interventions
  1. Drug: Lenvatinib
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

More than 2 prior systemic anticancer regimen treatments including immunotherapies for unresectable Stage III or Stage IV disease (if BRAF V600E mutation negative) or not previously treated with BRAF V600E-targeted therapy or received in the past more than 2 prior systemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy (if BRAF V600E mutation positive). --- V600E ---

More than 2 prior systemic anticancer regimen treatments including immunotherapies for unresectable Stage III or Stage IV disease (if BRAF V600E mutation negative) or not previously treated with BRAF V600E-targeted therapy or received in the past more than 2 prior systemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy (if BRAF V600E mutation positive). --- V600E --- --- V600E ---

More than 2 prior systemic anticancer regimen treatments including immunotherapies for unresectable Stage III or Stage IV disease (if BRAF V600E mutation negative) or not previously treated with BRAF V600E-targeted therapy or received in the past more than 2 prior systemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy (if BRAF V600E mutation positive). --- V600E --- --- V600E --- --- V600E ---

More than 2 prior systemic anticancer regimen treatments including immunotherapies for unresectable Stage III or Stage IV disease (if BRAF V600E mutation negative) or not previously treated with BRAF V600E-targeted therapy or received in the past more than 2 prior systemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy (if BRAF V600E mutation positive). --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Cohort 1 enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma, and is referred to as Cohort 1 or V600E BRAF negative. --- V600E ---

Cohort 1 enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma, and is referred to as Cohort 1 or V600E BRAF negative. --- V600E --- --- V600E ---

Cohort 2 enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy, and is referred to as Cohort 2 or V600E BRAF positive. --- V600E ---

Cohort 2 enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy, and is referred to as Cohort 2 or V600E BRAF positive. --- V600E --- --- V600E ---

Cohort 2 enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy, and is referred to as Cohort 2 or V600E BRAF positive. --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than (<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Objective Response Rate (ORR)

Time: From date of treatment start until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 (up to 24 weeks)

Secondary Outcomes

Description: PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death from any cause (whichever occurred first), as determined by IRR and Investigator based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% confidence interval (CI) when an adequate number of at risk participants warranted the estimates in the table below.

Measure: Progression Free Survival (PFS)

Time: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Description: OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date for each cohort. OS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below.

Measure: Overall Survival (OS)

Time: From date of treatment start until date of death from any cause or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Description: DCR, (DCR = CR + PR + SD) was defined as the percentage of participants who had a BOR of CR or PR or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT and IRR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to <10 mm.; PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR. SD defined as reduction in tumor volume of < 30% or an increase in the volume of 1 or more measurable lesions of < 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. BOR of SD, time from first administration of study drug until date of documented SD needed to be >=7 weeks based on IRR and Investigator's assessment.

Measure: Disease Control Rate (DCR)

Time: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Description: CBR, (CBR = CR + PR + durable SD rate) was defined as the percentage of participants who had a BOR of CR or PR or durable SD (dSD, SD lasting >=23 weeks) based on RECIST v1.1 for target lesions assessed by MRI/CT, IRR and Investigator's assessment. A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; OR = CR + PR. A BOR of dSD, the time from the first administration of study drug until the date of documented dSD needed to be ≥23 weeks based on IRR and Investigator's assessment.

Measure: Clinical Benefit Rate (CBR)

Time: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Description: Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECGs), and multi-gated acquisition (MUGA) scans or echocardiogram.

Measure: Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib

Time: From date of treatment start up to 30 days after the last dose, or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 9 months

Description: Blood samples were drawn at specific time points. Utilizing a standard protocol, the deoxyribonucleic acid (DNA) from whole blood was extracted and analyzed for specific biomarkers of absorption, distribution, metabolism, and excretion of lenvatinib. Some of the biomarkers analyzed included; Angiopoietin, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), FMS Like Tyrosine Kinase 3 Ligand (Flt3l) Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macro Colony Stimulating Factor (GM-CSF), Interleukin 1 Receptor Antagonist (IL-1RA), Interferon (IFN), Macrophage Inflammatory Protein (MIP) 1 alpha, Platelet Derived Growth Factor (PDGF), Stromal Cell Derived Factor (SDF) 1 alpha, Interleukin (IL), Transforming Growth Factor (TGF), Tumor Necrosis Factor (TNF), Vascular Endothelial Growth Factor (VEGF).

Measure: Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood

Time: Cycle 1 Day 15 (C1 D15), Cycle 2 Day 1 (C2 D1), Cycle 3 Day 1 (C3 D1), Off-Treatment/Phase Visit 98 (V98)

Description: Blood samples for the quantification of lenvatinib in plasma were obtained and processed using a standardized protocol. The lower limit of quantification was 0.25 ng/mL. Pharmacokinetic (PK) analysis was conducted using nonlinear mixed effects modeling. Descriptive statistics were used to summarize lenvatinib plasma concentration data.

Measure: Summary of Plasma Concentration of Lenvatinib

Time: Predose and 2 to 12 hours postdose at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), and Cycle 2 Day 1 (C2D1)

246 Low-dose Interleukin-2 and Pembrolizumab Among Patients With Metastatic Melanoma and Renal Cell Carcinoma

This study will evaluate the safety and disease control rate of the combination of pembrolizumab plus low-dose interleukin-2 in patients who have either advanced melanoma or renal cell cancer.

NCT03111901
Conditions
  1. Carcinoma, Renal Cell
  2. Melanoma
Interventions
  1. Drug: Pembrolizumab
  2. Drug: Interleukin-2
MeSH:Carcinoma Melanoma Carcinoma, Renal Cell
HPO:Carcinoma Clear cell renal cell carcinoma Cutaneous melanoma Melanoma Papillary renal cell carcinoma Renal cell carcinoma

If the melanoma expresses a BRAF mutation of V600E, V600K, or V600R patient must have received and progressed through a BRAF inhibitor or have failed that therapy due to toxicity. --- V600E ---

Primary Outcomes

Description: Obtain preliminary data on the safety of LD-IL2 with pembrolizumab

Measure: Safety: adverse event profile

Time: up to 90 days post-treatment

Description: Estimate the disease control rate (CR+PR+SD by RECIST 1.1) among candidate patients with metastatic melanoma treated with pembrolizumab and LD-IL2 and to determine whether disease control is significantly improved. SD for 6 months or more will be considered SD for the purpose of this assessment.

Measure: Disease control rate: melanoma

Time: baseline and every 9 weeks (up to week 104)

Description: Estimate the disease control rate (CR+PR+SD by RECIST 1.1) among patients with metastatic renal cell cancer treated with pembrolizumab and LD-IL2 and to determine whether disease control is significantly improved. SD for 6 months or more will be considered SD for the purpose of this assessment.

Measure: Disease control rate: renal cell cancer

Time: baseline and every 9 weeks (up to week 104)

Secondary Outcomes

Description: Estimate progression-free survival defined as the duration of time from first response (SD/PR/CR) to time of recurrence/progression or death from any cause, whichever occurs first

Measure: Progression free survival: metastatic melanoma

Time: From first response (SD/PR/CR) to time of recurrence/progression or death from any cause, whichever occurs first, assessed for an estimated total of 120 months.

Description: Estimate progression-free survival defined as the duration of time from first response (SD/PR/CR) to time of recurrence/progression or death from any cause, whichever occurs first

Measure: Progression free survival: renal cell cancer

Time: From first response (SD/PR/CR) to time of recurrence/progression or death from any cause, whichever occurs first, assessed for an estimated total of 120 months.

247 Analysis of the Role of Hepatocyte SLAMF3 Receptor and Drug Resistance Proteins (MDR) in Resistance to Treatment With Sorafenib in CHC Patients

Primary liver cancer or hepatocellular carcinoma (HCC) is the 7th most common cancer in humans; 9th in women (figures from the Association for Research against Cancer ARC). This cancer is a major public health problem on a global scale. Patients, whose diagnosis is often late, are at advanced stages of the pathology, even those who benefit from locoregional treatments have a poor prognosis and suffer from a lack of curative therapeutic strategies. CHC is highly refractory to cytotoxic chemotherapy and so far the response rates to conventional systemic chemotherapy has provided a clinical benefit where survival was prolonged by more than 25% in patients with advanced CHC. Further efforts are needed to effectively manage HCC. Knowledge of the mechanisms regulating proliferation and inhibiting the sensitivity of transformed cells to apoptosis is the key to the development of more effective therapeutic strategies. Several new therapies, called targeted therapies, are tested in clinical trials. Currently, the most effective molecular agent for targeting the Raf pathway is sorafenib capable of also inhibiting tyrosine kinases of VEGFR and PDGFR. Sorafenib, a multikinase inhibitor, decreases the proliferation of tumor cells in vitro that inhibit the activity of targets present in tumor cells (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and tumor vascularization VEGFR-2, VEGFR-3, and PDGFR-beta). Despite the real benefit of this treatment, its efficacy (three months of overall survival) and its indication remain limited to Child-Pugh A, WHO 0-2 patients in whom curative treatment is contraindicated. In addition, several patients have resistance to Sorafenib and thus find themselves in therapeutic failure, thus limiting the therapeutic choice for these patients. Resistance to treatment with Sorafenib limits the therapeutic choice. The mechanisms responsible for this resistance remain to be elucidated. Drug resistance proteins, MDR Multi-Drug Resistance, is a family of molecules whose expression increases in the cancer cell and ensures the repression of chemotherapy molecules outside the target cancer cell. This family includes the proteins ABCG2, MDR and MRP1. Our in vitro studies show that treatment of CHC Huh-7 cells with Sorafenib (10 mM) induces the specific expression of the transcripts of the MRP-1 protein without any effect on the expression of the ABCG2 and MDR protein. In addition, sorafenib has an effect on the expression of hepatocyte SLAMF3 receptor transcripts, a receptor recently identified in hepatocyte tissue. Indeed, it has been shown that the expression of SLAMF3 is lowered in the cancerous tissue compared to the healthy tissue and that the reintroduction of a strong expression in the cancer cell inhibits its proliferation by inhibiting the MAPK Erk pathway, Cancer cells to apoptosis and inhibits the uptake of tumor masses in the Nude mouse (I. Marcq, et al., 2013).

NCT03113604
Conditions
  1. Hepatocyte Receptor
  2. Hepatocellular Carcinoma
Interventions
  1. Other: Study on samples of tumor and peri-tumor tissues from patients with hepatocellular carcinoma
MeSH:Carcinoma, Hepatocellular
HPO:Hepatocellular carcinoma

Sorafenib, a multikinase inhibitor, decreases the proliferation of tumor cells in vitro that inhibit the activity of targets present in tumor cells (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and tumor vascularization VEGFR-2, VEGFR-3, and PDGFR-beta). --- V600E ---

Primary Outcomes

Measure: Rate of expression of SLAM3 and MDR transcripts, correlation with the responder status or not with Sorafenib

Time: 1 day

248 Astrocytoma / Desmoplastic Gamliogliomes (DIA / DIG) - Study of the French Cohort of the Last 20 Years : Clinical, Anatomopathological, Molecular and Radiological Charactersics

Astrocytomas / infantile desmoplastic gangliogliomas (DIA / DIG) are rare brain tumors usually affecting infants. They represent about 0.5% of all pediatric brain tumors. DIA / DIG occurs mainly in the first 2 years of life, with a sex ratio M / F of 1.7 to 1. From a histological point of view, DIA / DIG are neuroepithelial tumors. These tumors may have a purely astrocytic differentiation (DIA) or be composed of tumor cells with astrocytic and neuronal differentiation (DIG). The desmoplastic component is usually adjacent to the meninges and is defined by the increase or modification of connective tissues related to the presence of neoplastic cells with the formation of a collagen-rich extracellular matrix. Due to their benign biological behavior and favorable clinical course, they are classified in benign tumors, ie grade I according to the WHO classification. However, all tumors called DIA / DIG do not behave in a benign manner. Cases of metastatic cerebrospinal and malignant disorders have been described. It appears that about 40% of DIG cases require additional medical treatment such as chemotherapy, radiotherapy and / or new surgery, and 15% of infants and children with GIDD die from the disease. It is possible that what is grouped within the DIA / DIG is a heterogeneous group of tumors, evolution and prognosis very variable. The cytogenetic knowledge of DIA / DIG is very limited and is only available on small numbers of cases. Cytogenetic analyzes of several cases of DIG showed normal karyotypes. More recently, a CGH-Array study of 3 cases of DIA / DIG did not find any significant chromosomal gains or losses. It has been shown, however, that a mutation involving BRAF (BRAF rearrangement or BRAF V600E mutations) was a recurrent element in low grade gliomas, particularly in pediatric patients. It is also suggested that deregulation of BRAF activity in some DIA / DIG may indicate the importance of the MAPK (mitogen-activated protein kinase) pathway in signaling pathways for DIA / DIG development. However, data on the link between the BRAF gene and DIA / DIG remains very limited. Thus, further studies are needed to study the other members of the MAPK pathway in DIA / DIG (eg PI3K / AKT / mTOR). This could provide new therapeutic possibilities involving targeted therapies specific to the MAPK signaling pathway. It appears that DIA / DIG does not all behave in a benign manner and some would undergo a malignant transformation that could be due to chromosomal alterations such as, for example, TP53, PI3K. In addition, because of the limited number of cases, it would be interesting to study the characteristics of patients with DIA / DIG in order to study their characteristics and whether there are clinical, pathological, cytogenetic and / Molecular forms between benign and malignant forms.

NCT03115164
Conditions
  1. Astrocytoma
  2. Ganglioglioma Desmoplastics and Infantile
Interventions
  1. Other: To study the characteristics of patients with DIA / DIG
MeSH:Astrocytoma Ganglioglioma
HPO:Astrocytoma Subependymal giant-cell astrocytoma

It has been shown, however, that a mutation involving BRAF (BRAF rearrangement or BRAF V600E mutations) was a recurrent element in low grade gliomas, particularly in pediatric patients. --- V600E ---

Primary Outcomes

Measure: Distribution of the characteristics of patients with DIA / DIG treated in the French SFCE pediatric oncology centers according to whether these tumors are benign or present a malignant transformation

Time: 1 day

249 A Phase I Open-Label Dose Escalation of GD3 ADC (Pfizer PF-06688992) in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma (B802WI209568)

The purpose of this research study is to learn about the safety and effectiveness of the study drug, PF-06688992. Before this study, PF-06688992 has never been given to people. PF-06688992 is a targeted therapy for people with cancer. The investigators linked a chemotherapy drug to an antibody (protein found in the blood). The antibody will connect to GD3 which is found on most melanomas but on very few other cells in the body. The investigators hope that in this way, it will deliver this chemotherapy directly to the melanoma and not to normal tissues.

NCT03159117
Conditions
  1. Melanoma
Interventions
  1. Drug: PF-06688992
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

- Patients whose melanomas harbor a BRAF V600E or V600K mutation must have progressed on a RAF inhibitor. --- V600E ---

Primary Outcomes

Description: using a Bayesian dose escalation scheme

Measure: the Recommended Phase 2 Dose

Time: 1 year

250 Umbrella Protocol for Phase I/IIa Trials of Molecularly Matched Targeted Therapies Plus Radiotherapy in Patients With Newly Diagnosed Glioblastoma Without MGMT Promoter Methylation: NCT Neuro Master Match - N²M² (NOA-20)

The objective of N²M² is the improvement of overall survival of patients with glioblastoma with an unmethylated MGMT promoter based on molecular characterization and use of targeted compounds in a modern trial design. The progression-free survival rate at six months (PFS-6) will be used to make decisions.

NCT03158389
Conditions
  1. Glioblastoma, Adult
Interventions
  1. Drug: APG101
  2. Drug: Alectinib
  3. Drug: Idasanutlin
  4. Drug: Atezolizumab
  5. Drug: Vismodegib
  6. Drug: Temsirolimus
  7. Drug: Palbociclib
MeSH:Glioblastoma
HPO:Glioblastoma multiforme

BRAF V600E mutation and a distinct treatment or some others, but it is expected that these linear relations will be replaced in a learning system by relations that take upstream and downstream target alterations and also parallel signaling pathways into account and may therefore already predict a certain likelihood of resistance development. --- V600E ---

Primary Outcomes

Description: defined as the proportion of patients free of progression at 6 months after study entry. PFS will be calculated from study entry until clinical or radiographic progression or death, whichever comes first.Progression will be evaluated according to Response Assessment in Neurooncology (RANO) criteria or Immunotherapy Response Assessment in Neurooncology (iRANO) criteria.

Measure: PFS-6 rate

Time: 6 months

Secondary Outcomes

Description: Toxic effects will be graded according to CTCAE v5.0.

Measure: Incidence of Treatment-Emergent Adverse Events (AE)

Time: 6 months

Description: defined as the time from first administration of the investigational medicinal product (IMP) to time of death from any cause.

Measure: Overall survival (OS)

Time: 6 months

251 Pembrolizumab in Combination With Dabrafenib and Trametinib as a Neoadjuvant Strategy Prior to Surgery in BRAF-Mutated Anaplastic Thyroid Cancer

This phase II trial studies the effect of pembrolizumab, dabrafenib, and trametinib before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer. BRAF V600E is a specific mutation (change) in the BRAF gene, which makes a protein that is involved in sending signals in cells and in cell growth. It may increase the growth and spread of tumor cells. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pembrolizumab, dabrafenib, and trametinib may help to control BRAF V600E-mutated anaplastic thyroid cancer when given before surgery.

NCT04675710
Conditions
  1. Thyroid Gland Anaplastic Carcinoma
  2. Thyroid Gland Squamous Cell Carcinoma
Interventions
  1. Procedure: Conventional Surgery
  2. Drug: Dabrafenib
  3. Radiation: Intensity-Modulated Radiation Therapy
  4. Biological: Pembrolizumab
  5. Other: Quality-of-Life Assessment
  6. Drug: Trametinib
MeSH:Carcinoma Thyroid Neoplasms Thyroid Carcinoma, Anaplastic Thyroid Diseases
HPO:Abnormality of the thyroid gland Anaplastic thyroid carcinoma Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Pembrolizumab, Dabrafenib, and Trametinib Before Surgery for the Treatment of BRAF-Mutated Anaplastic Thyroid Cancer This phase II trial studies the effect of pembrolizumab, dabrafenib, and trametinib before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer. --- V600E ---

BRAF V600E is a specific mutation (change) in the BRAF gene, which makes a protein that is involved in sending signals in cells and in cell growth. --- V600E ---

Pembrolizumab, dabrafenib, and trametinib may help to control BRAF V600E-mutated anaplastic thyroid cancer when given before surgery. --- V600E ---

Diagnosis may include consistent with or suggestive of terminology associated with: anaplastic thyroid carcinoma, undifferentiated carcinoma, squamous carcinoma; carcinoma with spindled, giant cell, or epithelial features; poorly differentiated carcinoma with pleomorphism, extensive necrosis with tumor cells present - Must have a BRAFV600E mutation-positive tumor, as determined by BRAF V600E immunohistochemistry on tumor tissue, genetic/molecular testing of tumor, or cell free (cf)NDA liquid biopsy - Total bilirubin =< 1.5 x upper limit of normal (ULN). --- V600E ---

Primary Outcomes

Description: Overall R0/R1 resection rate will be defined by proportion of patients who undergo successful thyroidectomy with clear (R0) or microscopically positive (R1) surgical margins. We will test the hypothesis that the R0/R1 resection rate is greater than historical rate of 5%.

Measure: Complete gross surgical resection (R0 or R1 resection)

Time: Up to 5 cycles (1 cycle = 21 days)

Description: OS will be measured as the time from the start of any trial treatment to death from any causes. Kaplan-Meier method will be used to estimate the median survival time across all patients and its 95% confidence intervals (CI).

Measure: Overall survival (OS)

Time: Up to 72 months

Secondary Outcomes

Description: Objective tumor response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Measure: Tumor response

Time: Up to 42 months

Description: PFS will be measured as the time from the start of the treatment to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by RECIST version 1.1.

Measure: Progression free survival (PFS)

Time: Up to 42 months

Description: Surgical morbidity/complexity will be measured at enrollment, prior to surgery and at surgery. The Thyroid Neck Group Morbidity Complexity Scoring and MGH/MEE-MSK-MD Anderson (MMM) Surgical Morbidity Complexity Score are incorporated, specifying on a scale with 5 levels of complexity and morbidity of the surgery [mild (level 0), moderate (level 1), severe (level 2), very severe (level 3), and unresectable (level 4)].

Measure: Surgical morbidity/complexity

Time: Up to 5 cycles (1 cycle = 21 days)

Description: Frequency and severity of adverse events as a measure of safety profile for neoadjuvant concurrent administration of dabrafenib, trametinib, and pembrolizumab (DTP) will be assessed using Common Terminology Criteria for Adverse Events version 5.0.

Measure: Number of patients with adverse events as a measure of safety of neoadjuvant dabrafenib, trametinib, and pembrolizumab

Time: Up to 5 cycles (1 cycle = 21 days)

Description: Frequency and severity of adverse events as a measure of safety profile for concurrent administration of postoperative pembrolizumab with IMRT will be assessed using Common Terminology Criteria for Adverse Events version 5.0.

Measure: Number of patients with adverse events as a measure of safety of postoperative pembrolizumab plus IMRT

Time: Over the course of adjuvant IMRT plus 2 weeks of safety follow-up, assessed up to 2 months

Description: Locoregional control will be measured as the time from the start of any trial treatment to the first locoregional recurrence/progression event.

Measure: Locoregional control

Time: Up to 42 months

Description: Changes of health-related quality of life will be measured by the European Quality of Life 5 Dimension Questionnaire (EQ-5D). The EQ-5D consists of health state description and evaluation. The health state description consists of five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), with each dimension specifying five levels of severity [best (1)-worst (5)]. The health state evaluation is assessed using the visual analogue scale ([worse (0)-best (100)].

Measure: Health related quality of life

Time: Up to 42 months

Description: Symptom burden experienced by patients will be measured by the M.D. Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) instrument.

Measure: Patient-reported symptoms

Time: Up to 42 months

252 An Open-Label, Multi-Center Study to Investigate the Objective Response Rate, Safety, and Pharmacokinetics of GSK1120212, a MEK Inhibitor, in BRAF Mutation-positive Melanoma Subjects Previously Treated With or Without a BRAF Inhibitor

MEK113583 is a Phase II open-label, multi-site study to investigate the objective response rate, safety, and pharmacokinetics of GSK1120212 in subjects with BRAF mutation-positive melanoma who were previously treated with or without a BRAF inhibitor. GSK1120212 is a potent and highly selective inhibitor of MEK activation and kinase activity.

NCT01037127
Conditions
  1. Cancer
Interventions
  1. Drug: GSK1120212
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

The number of participants with best confirmed response was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. --- V600E ---

The number of participants with best confirmed response was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. --- V600E --- --- V600E ---

PFS was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. --- V600E ---

PFS was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. --- V600E --- --- V600E ---

- Documented positive BRAF mutation (V600E, V600K, or V600D). --- V600E ---

Primary Outcomes

Description: Best confirmed response was assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Best response was measured either as a complete response (CR), defined as the disappearance of all target lesions and pathological lymph nodes <10 millimeters (mm), or a partial response (PR), defined as at least a 30% decrease in the sum of the diameters of target lesions. To be assigned a status of confirmed CR or PR, a confirmatory disease assessment was required no less than 28 days after the criteria for response were first met.

Measure: Number of Participants With Best Confirmed Response

Time: From Baseline (Day 1) until the time of the first documented evidence of a confirmed complete response or partial response (up to approximately 25 weeks)

Description: The number of participants with best confirmed response was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. Objective response was assessed per RECIST version 1.1. Objective response was measured either as CR, defined as the disappearance of all target lesions and pathological lymph nodes <10 mm, or PR, defined as at least a 30% decrease in the sum of the diameters of target lesions. To be assigned a status of confirmed CR or PR, a confirmatory disease assessment was required no less than 28 days after the criteria for response were first met. Brain metastasis is a cancer that has spread to the brain from another location of the body.

Measure: Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors

Time: From Baseline (Day 1) until the time of the first documented evidence of a confirmed CR or PR (up to approximately 25 weeks)

Description: An interim analysis was performed using data collected approximately 12 and 13 weeks after the 30th participant was enrolled in the prior BRAF inhibitor and prior standard therapy groups, respectively. The best unconfirmed response by the investigator per RECIST version 1.1 was assessed. The study design permitted stopping the study for futility if <3 best confirmed responses were observed in the first 30 participants of each treatment arm after completing the first post-dose assessment at Week 8. Best response was measured as either a CR, defined as the disappearance of all target lesions and pathological lymph nodes <10 millimeters, or a PR, defined as at least a 30% decrease in the sum of the diameters of target lesions.

Measure: Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8)

Time: Week 8

Secondary Outcomes

Description: Human plasma samples were analyzed for trametinib using a validated analytical method.

Measure: Mean Plasma Concentrations

Time: Day 15, pre-dose, 0.5-2 hours (hrs) post-dose, 2-4 hrs post-dose, and 4-8 hrs post-dose; Week 4, pre-dose; Week 8, pre-dose; Week 12, pre-dose

Description: An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. AE and serious AE (SAE) data were collected from the start of the investigational product and continued until the End of Treatment Visit. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

Measure: Number of Participants With Any Adverse Event (AE)

Time: From the date of the first dose of study medication until 28 days after the last dose (up to 477 days)

Description: Duration of tumor response is defined as the time from the first documented evidence of a CR or PR to disease progression (at least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; unequivocal progression of non-target lesions, or the appearance of a new lesion) or death due to any cause. No participants who were previously treated with BRAF inhibitors had a CR, defined as the disappearance of all target lesions and pathological lymph nodes <10 millimeters, or a PR, defined as at least a 30% decrease in the sum of the diameters of target lesions; thus, no duration of response data can be presented.

Measure: Duration of Tumor Response

Time: From the time of the first documented evidence of a confirmed CR or PR until disease progression or death due to any cause (up to approximately 40 weeks)

Description: PFS is defined as the interval between the treatment start date and the earliest date of disease progression (at least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; unequivocal progression of non-target lesions, or the appearance of a new lesion) or death due to any cause, whichever occurred first. Participants who had not progressed or died were censored at the date of the last adequate tumor assessment at the time of the cut-off.

Measure: Progression-free Survival (PFS)

Time: Baseline (Day 1) until the time of disease progression or death due to any cause (up to approximately 57 weeks)

Description: PFS was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. Per RECIST version 1.1, PFS is defined as the interval between the treatment start date and the earliest date of disease progression (at least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; unequivocal progression of non-target lesions, or the appearance of a new lesion) or death due to any cause, whichever occurred earliest. Brain metastasis is a cancer that has spread to the brain from another location of the body.

Measure: PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors

Time: Baseline (Day 1) until the time of disease progression or death due to any cause (up to approximately 57 weeks)

Description: Overall survival is defined as the time from the treatment start date until death due to any cause. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off.

Measure: Overall Survival

Time: Baseline (Day 1) until death due to any cause (up to 134 weeks)

Description: Overall survival (defined as the time from the treatment start date until death due to any cause) data data are presented as the number of participants who were alive 6 months, 12 months and 24 months after Baseline. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off.

Measure: Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline

Time: Month 6, Month 12 and Month 24

Description: Tumor progression was assessed as disease progression (DP), defined as at least a 20 percent increase in the sum of diameters of target lesions (representative of all involved organs), taking as reference the smallest sum on study; unequivocal progression of non-target lesions; or the appearance of a new lesion. Because melanoma often progresses to the brain/central nervous system (CNS) and this study enrolled approximately 20% participants with prior brain metastases, tumor progression in the brain/CNS was summarized. Paticipants could have been included in more than one category.

Measure: Number of Participants With Tumor Progression

Time: Baseline (Day 1) until tumor progression (up to approximately 57 weeks)

253 Phase II Clinical Trial of the MEK 1/2 Inhibitor AZD6244 in Cancers With BRAF Mutations Identified by Prospective Genotypic Analysis

The purpose of this research study is to determine if selumetinib is safe and effective in treating patients with cancers with a mutated BRAF gene. Selumetinib is an investigational drug that works by blocking a protein called MEK, which is known to play a role in the growth of cancer cells lines and tumors that have a mutated BRAF gene. There are multiple types of cancers that have mutations in the BRAF gene and depend on the activity of this gene for their growth and survival.

NCT00888134
Conditions
  1. Adult Solid Neoplasm
Interventions
  1. Drug: Selumetinib

Confidence intervals will be calculated and reported.. Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip. --- V600E ---

Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Adult Solid Neoplasm PRIMARY OBJECTIVES: I. To evaluate the objective response rate to AZD6244 (selumetinib) in patients with cancers other than melanoma in which BRAF mutations have been identified prospectively. --- V600E ---

Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Adult Solid Neoplasm PRIMARY OBJECTIVES: I. To evaluate the objective response rate to AZD6244 (selumetinib) in patients with cancers other than melanoma in which BRAF mutations have been identified prospectively. --- V600E --- --- V600E ---

To estimate the sensitivity and specificity of detection of the BRAF V600E mutation in circulating tumor cells (CTC) using a microfluidic platform (the 'CTC-chip'). --- V600E ---

Primary Outcomes

Description: Percentage of participants achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans (which are done every 6 weeks).

Measure: Objective Response Rate in Patients With Cancers Other Than Melanoma

Time: 4 years

Secondary Outcomes

Description: Correlation between response to AZD6244 and mutational analysis of AKT pathway (an intracellular signaling pathway important in regulating the cell cycle)

Measure: AKT Pathway Activity

Time: Up to 4 years

Description: Percentage of participants with either colon cancer or non-small cell lung cancer achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans.

Measure: Objective Response Rate in Patients With Non-small Cell Lung Cancers and Colon Cancers

Time: Up to 4 years

Description: Reported as percentage of participants alive and progression free at 4-months. Will be estimated using Kaplan-Meier survival curves. Confidence intervals will be calculated and reported.

Measure: Progression-free Survival

Time: 4 months

Measure: Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip

Time: Up to 4 years

254 A Phase I, Open-Label, Multiple-Dose, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of the BRAF Inhibitor GSK2118436 in Subjects With Solid Tumors

BRF112680 is a first-time-in-human study to establish the recommended dose and schedule of the orally administered GSK2118436. The recommended dose and regimen will be selected based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after the treatment of subjects with solid tumors. This is a two-part study. Part 1 will identify the recommended Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached. The recommended Part 2 dose will be expanded to up to 12 patients. Part 2 will explore further the safety, tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive tumors. In addition, the effect of GSK2118436 on midazolam will be assessed in a subset of patients in Part 2. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.

NCT00880321
Conditions
  1. Cancer
Interventions
  1. Drug: GSK2118436
  2. Drug: GSK2118436
  3. Drug: Midazolam

- Part 2/Cohort C only: Must have BRAF positive melanoma with the V600E mutation. --- V600E ---

Primary Outcomes

Measure: PK data, AEs, changes in laboratory values and vital signs, physical exam, clinical testing and PD data

Time: 21 days

Secondary Outcomes

Measure: GSK2118436 and its metabolite, PK parameters per protocol following single- and repeat-dose administration of GSK2118436

Time: 15 days

Measure: Change in PD markers including IL-8 in blood, pERK and other markers in tumor biopsies.

Time: 15 days

Measure: Correlation between PK, PD, and clinical endpoints.

Time: 15 days

Measure: Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0)

Time: approximately once every 2 months until the end of participation

Measure: Urinary ratio of 6-beta-hydroxycortisol to cortisol ratio

Time: 15 days

Measure: GSK2118436 PK parameters per protocol with and without food

Time: 15 days

Measure: Metabolic profiling in plasma and urine

Time: 15 days

Measure: Midazolam PK parameters per protocol

Time: 15 days

255 Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers

Background: - MEDI4736 is a drug that may help people s immune systems respond to and kill cancer cells. Olaparib is a drug that may inhibit repairing DNA damage of cancer cells. Cediranib is a drug that may stop the blood vessel growth of cancer cells. This study has two components. In the phase 1 component of the study, researchers want to investigate how well participants tolerate the combination of these drugs in treating advanced solid tumors, and in the phase 2 part of this study, researchers want to study if the combination treatments are effective in ovarian cancer. Objectives: - Phase 2 part of the study: To determine how effective this combination is in treating ovarian cancer. Eligibility: - Phase 2 part of the study: Adults age 18 or older with advanced or recurrent ovarian cancer that has no standard treatment. Design: - Participants will be screened with medical history, physical exam, and blood and urine tests. They will have CT or MRI scans. For these, they will lie in a machine that takes pictures of their bodies. - Phase 2 part of the study requests the participants to have tumor samples removed. - Participants will get MEDI4636 through an IV. A small plastic tube will be inserted into a vein. The drug will be given every 4 weeks until disease progression. - Participants will take olaparib or cediranib by mouth every day. - Every 28 days will be 1 cycle. For cycle 1, participants will have 2 study visits. All other cycles, they will have 1 visit. At these visits, they will repeat the screening procedures. - Patients will keep a drug and diarrhea diary. - Patients on cediranib will monitor their blood pressure and keep a blood pressure diary. - Participants who can become pregnant, or have a partner who can become pregnant, must practice an effective form of birth control. - After 12 cycles, participants will have 1-3 months of follow-up.

NCT02484404
Conditions
  1. Colorectal Neoplasms
  2. Breast Neoplasms
Interventions
  1. Drug: Olaparib
  2. Drug: Cediranib
  3. Drug: MEDI4736
MeSH:Neoplasms Colorectal Neoplasms Breast Neoplasms
HPO:Breast carcinoma Neoplasm Neoplasm of the breast Neoplasm of the large intestine

PHASE II MEDI4736 PLUS OLAPARIB OR CEDIRANIB STUDY ELIGIBILITY CRITERIA - NON-SMALL CELL LUNG CANCER - Histologically or cytologically confirmed advanced NSCLC with at least one prior line of platinum-based chemotherapy (or treatment with EGFR, ALK, or BRAF-targeted tyrosine kinase inhibitors if tumors harbor an EGFR-sensitizing mutation, ALK translocation, or BRAF V600E mutation, respectively). --- V600E ---

Primary Outcomes

Description: Determination of the recommended phase II dose (RP2D) Safety: number of Adverse events

Measure: Ph I Determine the recommended phase II dose (RP2D) and the safety of doublet therapies of MEDI4736/olaparib (MEDI-O) and MEDI4736/cediranib (MEDI-C) in patients with advanced solid tumors

Time: 28 Days

Description: Overall response rate

Measure: Ph II Determine overall response rate of MED-O and MEDI-C in patients with recurrent ovarian cancer

Time: Every 4 wks for Toxicity and every 8 wks for response

Secondary Outcomes

Description: Safety: number of Adverse events

Measure: Ph I doublet tx: determin the safety of the doublets, MEDI+O and MEDI+C

Time: every 28 days

Description: Response : Preliminary response rate

Measure: Ph I doublet tx:determine preliminary response rates of the doublets using RECIST v1.1

Time: every 8 weeks

Description: Pharmacokinetics + Safety: adverse events

Measure: Ph I doublet tx: determine the pharmacokinetics of the doublets and correlate with safety.

Time: Cycle 1 Days 1 and 15; Cycles 2 and beyond Day 1

Description: Correlative laboratory research results + safety (adverse events) and/or clinical outcome

Measure: Ph I doublet tx: explore changes in peripheral immune subsets, plasma cytokines and circulating endothelial cells with safety and/or clinical outcome of MEDI+C

Time: every 28 days

Description: PD-L1 expression obtained from archival tissue samples and clinical response

Measure: Ph I doublet:determine the potential relationship between PD-L1 expression obtained from archival tissue samples and clinical response

Time: every 28 days

Description: Safety (adverse events)

Measure: Ph I of triplet tx: determine the safety of MEDI+O+C

Time: every 28 days

Description: Response: Preliminary response rate

Measure: Ph I of triplet tx: determine preliminary response rates of MEDI+O+C using RECIST v1.1

Time: every 8 weeks

Description: Pharmacokinetics + Safety: adverse events

Measure: Ph I of triplet tx:determine the pharmacokinetics of the triplet and correlate with safety.

Time: Cycle 1 Days 1 and 15; Cycles 2 and beyond Day 1

Description: Correlative laboratory research results + safety (adverse events) and/or clinical outcome

Measure: Ph I of triplet tx: explore changes in peripheral immune subsets, plasma cytokines and circulating endothelial cells with safety and/or clinical outcome of MEDI+O+C

Time: every 28 days

Description: PD-L1 expression obtained from archival tissue samples and clinical response

Measure: Ph I of triplet tx: determine the potential relationship between PD-L1 expression obtained from archival tissue samples and clinical response

Time: every 28 days

Description: Progression-Free Survival (PFS) + safety (adverse events) + PD-L1 expression ontained from biopsies and clinical response

Measure: Ph II Cohort 1 OvCa; MEDI+O, MEDI+C and MEDI+O+C arms: To evaluate PFS, safety by CTCAE v4.0, and potential relationship between pretreatment tumor PD-L1 expression obtained from biopsies and clinical response

Time: every 28 days, every 8 weeks

Description: ORR + Safety (adverse events)

Measure: Ph II Cohort 2 NSCLC; MEDI+O and MEDI+C arms: To determine ORR, and safety by CTCAE v4.0

Time: every 28 days, every 8 weeks

Description: PFS + Safety (adverse events)

Measure: Ph II Cohort 3 SCLC; MEDI+O arm: To determine PFS and safety by CTCAE v4.0

Time: every 28 days, every 8 weeks

Description: ORR + safety (adverse events), duration of response and PSA responses.

Measure: Ph II Cohort 4 mCRPC; MEDI+O arm: To determine ORR, safety by CTCAE v4.0, duration of response and PSA responses.

Time: every 28 days, every 8 weeks

Description: ORR + safety (adverse events)

Measure: Ph II Cohort 5 TNBC; MEDI+O arm: To determine PFS, safety by CTCAE v4.0, and potential relationship between pretreatment tumor PD-L1 expression obtained from biopsies and clinical response

Time: every 28 days, every 8 weeks

256 A Phase I, Open-label, Excretion Balance, Pharmacokinetic and Metabolism Study After Single Oral Dose of 14C-labeled RO5185426 in Previously Treated and Untreated Patients With Metastatic Melanoma

This open-label, non-randomized study will assess the mass balance, metabolism, routes and rates of elimination as well as efficacy and safety of RO5185426 (RG7204; PLEXXIKON; PLX4032) in previously treated or untreated patients with metastatic melanoma. Patients will receive continuous twice daily oral treatment with RO5185426. On Day 15, a 14C-labeled dose will be administered. Anticipated time on study treatment is until disease progression occurs.

NCT01164891
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: RO5185426
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Malignant Melanoma Melanoma null --- V600E ---

Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) - Prior treatment for metastatic melanoma allowed; >/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug - Positive BRAF V600E mutation result (by Roche CoDx test) - ECOG performance status 0-1 - Adequate hematologic, renal and liver function - Body Mass Index (BMI) 18 to 32 kg/m2 inclusive Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression, or carcinomatous meningitis - Anticipated or ongoing administration of any anticancer therapies other than those administered in this study - Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug - Known clinically significant active infection - Known HIV positivity or AIDS-related illness, active HBV, or active HCV - Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix - Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration - Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426 Malignant Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Measure: Plasma RO5185426 Trough Concentrations on Days 15,16, and 17

Time: Pre-dose on Days 15, 16 and 17

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1 millisieverts (mSv).

Measure: Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: Time to Reach Cmax in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1mSv.

Measure: Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUClast) of 14C-RO5185426 in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: Half-life of 14C-labeled RO5185426 in Both Blood and Plasma

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: AUC Ratio of Blood:Plasma 14C-labeled RO5185426

Time: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Description: Urinary and fecal samples were analyze for the percentage dose recovered as total radioactivity. The radioactivity was determined on a Packard liquid scintillation counter. Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Measure: 14C-labeled RO5185426 Recovery: Percentage of Dose Excreted in Feces and Urine

Time: Urine:0 hour (pre dose),in quantitative fraction(0-6,6-12,12-24 hours) post dose on Day 15,during 24 hour interval thereafter;Feces:From Day 14 upto pre dose on Day 15,during 24 hour interval post dose until recovery criterion;(maximum:432 hours for both)

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.

Measure: Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite

Time: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15

Description: Collection of samples for radioactivity continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48 hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). The concentrations were measured in nanogram equivalent per gram which was calculated based on ratio of dosed radioactivity and the last dose of RO5185426. The concentration values represented the drug portion of the last dose. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.

Measure: Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels

Time: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over two time intervals for this analysis (0-24 + 24-48 hours, 48-72 + 72-96 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, and glucuronide) are reported.

Measure: Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite

Time: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over 2 time intervals (0-24 + 24-48 hours, 48-72 + 72-96 hours) for measurement of 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, glucuronide) levels.

Measure: Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples

Time: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples), Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.

Measure: Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite

Time: 0 up to 96 hours post dose on Day 15

Description: Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples). Data for parent drug (RO5185426) and metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.

Measure: Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples

Time: 0 up to 96 hours post dose on Day 15

Secondary Outcomes

Description: Best overall response (according to Response Evaluation Criteria In Solid Tumors 1.1 criteria) was defined as best response recorded from start of treatment until disease progression which included complete response (CR) or partial response (PR) that had been confirmed by second tumor assessment no less than (<) 4 weeks after criteria for response were first met. Confirmed CR: disappearance of all target and non-target lesions; no new lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeters (mm). Confirmed PR: at least 30% decrease in sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression: at least 20% increase in sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions.

Measure: Number of Participants With a Response by Confirmed Best Overall Response

Time: From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until disease progression, withdrawal from study or death (maximum 841 days)

Description: Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.

Measure: Overall Survival

Time: From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until death (maximum 841 days)

257 Phase II Trial of mTOR Inhibitor Temsirolimus Combined With MEK Inhibitor AZD 6244 in Patients With BRAF Mutant Stage IV Melanoma

The purpose of this study is to find out how often two investigational drugs that are given together will shrink the patient's tumor and how well they will prolong the time it takes their tumor to grow. The investigators also wish to find out how they affect certain substances in the patient's tumor and in their blood important for tumor growth. The combination of these drugs is experimental, and has not been proven to help treat melanoma

NCT01166126
Conditions
  1. Mucosal Melanoma
  2. Recurrent Melanoma
  3. Stage IV Melanoma
Interventions
  1. Drug: temsirolimus
  2. Drug: selumetinib
  3. Other: laboratory biomarker analysis
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma PRIMARY OBJECTIVES: I. To determine the clinical response rate (Response Evaluation Criteria in Solid Tumors [RECIST]) and one-year overall survival to the study drugs temsirolimus and AZD6244 (selumetinib) hydrogen sulfate in BRAF V600E mutant unresectable stage IV melanoma. --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma PRIMARY OBJECTIVES: I. To determine the clinical response rate (Response Evaluation Criteria in Solid Tumors [RECIST]) and one-year overall survival to the study drugs temsirolimus and AZD6244 (selumetinib) hydrogen sulfate in BRAF V600E mutant unresectable stage IV melanoma. --- V600E --- --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma PRIMARY OBJECTIVES: I. To determine the clinical response rate (Response Evaluation Criteria in Solid Tumors [RECIST]) and one-year overall survival to the study drugs temsirolimus and AZD6244 (selumetinib) hydrogen sulfate in BRAF V600E mutant unresectable stage IV melanoma. --- V600E --- --- V600E --- --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma PRIMARY OBJECTIVES: I. To determine the clinical response rate (Response Evaluation Criteria in Solid Tumors [RECIST]) and one-year overall survival to the study drugs temsirolimus and AZD6244 (selumetinib) hydrogen sulfate in BRAF V600E mutant unresectable stage IV melanoma. --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Inclusion Criteria: - Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained - Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma) - Tumor must be BRAF V600E mutation positive from a certified lab - At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment) - Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period - Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration - Life expectancy >= 3 months - ECOG performance status of 0 or 1 - Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible - WBC >= 3000 cells/mm^3 - ANC >= 1500 cells/mm^3 - Platelets >= 100,000/mm^3 - Hematocrit >= 30% - Hemoglobin >= 9 g/dL - Creatinine =< 2.0 mg/dL - AST/ALT =< 2 x ULN - Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL) - HIV negative - HBsAg negative - Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR - Patients with hyperlipidemia must have adequate control with a lipid lowering agent Exclusion Criteria: - Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years - Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded - Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed - Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events - Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor - Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe - Tumor that is BRAF V600E mutation negative Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma PRIMARY OBJECTIVES: I. To determine the clinical response rate (Response Evaluation Criteria in Solid Tumors [RECIST]) and one-year overall survival to the study drugs temsirolimus and AZD6244 (selumetinib) hydrogen sulfate in BRAF V600E mutant unresectable stage IV melanoma. --- V600E --- --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: Anti-tumor response (CR+PR) was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Number of Participants With Complete Response (CR) and Partial Response (PR)

Time: 1 year

Description: The one-year overall survival of the combination of temsirolimus and AZD6244 Hydrogen Sulfate.

Measure: Number of Participants With Overall Survival (OS) at One Year

Time: 1 year post last treatment

Secondary Outcomes

Description: Patients will be evaluated by physical examination and imaging assessments (brain MRI and CT scans of the chest, abdomen and pelvis). Disease progression will be defined by RECIST criteria on physical exam or diagnostic imaging assessments that are attributed to metastatic melanoma. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Measure: Number of Participants With Progression Free Survival (PFS) at 6 Months.

Time: 6 months from day 1 of treatment

Description: Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.

Measure: Number of Participants With Related Serious Adverse Events (SAEs)

Time: 1 year

258 Kinetics of Perioperative Circulating DNA in Cancer Surgery

The aim of this study was to determine the kinetics of perioperative circulating DNA in three types of cancer. This first step will enable further studies comparing the potential impact of certain techniques or anesthetic products on cancer surgery.

NCT03284684
Conditions
  1. Breast Cancer
  2. Prostate Cancer
  3. Colon Cancer
Interventions
  1. Other: Blood test
MeSH:Colonic Neoplasms
HPO:Colon cancer Neoplasm of the colon

Change in plasma concentration of BRAF DNA fragments with V600E mutation. --- V600E ---

Primary Outcomes

Description: ng/mL in plasma

Measure: Change in concentration of total mutant circulating DNA

Time: Nine timepoints between Day-1 to Day 3

Description: ng/mL in plasma

Measure: Change in proportion of mutant circulating DNA

Time: Nine timepoints between Day-1 to Day 3

Description: concentration of long ACTB ctDNA fragments/concentration of short ACTB ctDNA fragments

Measure: Change in integrity index of circulating DNA for ACTB gene

Time: Nine timepoints between Day-1 to Day 3

Description: concentration of long KRAS ctDNA fragments/concentration of short KRAS ctDNA fragments

Measure: Change in integrity index of circulating DNA for KRAS gene

Time: Nine timepoints between Day-1 to Day 3

Secondary Outcomes

Description: ng/mL in plasma

Measure: Change in plasma concentration of long (~ 290bp) fragments of ACTB gene

Time: Nine timepoints between Day-1 to Day 3

Description: ng/mL in plasma

Measure: Change in plasma concentration of short (~ 145bp) fragments of KRAS gene

Time: Nine timepoints between Day-1 to Day 3

Description: ng/mL in plasma

Measure: Change in plasma concentration of long (~ 300bp) fragments of KRAS gene

Time: Nine timepoints between Day-1 to Day 3

Description: ng/mL in plasma

Measure: Change in plasma concentration of mutant KRAS DNA fragments

Time: Nine timepoints between Day-1 to Day 3

Description: ng/mL in plasma

Measure: Change in plasma concentration of BRAF DNA fragments with V600E mutation

Time: Nine timepoints between Day-1 to Day 3

259 A Randomized, Phase 2, Double-blind Study to Evaluate the Efficacy of Dostarlimab Plus Chemotherapy Versus Pembrolizumab Plus Chemotherapy in Metastatic Non-Squamous Non-Small Cell Lung Cancer

NSCLC comprises of approximately 84 percent (%) of all lung cancers and is often diagnosed at advanced stage due to poor prognosis. Dostarlimab is an immunoglobulin G (IgG)4 kappa humanized monoclonal antibody (mAb) that binds with high affinity to programmed cell death protein 1 (PD 1), resulting in inhibition of binding to programmed death ligand 1 (PD L1) and programmed death ligand 2 (PD L2). This study aims to compare the efficacy and safety PD-1 inhibitors dostarlimab and pembrolizumab, when administered in combination with chemotherapy (pemetrexed, cisplatin and carboplatin), in participants with non-squamous NSCLC without a known sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or receptor tyrosine kinase-1 (ROS-1) mutation, BRAF V600E mutation, or other genomic aberration for which an approved targeted therapy is available. A total of approximately 240 participants will be enrolled in the study for a period of 5 years.

NCT04581824
Conditions
  1. Lung Cancer, Non-Small Cell
Interventions
  1. Drug: Dostarlimab
  2. Drug: Pembrolizumab
  3. Drug: Chemotherapy
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

This study aims to compare the efficacy and safety PD-1 inhibitors dostarlimab and pembrolizumab, when administered in combination with chemotherapy (pemetrexed, cisplatin and carboplatin), in participants with non-squamous NSCLC without a known sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or receptor tyrosine kinase-1 (ROS-1) mutation, BRAF V600E mutation, or other genomic aberration for which an approved targeted therapy is available. --- V600E ---

Primary Outcomes

Description: ORR will be evaluated by RECIST v1.1 based on blinded independent central review (BICR) and will be defined as the proportion of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) in the analysis population.

Measure: Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1).

Time: Up to 5 years

Secondary Outcomes

Description: OS is defined as the time from the date of randomization to the date of death by any cause.

Measure: Overall survival (OS)

Time: Up to 5 years

Description: PFS will be evaluated using RECIST v1.1 based on Investigator assessment and is defined as the time from the date of randomization to the date of progressive disease (PD) or death by any cause, whichever occurs first.

Measure: Progression free survival (PFS) by RECIST v1.1

Time: Up to 5 years

Description: A TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment.

Measure: Number of participants with treatment-emergent adverse events (TEAEs)

Time: Up to 5 years

Description: An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is an important medical event that may jeopardize the participant or may require medical or surgical intervention to prevent one of the above outcomes

Measure: Number of participants with serious adverse events (SAEs)

Time: Up to 5 years

Description: The irAEs are events which may be severe or fatal and can occur in participants treated with monoclonal antibodies directed against immune checkpoints, including pembrolizumab and dostarlimab. While irAEs (eg, diarrhea/colitis, pneumonitis, nephritis, hypophysitis, adrenalitis, thyroiditis, severe skin reactions, uveitis, myocarditis, and hepatotoxicity) usually occur during treatment, symptoms can also manifest after discontinuation of treatment.

Measure: Number of participants with immune related adverse events (irAEs)

Time: Up to 5 years

Description: Number of participants with TEAEs leading to death will be assessed.

Measure: Number of participants with TEAEs leading to death

Time: Up to 5 years

Description: Number of participants with AELDs will be assessed.

Measure: Number of participants with adverse events leading to discontinuation (AELD)

Time: Up to 5 years

Description: Blood and urine samples will be collected to evaluate hematology, clinical chemistry, thyroid function and urinalysis lab parameters.

Measure: Number of participants with clinically significant changes in hematology, clinical chemistry, thyroid function and urinalysis lab parameters.

Time: Up to 5 years

Description: Number of participants with abnormal vital signs will be assessed.

Measure: Number of participants with abnormal vital signs

Time: Up to 5 years

Description: Performance status will be assessed using the ECOG scale (Grade 0-4). Grade 0 indicates fully active, able to carry on all pre-disease performance without restriction and Grade 4 indicates completely disabled, cannot carry on any self-care and totally confined to bed or chair.

Measure: Number of participants with abnormal Eastern Cooperative Oncology Group (ECOG) performance status

Time: Up to 5 years

Description: Participants will be supine or in a semi-recumbent position and rested for approximately 2 minutes before ECGs are recorded.

Measure: Number of participants with abnormal electrocardiogram (ECG) parameters

Time: Up to 5 years

Description: Physical examination will include assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight will also be measured and recorded.

Measure: Number of participants with abnormal physical examination

Time: Up to 5 years

Description: Concomitant medications will be recorded.

Measure: Number of participants receiving concomitant medications

Time: Up to 5 years

260 BRIM 3: A Randomized, Open-Label, Controlled, Multicenter, Phase III Study in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma With V600E BRAF Mutation Receiving Vemurafenib (RO5185426) or Dacarbazine

This randomized, open-label study evaluated the efficacy, safety and tolerability of vemurafenib (RO5185426) as compared to dacarbazine in previously untreated patients with metastatic melanoma. Patients were randomized to receive either vemurafenib 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Study treatment was continued until disease progression or unacceptable toxicity occurred. The data and safety monitoring board recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib, and the protocol was amended accordingly on January 14, 2011, as both overall survival and progression-free survival endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib.

NCT01006980
Conditions
  1. Malignant Melanoma
Interventions
  1. Drug: Vemurafenib
  2. Drug: Dacarbazine
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

BRIM 3: A Randomized, Open-Label, Controlled, Multicenter, Phase III Study in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma With V600E BRAF Mutation Receiving Vemurafenib (RO5185426) or Dacarbazine. --- V600E ---

The pharmacokinetics of vemurafenib were assessed at the beginning of each 21-day cycle using pre-dose and 2-4 hours post-dose sampling.. Inclusion Criteria: - adults, >/=18 years of age - metastatic melanoma, stage IIIC or IV (AJCC) - treatment-naïve (no prior systemic anticancer therapy) - positive for BRAF V600E mutation - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active central nervous system metastases - history of carcinomatous meningitis - severe cardiovascular disease within 6 months prior to study drug administration - previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix Inclusion Criteria: - adults, >/=18 years of age - metastatic melanoma, stage IIIC or IV (AJCC) - treatment-naïve (no prior systemic anticancer therapy) - positive for BRAF V600E mutation - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active central nervous system metastases - history of carcinomatous meningitis - severe cardiovascular disease within 6 months prior to study drug administration - previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix Malignant Melanoma Melanoma null --- V600E ---

The pharmacokinetics of vemurafenib were assessed at the beginning of each 21-day cycle using pre-dose and 2-4 hours post-dose sampling.. Inclusion Criteria: - adults, >/=18 years of age - metastatic melanoma, stage IIIC or IV (AJCC) - treatment-naïve (no prior systemic anticancer therapy) - positive for BRAF V600E mutation - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active central nervous system metastases - history of carcinomatous meningitis - severe cardiovascular disease within 6 months prior to study drug administration - previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix Inclusion Criteria: - adults, >/=18 years of age - metastatic melanoma, stage IIIC or IV (AJCC) - treatment-naïve (no prior systemic anticancer therapy) - positive for BRAF V600E mutation - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active central nervous system metastases - history of carcinomatous meningitis - severe cardiovascular disease within 6 months prior to study drug administration - previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix Malignant Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Description: An Overall survival event was defined as death due to any cause. The number of participants with overall survival events is reported.

Measure: Overall Survival

Time: From randomization (initiated January 2010) to December 30 2010. Median follow-up time in the vemurafenib group was 3.75 months (range 0.3 to 10.8) and in the dacarbazine group was 2.33 months (range <0.1 to 10.3).

Description: A progression-free survival (PFS) event was defined as disease progression or death due to any cause. Tumor response (progression) was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria using computed tomography (CT) scans or magnetic resonance imaging (MRI).

Measure: Progression-free Survival

Time: From randomization (initiated January 2010) to December 30 2010.

Secondary Outcomes

Description: BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Participants who never received study treatment and treated participants without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion and no new lesion.

Measure: Participants With a Best Overall Response (BOR) of Complete Response or Partial Response

Time: From randomization (initiated January 2010) until December 30, 2010

Description: Duration of response was defined as the time between the date of the earliest qualifying response and the date of disease progression or death due to any cause. Duration of response was calculated only for participants who had a best overall response of Complete Response or Partial Response and was estimated using the Kaplan-Meier method.

Measure: Duration of Response

Time: From randomization (initiated in January 2010) until December 30, 2010.

Description: Time to response was defined as the time from randomization to confirmed response (complete response or partial response).

Measure: Time to Confirmed Response

Time: From randomization (initiated January 2010) until December 30, 2010.

Description: Treatment failure was defined as a secondary endpoint in the protocol, defined as death, disease progression or premature withdrawal of study treatment. This endpoint was not included in the Statistical analysis plan; therefore no analyses of time to treatment failure were performed.

Measure: Time to Treatment Failure

Time: approximately 3 years

Description: The intensity of AEs was graded according to the NCI Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a five-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening and Death). A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution, for example is life-threatening, requires hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or requires intervention to prevent one or other of the outcomes listed above.

Measure: Number of Participants With Adverse Events (AEs)

Time: From randomization (initiated January 2010) until December 30, 2010.

Description: The pharmacokinetics of vemurafenib were assessed at the beginning of each 21-day cycle using pre-dose and 2-4 hours post-dose sampling.

Measure: Pre and Post-dose Plasma Vemurafenib Concentration by Study Day

Time: Plasma samples were collected before the morning dose (troughs) and 2-4 hours after the morning dose at the beginning of each cycle (Days 1, 22, 43, 64, 106, 148 and 190).

261 Phase 2 Study Comparing Pembrolizumab With Intermittent/Short-term Dual MAPK Pathway Inhibition Plus Pembrolizumab in Patients Harboring the BRAFV600 Mutation

This is a Phase 2 trial consisting of 24 patients receiving the combination of dabrafenib + trametinib + pembrolizumab in 3 different dosing schemes and 8 patients receiving pembrolizumab standard monotherapy. All patients start with pembrolizumab standard therapy for 6 weeks and will then be randomized to continue pembrolizumab monotherapy or to receive additional intermitted/short-term dabrafenib + trametinib. Stratification will be baseline LDH level and baseline PD-L1 expression.

NCT02625337
Conditions
  1. Metastatic Melanoma
Interventions
  1. Drug: Pembrolizumab
  2. Drug: Dabrafenib
  3. Drug: Trametinib
  4. Procedure: Biopsy
  5. Procedure: Blood taking
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

In addition to the primary readout (broadening of the melanoma-specific T cell response in peripheral blood), we will analyze the effect of the different therapy schemes on tumor immune cell infiltration (IHC for CD3, CD4, CD8, CD68, FoxP3, PD-L1, PD-L2, PD-1, CD11b, HLA).. Inclusion Criteria: - Adults at least 18 years of age - World Health Organization (WHO) Performance Status 0-2 - Histologically/cytologically confirmed stage IV BRAF V600E or K metastatic melanoma - Measurable disease according to RECIST 1.1 - At least one easy accessible lesion (s.c., lymph node) that can be repeatedly biopsied - Patient willing to undergo triple tumor biopsies during screening, at week 6, week 8 (cohorts 2-4 only), week 12, at week 18, and in case of disease progression. --- V600E ---

Inclusion Criteria: - Adults at least 18 years of age - World Health Organization (WHO) Performance Status 0-2 - Histologically/cytologically confirmed stage IV BRAF V600E or K metastatic melanoma - Measurable disease according to RECIST 1.1 - At least one easy accessible lesion (s.c., lymph node) that can be repeatedly biopsied - Patient willing to undergo triple tumor biopsies during screening, at week 6, week 8 (cohorts 2-4 only), week 12, at week 18, and in case of disease progression. --- V600E ---

Primary Outcomes

Description: Safety as measured by SUSARs during treatment week 0 till week 18.

Measure: Safety of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by SUSARs.

Time: 18 weeks from baseline

Description: Feasibility as measured by adherence to the timelines in the study protocol (week 0 till week 18).

Measure: Feasibility of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by adherence to the timelines in the study protocol.

Time: 18 weeks from baseline.

Description: Readout will be the alterations in magnitude or breadth of the self-antigen specific T cell responses in the time interval pre-treatment to week 18 intrapatient, and interpatient, pembrolizumab only (cohort 1) versus pembrolizumab plus intermittent dabrafenib/ trametinib (cohorts 2-4). To this purpose, we will analyze melanoma antigen-specific T cells responses by HLA-A2-restricted MHC-tetramer staining.

Measure: The immune-activating capacity of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy

Time: 18 weeks from baseline.

Secondary Outcomes

Description: Rates of response at week 6, week 12, week 18 according to RECIST 1.1 criteria

Measure: To determine rates of response at week 6, 12, week 18.

Time: Screening, week 6, 12 and 18

Description: Progression-free survival (PFS) starting from randomization to progression using RECIST 1.1 criteria.

Measure: To determine progression-free survival starting from randomization.

Time: From randomisation until PD, median 10 months.

Description: Rate and type of late adverse events

Measure: Long-term toxicities of intermittent dabrafenib + trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy

Time: From beyond week 18, up to 2 years follow-up.

Other Outcomes

Description: As the short addition of dabrafenib+trametinib will induce for short time tumor regressions we will analyze cohorts 2-4 with a second baseline, namely the end of the targeted therapy at week 12, for progression free survival using to RECIST 1.1

Measure: To describe time to progression beginning from week 12 (cohorts 2-4).

Time: Randomisation until week 12.

Description: In addition to the primary readout (broadening of the melanoma-specific T cell response in peripheral blood), we will analyze the effect of the different therapy schemes on tumor immune cell infiltration (IHC for CD3, CD4, CD8, CD68, FoxP3, PD-L1, PD-L2, PD-1, CD11b, HLA).

Measure: Changes of immune parameters within the tumor.

Time: 18 weeks from baseline.

262 A Three Arms Prospective, Randomized Phase II Study to Evaluate the Best Sequential Approach With Combo Immunotherapy (Ipilimumab/Nivolumab) and Combo Target Therapy (LGX818/MEK162) in Patients With Metastatic Melanoma and BRAF Mutation

To evaluate the best sequencing approach with the combination of target agents (LGX818 plus MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in patients with metastatic melanoma and BRAF V600 mutation.

NCT02631447
Conditions
  1. Metastatic Melanoma
Interventions
  1. Drug: LGX818
  2. Drug: MEK162
  3. Drug: Nivolumab
  4. Drug: Ipilimumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

4. Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria; 5. Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment; 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; 7. Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E ---

Primary Outcomes

Description: OS is defined as the time between the date of randomization and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive. OS data will be collected continuously while subjects are on study medication and every 3 months via in-person or phone contact after discontinuation of study medication

Measure: Overall Survival

Time: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

Secondary Outcomes

Description: PFS is defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Tumor responses will be assessed by the Investigator according to RECIST Criteria (version 1.1)

Measure: Total Progression free survival

Time: Baseline (Day 1), every 6 weeks until second disease progression is documented (Approximately around 2 years)

Description: Percentage of patients alive at 2 and 3 years will be reported using Wilson score intervals.

Measure: Percentage of patients alive at 2 and 3 years;

Time: Time Frame: at 24^ and 36^ month

Description: It will be calculated as the percentage of ITT population patients who have a CR o o PR before any evidence of progression (as defined by RECIST).

Measure: Best overall response rate (BORR);

Time: Time Frame: up to 24 months

Description: It will be calculated as the percentage of ITT population patients who have a CR o o PR before any evidence of progression (as defined by RECIST).

Measure: Duration of response (DoR);

Time: Time Frame: up to 24 months

Description: Safety and tolerability will be assessed in terms od AEs, laboratory data, ECG data, vitals signs and weight, which will be collected for all patients. AEs (both in terms od MedDRA preferred terms and CTCAE grade), laboratory data, ECG data, vital signs and weight will be listes individually by patient and summarized by treatment received. ECG changes will be summarized for each treatment group.

Measure: Toxicity of the investigational medicinal products (IMPs).

Time: Time Frame: up to 24 months

Description: Changes from baseline in EQ-5D and QLQ-C30 total score will be summarized by means of descriptive statistical methods.

Measure: Quality of life and general health

Time: Time Frame: up to 24 months

Description: 3 years PFS rate; calculated from the date of randomization;

Measure: 3 years PFS rate

Time: Time Frame: up to 36 months

263 A Phase II (BRF113710) Single-arm, Open-label Study of GSK2118436 in BRAF Mutant Metastatic Melanoma

BRF113710 is a Phase II, single-arm, open-label study to assess the efficacy, safety, and tolerability of GSK2118436 administered twice daily as a single agent in subjects with BRAF mutant metastatic melanoma. Subjects will receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.

NCT01153763
Conditions
  1. Melanoma
Interventions
  1. Drug: GSK2118436
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) as Assessed by the Investigator for Participants Who Had a BRAF V600E Mutation. --- V600E ---

The analysis was performed on Primary efficacy Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600E mutation.. Number of Participants With a Best Overall Response of CR or PR as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation. --- V600E ---

The analysis was performed on Secondary efficacy analysis Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600K mutation.. Progression-free Survival (PFS) as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600E Mutation. --- V600K --- --- V600E ---

For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.. Duration of Response as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600E Mutation. --- V600E ---

The analysis was performed on Secondary efficacy Population and only those participants who had a CR or PR were analyzed.. Overall Survival for Participants Who Had a BRAF V600E Mutation. --- V600E ---

One participant out of the 92 participants (76 BRAF V600E patients + 16 BRAF V600K patients) did not have SBP and DBP collected after baseline.. Number of Participants With Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Levels. --- V600E ---

Primary Outcomes

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeter (mm) in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment was required at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later were required to be confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Primary efficacy Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600E mutation.

Measure: Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) as Assessed by the Investigator for Participants Who Had a BRAF V600E Mutation

Time: Up to 60 months

Secondary Outcomes

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment had to have been performed at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later should have been confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Secondary efficacy analysis Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600K mutation.

Measure: Number of Participants With a Best Overall Response of CR or PR as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation

Time: Up to 60 months

Description: PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent confidence interval (CI). For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.

Measure: Progression-free Survival (PFS) as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600E Mutation

Time: Up to 60 months

Description: PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent CI. For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.

Measure: Progression-free Survival (PFS) as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation

Time: Up to 60 months

Description: Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Primary efficacy Population and only those participants who had a CR or PR were analyzed.

Measure: Duration of Response as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600E Mutation

Time: Up to 60 months

Description: Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Secondary efficacy Population and only those participants who had a CR or PR were analyzed.

Measure: Duration of Response as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation

Time: Up to 60 months

Description: Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using kaplan-Meier model and median and 95 percent CI was presented.

Measure: Overall Survival for Participants Who Had a BRAF V600E Mutation

Time: Up to 60 months

Description: Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using Kaplan-Meier model and median and 95 percent CI was presented.

Measure: Overall Survival for Participants Who Had a BRAF V600K Mutation

Time: From the first dose to death due to any cause (up to 60 months)

Description: An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs including systemic allergic and non-allergic reactions as well as local site injection-related reactions were counted throughout treatment phase and follow up phase. Systemic allergic reactions included facial paralysis, flushing, hypersensitivity and rash pruritic. Injection related reactions were considered as systemic non-allergic reactions. Local site reactions included injection site bruising, erythema, pain and reaction. The analysis was performed on All treated Population which comprised of all participants that receive at least one dose of dabrafenib.

Measure: Number of Participants With AEs and Serious Adverse Events (SAEs)

Time: Up to 60 months

Description: Blood samples were collected from participants for evaluation of change from Baseline in toxicity grades in clinical chemistry and hematology parameters. The clinical chemistry parameters included alkaline phosphatase, Alanine amino transferase (ALT), Aspartate amino transferase (AST), total bilirubin, creatinine, glucose, potassium, magnesium, sodium and phosphorus. The hematology parameters included hemoglobin, total neutrophils, platelets and white blood cells (WBC). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst case post-baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Measure: Number of Participants With Change From Baseline in Clinical Chemistry and Hematology Toxicity Grades

Time: Up to 60 months

Description: Number of participants with change from Baseline in temperature and pulse rate were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as decrease to <=35, change to normal or no change and increase to >=38. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst case post-baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.

Measure: Number of Participants With Change From Baseline in Temperature and Pulse Rate

Time: Up to 60 months

Description: Number of participants with increase from Baseline in SBP and DBP were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as any increase to >=80 and increase to >=100 for DBP and as any increase to >=120 and increase to >=160 for SBP. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. One participant out of the 92 participants (76 BRAF V600E patients + 16 BRAF V600K patients) did not have SBP and DBP collected after baseline.

Measure: Number of Participants With Increase From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Time: Up to 60 months

Description: LVEF was defined as the percentage of blood pumped out of the left ventricle. Change from Baseline in worst-case post Baseline was presented as no change or any increase and any decrease values. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.

Measure: Number of Participants With Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Levels

Time: Up to 60 months

264 A Phase 1 / 2 Open Label, Multi-Arm, Multicenter Study of MK-1308 in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors

This study will assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of escalating doses of quavonlimab when used in combination with pembrolizumab in participants with advanced solid tumors.

NCT03179436
Conditions
  1. Advanced Solid Tumors
Interventions
  1. Biological: Quavonlimab
  2. Biological: Pembrolizumab
  3. Drug: Pembrolizumab/Quavonlimab
  4. Drug: cisplatin
  5. Drug: carboplatin
  6. Drug: pemetrexed
  7. Drug: nab-paclitaxel
  8. Drug: paclitaxel
MeSH:Neoplasms
HPO:Neoplasm

Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions - Participants with unresectable Stage III or IV disease must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies (combinations with anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4] agents will not be allowed) - Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of Stage III or IV melanoma and have disease recurrence (unresectable loco-regional disease or distant metastases) while on active treatment or within 6 months of stopping anti-PD-1 are eligible - Have submitted pre-trial imaging and provided a baseline tumor sample - Proto-oncogene B-raf (BRAF) V600 mutation-positive melanoma participants should have received targeted therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, alone or in combination) prior to enrolling on this study; however, they are not required to progress on this treatment prior to enrollment - BRAF V600E mutation-positive melanoma participants who have NOT received a BRAF inhibitor (either as adjuvant therapy or in the metastatic disease setting) with lactate dehydrogenase (LDH) < local upper limit of normal (ULN), no clinically significant tumor-related symptoms, and absence of rapidly progressing metastatic melanoma. --- V600E ---

Primary Outcomes

Description: DLTs will be assessed during the first 6 weeks (2 cycles) of treatment for the Dose Escalation and the first 3 weeks (1 cycle) of treatment for the Dose Confirmation. DLT is defined as toxicity that is possibly, probably, or definitely related to study therapy and may result in a change in the given dose. DLTs include Grade (Gr)4 non-hematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days (except thrombocytopenia); most non-hematologic AEs ≥ Gr 3 in severity; any Gr 3 or Gr 4 non-hematologic laboratory value that requires clinically significant medical intervention, leads to hospitalization, persists for >1 week, or results in a drug-induced liver injury; Gr 3 or Gr 4 febrile neutropenia; a prolonged delay in initiating Cycle 2 or 3 of Dose Escalation or Cycle 2 of Dose Confirmation due to treatment-related toxicity; any treatment-related toxicity that causes the participant to discontinue treatment during the DLT observation period, and Gr 5 toxicity.

Measure: Number of participants with a Dose Limiting Toxicity (DLT)

Time: Up to 6 weeks

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Measure: Number of participants with ≥1 adverse event (AE)

Time: Up to approximately 2.5 years

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Measure: Number of participants discontinuing study treatment due to an AE

Time: Up to approximately 2 years

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Measure: Coformulation Phase: Number of participants with ≥1 AE

Time: Up to approximately 2.5 years

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Measure: Coformulation Phase: Number of participants discontinuing study treatment due to an AE

Time: Up to approximately 2 years

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Measure: Efficacy Expansion: Number of participants with ≥1 AE

Time: Up to approximately 2.5 years

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment

Measure: Efficacy Expansion: Number of participants discontinuing study treatment due to an AE

Time: Up to approximately 2 years

Description: ORR is defined as the percentage of participants in the analysis population whose best overall response (BOR) is confirmed complete response (CR) or partial response (PR) as assessed by BICR and based on imaging per modified RECIST 1.1. Tumor responses evaluated using modified RECIST 1.1 follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and require confirmation per RECIST 1.1. According to modified RECIST 1.1, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR according to modified RECIST 1.1 is at least a 30% decrease in the sum of diameters (SOD) of target lesions as assessed by the investigator, taking as reference the baseline SOD.

Measure: Efficacy Expansion: Objective Response Rate (ORR) as assessed by blinded independent central review (BICR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Time: Up to approximately 4 years

Description: DLTs will be assessed during the first 6 weeks of treatment for the Coformulation Phase for Arms I and L. A DLT is defined as toxicity that is possibly, probably, or definitely related to study therapy and may result in a change in the given dose. DLTs include Grade (Gr)4 non-hematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days (except thrombocytopenia); most non-hematologic AEs ≥ Gr 3 in severity; any Gr 3 or Gr 4 non-hematologic laboratory value that requires clinically significant medical intervention, leads to hospitalization, persists for >1 week, or results in a drug-induced liver injury; Gr 3 or Gr 4 febrile neutropenia; a prolonged delay in initiating Cycle 2 of the Coformulation Phase due to treatment-related toxicity; any treatment-related toxicity that causes the participant to discontinue treatment during the DLT observation period, and Gr 5 toxicity.

Measure: Coformulation Phase: Number of participants with ≥1 DLT

Time: Up to 6 weeks

Description: ORR is defined as the percentage of participants in the analysis population whose best overall response (BOR) is confirmed complete response (CR) or partial response (PR) as assessed by BICR and based on imaging per modified RECIST 1.1. Tumor responses evaluated using modified RECIST 1.1 follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and require confirmation per RECIST 1.1. According to modified RECIST 1.1, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR according to modified RECIST 1.1 is at least a 30% decrease in the sum of diameters (SOD) of target lesions as assessed by the investigator, taking as reference the baseline SOD.

Measure: Coformulation Phase: Objective Response Rate (ORR) as assessed by blinded independent central review (BICR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Time: Up to approximately 4 years

Secondary Outcomes

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of quavonlimab.

Measure: Dose Escalation: Area under the plasma concentration time curve (AUC) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 5, 9. Cycle length = 21 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of quavonlimab.

Measure: Dose Escalation: Minimum concentration (Cmin) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 5, 9. Pre-dose at Cycles 6, 7, and every 4 cycles after Cycle 9 up to 2 years. Cycle length = 21 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of quavonlimab.

Measure: Dose Escalation: Maximum concentration (Cmax) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 5, 9. Cycle length = 21 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of pembrolizumab.

Measure: Dose Escalation: Area under the plasma concentration time curve (AUC) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 2, 3, 5, 9. Cycle length = 21 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of pembrolizumab.

Measure: Dose Escalation: Minimum concentration (Cmin) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 2, 3, 5, 9. Pre-dose at Cycles 6, 7, and every 4 cycles after Cycle 9 up to 2 years. Cycle length = 21 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of pembrolizumab.

Measure: Dose Escalation: Maximum concentration (Cmax) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 2, 3, 5, 9. Cycle length = 21 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of quavonlimab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Dose Escalation: Quavonlimab anti-drug antibody levels

Time: Pre-dose at Cycles 1 through 9 and every 4 cycles up to 2 years. Cycle length = 21 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Dose Escalation: Pembrolizumab anti-drug antibody levels

Time: Pre-dose at Cycles 1 through 9 and every 4 cycles up to 2 years. Cycle length = 21 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of quavonlimab.

Measure: Dose Confirmation: Area under the plasma concentration time curve (AUC) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 4, and 8. Cycle length = 21 days. No post-dose samples for Cycles 2, 4, and 8 for Arms B, C, and D.

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of quavonlimab.

Measure: Dose Confirmation: Minimum concentration (Cmin) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 4, and 8. Pre-dose at Cycles 5, 6, and every 4 cycles after Cycle 8 up to 2 years. Cycle length = 21 days. No post-dose samples for Cycles 2, 4, and 8 for Arms B, C, and D.

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of quavonlimab.

Measure: Dose Confirmation: Maximum concentration (Cmax) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 4, and 8. Cycle length = 21 days. No post-dose samples for Cycles 2, 4, and 8 for Arms B, C, and D.

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of pembrolizumab.

Measure: Dose Confirmation: Area under the plasma concentration time curve (AUC) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 4, and 8. Cycle length = 21 days. No post-dose samples for Cycles 2, 4, and 8 for Arms B, C, and D.

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of pembrolizumab.

Measure: Dose Confirmation: Minimum concentration (Cmin) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 4, and 8. Pre-dose at Cycles 5, 6, and every 4 cycles after Cycle 8 up to 2 years. Cycle length = 21 days. No post-dose samples for Cycles 2, 4, and 8 for Arms B, C, and D.

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of pembrolizumab.

Measure: Dose Confirmation: Maximum concentration (Cmax) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 15) for Cycles 1, 2, 3, 4, and 8. Cycle length = 21 days. No post-dose samples for Cycles 2, 4, and 8 for Arms B, C, and D.

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of quavonlimab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Dose Confirmation: Quavonlimab anti-drug antibody levels

Time: Pre-dose at Cycles 1 through 9 and every 4 cycles up to 2 years. Cycle length = 21 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Dose Confirmation: Pembrolizumab anti-drug antibody levels

Time: Pre-dose at Cycles 1 through 9 and every 4 cycles up to 2 years. Cycle length = 21 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of quavonlimab.

Measure: Efficacy Expansion: Area under the plasma concentration time curve (AUC) of quavonlimab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of quavonlimab.

Measure: Efficacy Expansion: Minimum concentration (Cmin) of quavonlimab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of quavonlimab.

Measure: Efficacy Expansion: Maximum concentration (Cmax) of quavonlimab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of pembrolizumab.

Measure: Efficacy Expansion: Area under the plasma concentration time curve (AUC) of pembrolizumab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of pembrolizumab.

Measure: Efficacy Expansion: Minimum concentration (Cmin) of pembrolizumab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of pembrolizumab.

Measure: Efficacy Expansion: Maximum concentration (Cmax) of pembrolizumab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of quavonlimab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Efficacy Expansion: Quavonlimab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Efficacy Expansion: Pembrolizumab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. Cycle length = 42 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of quavonlimab.

Measure: Coformulation Phase: Area under the plasma concentration time curve (AUC) of quavonlimab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of quavonlimab.

Measure: Coformulation Phase: Minimum concentration (Cmin) of quavonlimab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of quavonlimab.

Measure: Coformulation Phase: Maximum concentration (Cmax) of quavonlimab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of pembrolizumab.

Measure: Coformulation Phase: Area under the plasma concentration time curve (AUC) of pembrolizumab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of pembrolizumab.

Measure: Coformulation Phase: Minimum concentration (Cmin) of pembrolizumab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of pembrolizumab.

Measure: Coformulation Phase: Maximum concentration (Cmax) of pembrolizumab

Time: Pre-dose Day 1 and post-dose Day 21 for Cycles 1 through 4. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of quavonlimab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Coformulation Phase: Quavonlimab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Coformulation Phase: Pembrolizumab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. Cycle length = 42 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of quavonlimab.

Measure: Japanese Cohort: Area under the plasma concentration time curve (AUC) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of quavonlimab.

Measure: Japanese Cohort: Minimum concentration (Cmin) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Pre-dose at every 4 cycles after Cycle 4 up to 2 years. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of quavonlimab.

Measure: Japanese Cohort: Maximum concentration (Cmax) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of pembrolizumab.

Measure: Japanese Cohort: Area under the plasma concentration time curve (AUC) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of pembrolizumab.

Measure: Japanese Cohort: Minimum concentration (Cmin) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Pre-dose at every 4 cycles after Cycle 4 up to 2 years. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of pembrolizumab.

Measure: Japanese Cohort: Maximum concentration (Cmax) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of quavonlimab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Japanese Cohort: Quavonlimab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. After Cycle 4 pre-dose for every 2 cycles up to 2 years. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Japanese Cohort: Pembrolizumab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. After Cycle 4 pre-dose for every 2 cycles up to 2 years. Cycle length = 42 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of quavonlimab.

Measure: Chinese Cohort: Area under the plasma concentration time curve (AUC) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of quavonlimab.

Measure: Chinese Cohort: Minimum concentration (Cmin) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Pre-dose at every 4 cycles after Cycle 4 up to 2 years. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of quavonlimab.

Measure: Chinese Cohort: Maximum concentration (Cmax) of quavonlimab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: AUC is the area under the plot of plasma concentration of drug against time after drug administration. Blood samples will be collected at multiple time points to assess the AUC of pembrolizumab.

Measure: Chinese Cohort: Area under the plasma concentration time curve (AUC) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points to assess the Cmin of pembrolizumab.

Measure: Chinese Cohort: Minimum concentration (Cmin) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Pre-dose at every 4 cycles after Cycle 4 up to 2 years. Cycle length = 42 days

Description: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points to assess the Cmax of pembrolizumab.

Measure: Chinese Cohort: Maximum concentration (Cmax) of pembrolizumab

Time: Pre- and post-dose at multiple time points (up to Day 21) for Cycles 1 through 4. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of quavonlimab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Chinese Cohort: Quavonlimab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. After Cycle 4 pre-dose for every 2 cycles up to 2 years. Cycle length = 42 days

Description: Blood samples will be collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The percentage of participants who develop anti- antibodies will be presented.

Measure: Chinese Cohort: Pembrolizumab anti-drug antibody levels

Time: Pre-dose Cycles 1 through 4 on Day 1. After Cycle 4 pre-dose for every 2 cycles up to 2 years. Cycle length = 42 days

Description: ORR is defined as the percentage of participants in the analysis population whose BOR is confirmed CR or PR as assessed by investigator and based on imaging per modified RECIST 1.1. Tumor responses evaluated using modified RECIST 1.1 follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and require confirmation per RECIST 1.1. According to modified RECIST 1.1, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR according to modified RECIST 1.1 is at least a 30% decrease in the SOD of target lesions as assessed by the investigator, taking as reference the baseline SOD.

Measure: Dose Escalation: Objective Response Rate (ORR) as assessed by investigator based on modified RECIST Version 1.1

Time: Up to approximately 4 years

Description: ORR is defined as the percentage of participants in the analysis population whose BOR is confirmed CR or PR as assessed by investigator and based on imaging per modified RECIST 1.1. Tumor responses evaluated using modified RECIST 1.1 follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and require confirmation per RECIST 1.1. According to modified RECIST 1.1, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR according to modified RECIST 1.1 is at least a 30% decrease in the SOD of target lesions as assessed by the investigator, taking as reference the baseline SOD.

Measure: Dose Confirmation: Objective Response Rate (ORR) as assessed by investigator based on modified RECIST Version 1.1

Time: Up to approximately 4 years

Description: ORR is defined as the percentage of participants in the analysis population whose BOR is confirmed CR or PR as assessed by investigator and based on imaging per modified RECIST 1.1. Tumor responses evaluated using modified RECIST 1.1 follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and require confirmation per RECIST 1.1. According to modified RECIST 1.1, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR according to modified RECIST 1.1 is at least a 30% decrease in the SOD of target lesions as assessed by the investigator, taking as reference the baseline SOD.

Measure: Coformulation: Objective Response Rate (ORR) as assessed by investigator based on modified RECIST Version 1.1

Time: Up to approximately 4 years

Description: DOR was defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first (for responders only).

Measure: Efficacy Expansion: Duration of Response (DOR) as assessed by BICR based on modified RECIST Version 1.1

Time: Up to approximately 4 years

Description: DOR was defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first (for responders only).

Measure: Coformulation: Duration of Response (DOR) as assessed by BICR based on modified RECIST Version 1.1

Time: Up to approximately 4 years

265 A Phase 3, Randomized, Double-blind Study of Encorafenib and Binimetinib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab in Participants With BRAF V600E/K Mutation-Positive Metastatic OR Unresectable Locally Advanced Melanoma

This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma.

NCT04657991
Conditions
  1. Melanoma
Interventions
  1. Drug: Encorafenib
  2. Drug: Binimetinib
  3. Drug: Pembrolizumab
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

A Phase 3, Randomized, Double-blind Study of Encorafenib and Binimetinib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab in Participants With BRAF V600E/K Mutation-Positive Metastatic OR Unresectable Locally Advanced Melanoma. --- V600E ---

Encorafenib and Binimetinib Plus Pembrolizumab Versus Pembrolizumab for V600E/K Positive Melanoma This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma. --- V600E ---

Encorafenib and Binimetinib Plus Pembrolizumab Versus Pembrolizumab for V600E/K Positive Melanoma This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma. --- V600E --- --- V600E ---

- ECOG performance status 0 or 1. - Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay (eg, US FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent), obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory. --- V600E ---

Melanoma Melanoma This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma. --- V600E ---

Primary Outcomes

Description: A DLT is defined as any adverse event or laboratory value that is assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring within the first 2 cycles of treatment.

Measure: Safety Lead In (SLI): Incidence of Dose Limiting Toxicities (DLTs)

Time: First 2 Cycles of Treatment (cycles are 21 days)

Description: PFS is defined as the time from the date of randomization to the first date of documented disease progression as determined by BICR assessment per RECIST 1.1 or death due to any cause, whichever occurs first.

Measure: Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR)

Time: Time from the date of randomization to the date of first documented disease progression, as determined by BICR assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks for 24 months)

Secondary Outcomes

Description: AEs, laboratory parameters, vital signs and cardiac abnormalities will be graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 4.03).

Measure: Safety Lead in (SLI) and Phase 3: Incidence and severity of Adverse Events (AEs) and changes in clinical laboratory parameters, vital signs, and cardiac assessments.

Time: Time from first dose of study intervention through 28 days after the last dose of study intervention.

Description: ORR is defined as the proportion of participants with a confirmed BOR of either CR or PR, as determined by BICR and investigator assessment per RECIST v1.1

Measure: Safety Lead in (SLI) and Phase 3: Objective Response Rate (ORR)

Time: Time from the date after the first dose of first dose (SLI) or the date of randomization (Phase 3) until documented PD, or start of subsequent anticancer therapy (approximately every 9 weeks).

Description: DCR is defined as the proportion of participants with a confirmed BOR of CR, PR or SD, as determined by BICR and investigator assessment per RECIST v1.1.

Measure: Safety Lead in (SLI) and Phase 3: Disease Control Rate (DCR)

Time: Time from the date after the first dose of first dose (SLI) or the date of randomization (Phase 3) until documented PD, or start of subsequent anticancer therapy (approximately every 9 weeks)

Description: TTR is defined as the time from the date of randomization to the date of first documented response (CR or PR), as determined by BICR and investigator or assessment per RECIST v1.1.

Measure: Safety Lead in (SLI) and Phase 3: Time to Response (TTR)

Time: Time from the date of first dose to the date of first documented response (CR or PR), as determined by investigator assessment per RECIST v1 (approximately every 9 weeks)

Description: OS is defined as the time from the date of randomization to the date of death due to any cause

Measure: Phase 3: Overall Survival (OS)

Time: Time from the date of randomization to the date of death due to any cause.

Description: PFS by investigator is defined as the time from the date of randomization to the first date of documented disease progression as determined by investigator assessment per RECIST 1.1 or death due to any cause, whichever occurs first.

Measure: Phase 3: Progression Free Survival (PFS) by Investigator

Time: The time from the date of randomization to the date of first documented disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks)

Description: DOR is defined as the time from the date of first documented response to the date of first documented disease progression, as determined by BICR and investigator assessment or death due to any cause, whichever occurs first.

Measure: Phase 3: Duration of Response (DOR)

Time: Time from date of first documented response (CR or PR) to the date of first documented disease progression, as determined by BICR and investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks)

Description: PFS2 is defined as the time from the date of randomization to the date of second objective disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first.

Measure: Phase 3: Progression Free Survival 2 (PFS2)

Time: The time from the date of randomization to the date of second objective disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks)

Description: To measure plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)

Measure: Safety Lead in (SLI): Plasma concentration-time profiles and Pharmacokinetic (PK) parameter estimates for encorafenib and binimetinib.

Time: Cycle 2, Day 1

Description: To measure the plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)

Measure: Phase 3: Plasma concentrations of encorafenib and binimetinib.

Time: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 (Each Cycle is 21 days)

Description: EORTC QLQ-30 includes 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/Quality of Life scale

Measure: Phase 3: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30): change from baseline in the global health status/QoL score.

Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 months

Description: The FACT-M is a melanoma-specific quality of life questionnaire that is composed of items from the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, melanoma-specific items, and items related to melanoma surgery

Measure: Phase 3: Change from baseline in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) subscale score.

Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 months

Description: The EQ-5D-5L is a standardized measure of health utility that provides a single index value of health status and contains 1 item for each of 5 dimensions of HRQoL (ie, mobility, self-care, usual activities, pain or discomfort, and anxiety or depression).

Measure: Phase 3: Change from baseline in 5-level EuroQol-5D (EQ-5D-5L) index score and visual analog scale (VAS)

Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 months

Description: The PGIS is a single 1-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time by using a 4-point Likert scale that ranges from (1) = "none (no symptoms)" to (4) = "severe".

Measure: Phase 3: Change from baseline in Patient Global Impression of Severity (PGIS) score

Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 months

Description: The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change since starting treatment as rated on a 5-point Likert scale anchored by (1) "much better" to (5) "much worse", with (4) = "no change"

Measure: Phase 3: Patient Global Impression of Change (PGIC) score

Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 months

266 A Randomized, Open Label Phase 2/3 Study Comparing Cobolimab + Dostarlimab + Docetaxel To Dostarlimab + Docetaxel To Docetaxel Alone In Participants With Advanced Nonsmall Cell Lung Cancer Who Have Progressed On Prior Anti-PD-(L)1 Therapy And Chemotherapy (COSTAR Lung)

This is a multi-center, parallel group treatment, Phase 2 open label study evaluating cobolimab in combination with dostarlimab and docetaxel in participants with advanced Nonsmall cell Lung Cancer (NSCLC) who have progressed on prior anti-PD-(L)1 therapy and chemotherapy.

NCT04655976
Conditions
  1. Lung Cancer, Non-Small Cell
Interventions
  1. Biological: Cobolimab
  2. Biological: Dostarlimab
  3. Drug: Docetaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Participant has actionable driver mutations such as epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, neurotrophic receptor tyrosine kinase (NTRK) fusions, c ros oncogene 1 (ROS1) rearrangement, or proto oncogene B raf (BRAF) V600E mutation. --- V600E ---

Primary Outcomes

Description: OS is defined as survival from the date of randomization to the date of death by any cause

Measure: Overall survival (OS) in participants receiving cobolimab + dostarlimab + docetaxel relative to participants receiving docetaxel alone

Time: Up to 44 months

Description: OS is defined as survival from the date of randomization to the date of death by any cause

Measure: OS in participants receiving dostarlimab + docetaxel relative to participants receiving docetaxel alone

Time: Up to 44 months

Secondary Outcomes

Description: OS is defined as survival from the date of randomization to the date of death by any cause

Measure: OS in participants receiving cobolimab + dostarlimab + docetaxel relative to participants receiving dostarlimab + docetaxel

Time: Up to 44 months

Description: Confirmed ORR is defined as the proportion of participants who have achieved confirmed complete response (CR) or confirmed partial response (PR), evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on Investigator assessment

Measure: Objective response rate (ORR)

Time: Up to 44 months

Description: PFS is defined as the length of time until disease progression, from the time of randomization to the earliest date of assessment of disease progression based on RECIST version 1.1 by Investigator assessment or death by any cause

Measure: Progression free survival (PFS)

Time: Up to 44 months

Description: DOR is defined as the time from first documented response (CR/PR) until the time of first documentation of disease progression based on RECIST version 1.1 by Investigator assessment or death, whichever occurs first

Measure: Duration of response (DOR)

Time: Up to 44 months

Description: TTD in lung cancer is defined as time from randomization to meaningful deterioration on a composite endpoint of dyspnea, chest pain, and cough, from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 13 item Lung Cancer Module (EORTC QLQ LC13)

Measure: Time to deterioration (TTD)

Time: Up to 44 months

Description: EORTC QLQ-C30 is a questionnaire used to measure health related quality of life (HRQoL) in participants with cancer.

Measure: Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 item Core Module (EORTC QLQ-C30) assessment

Time: Baseline (Day 1) and up to 44 months

Description: EORTC QLQ LC13 is a lung cancer specific questionnaire module designed to supplement the EORTC QLQ C30.

Measure: Change from Baseline in the EORTC QLQ LC13 assessment

Time: Baseline (Day 1) and up to 44 months

Measure: Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and immune related adverse event (irAEs)

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Measure: Number of participants with TEAEs leading to death

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Measure: Number of participants with adverse events (AEs) leading to discontinuation

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Description: Blood and urine samples will be collected for the assessment of hematology, clinical chemistry, thyroid function and urinalysis lab parameters

Measure: Number of participants with clinically significant changes in hematology, clinical chemistry, thyroid function and urinalysis lab parameters

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Measure: Number of participants with abnormal findings in vital signs

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Description: Performance status will be assessed using the ECOG performance status scale. Scales range from grade 0 to 4, grade 0 denoting fully active and grade 4 completely disabled.

Measure: Number of participants with indicated Eastern Cooperative Oncology Group (ECOG) performance status

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Description: 12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR interval, QRS interval, QT interval, Corrected QT interval using the Fridericia's formula (QTcF) and Bazett's formula (QTcB) interval.

Measure: Number of participants with abnormal findings in Electrocardiogram (ECG) Parameters

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Measure: Number of participants with usage of concomitant medications

Time: From consent signature (Day -28) until the 90 day post last dose follow-up

Measure: Number of participants with abnormal physical examinations

Time: From consent signature (Day -28) until the 90 day post last dose follow-up


HPO Nodes


HP:0002664: Neoplasm
Genes 1522
SF3B1 GFI1B IGF2 FIBP RPS7 WT1 COL7A1 TREX1 HSPG2 CASP8 SLC22A18 MC1R TFE3 KRAS PLAG1 OFD1 BRAF NUMA1 KRT16 PSENEN CTPS1 APC SOX9 FANCM OPCML CDKN2A RPS15A CTNNB1 SDHD EDN3 FCN3 NELFA GJC2 MALT1 HPGD GLI1 CD70 SPINK1 LETM1 PMS1 LRP5 HNF1B EXT1 TCF4 ELMO2 MET ANTXR1 KRT16 KRT10 PAX4 SETBP1 TERT WT1 SMARCB1 GJB6 HRAS STK11 BUB1B GNPTAB MYD88 MCC GJB2 BRCA1 TP63 PDGFRL TARS1 NF1 FGFR3 KARS1 BARD1 BRIP1 GATA2 IL1RN BRAF CD81 TNFRSF13B TYROBP AR LIG4 KLF11 ABL1 MVK BMPR1A PIK3CA B3GALT6 SLC37A4 SOS1 TSC1 FGFR3 ATRX FANCG TET2 KIT SRP72 MPL TP53 SMAD4 EVC2 MAPRE2 DLST BRCA1 DICER1 HRAS AKT1 RNR1 TSC1 TNPO3 XRCC4 DNMT3A NEUROD1 THPO MN1 NOD2 SRSF2 PPM1D FLT4 ATP7A IL7 KRAS GDNF WNT10A EPAS1 COL1A1 IL1B MRAP ADAMTS3 PRKCD SUFU PTCH1 ERCC3 KRT14 CXCR4 HOXD13 IGF2 LIG4 PALB2 BLM NRAS ERCC3 FOXP1 SDHD TP53 PKD2 PDX1 TINF2 ADA2 MYF6 RHBDF2 POU6F2 PHKG2 CDKN2A RUNX1 ERCC2 MAP2K2 WT1 USB1 GATA4 FGFR2 ACD CR2 MUTYH ARL6IP6 FAH MSH2 RASA1 NEK1 SOX6 NR0B1 LIG4 CDKN2B NF1 NF1 POLE RPL35 SRY SDHAF2 FANCL CPLX1 FAS PRKAR1A PHB SDHA CALR PIK3R1 FAN1 TET2 TMEM216 RSPO1 SEMA3D MDM4 SDHD HRAS NUP214 GJA1 PIK3CA CCND1 RNF6 MSH2 C11ORF95 MVK MCM4 FLI1 TINF2 KIAA0753 ECM1 ARSA ERCC2 SOX2 SDHC SLC26A2 MPL VANGL1 PUF60 RAD51D POT1 CR2 ESCO2 FOXE1 PMVK SRY GJB4 TRIM37 KIT EXT2 PDGFB KIF1B FANCF IGF2R MLH1 GDNF PIK3CA ASCC1 ASCL1 TCIRG1 APPL1 RPS19 BCL10 IGF2 NRAS FLT3 STAT1 BCL10 RMRP GNAI3 KRAS GPR101 BAP1 NKX2-1 MAX BMPR1A DDB2 SMARCB1 RAD51 FGFR3 ALX4 BTK MSH6 NOTCH3 DICER1 CXCR4 CCBE1 RET WT1 TP53 PALLD RNASEH2B WT1 ATR CCND1 KCNQ1OT1 SMAD4 AHCY STK11 FANCC TRNK BCL6 SMAD4 SKIV2L HMBS TP53 TERT PHOX2B SNAI2 BRAF TCOF1 FANCI NRAS REST SDHC HBB HFE CREBBP MET SEC23A CEP57 CTLA4 TRIM28 SMAD7 GNAS BRCA2 PALB2 FGF8 SBDS RET ALK GJB2 CPLANE1 GPC3 TCTN3 PTEN RB1 INTU CYP26C1 LEMD3 PRLR CDON NLRP1 GPR101 DHH HNF4A MMEL1 DNASE1L3 RASGRP1 ATRX CHEK2 FANCA SPRED1 DNM2 FLT4 CHEK2 RPS19 KLLN HACE1 HNF1A PTPN11 CDKN1B GAS1 BRCA2 KCNQ1OT1 NPM1 FGFR3 MC1R MINPP1 PTPN11 TSC2 ABCA5 BRCA2 PLCB4 SCN11A HNF1A BRAF RB1 CBL ARHGAP26 SUFU PTPRJ C1S APC IRF5 GNAQ GDNF TERT MYSM1 XPC TMC8 COL4A5 ERBB3 SLC26A4 CD96 NSUN2 PDGFRA FERMT1 TYR DNAJC21 MSH2 SH3GL1 TUBB RET BRAF ESR1 PAX3 RHBDF2 RTL1 WRN DYNC2LI1 ELANE EXOC6B RPS26 EWSR1 VHL PIGA GCGR POU6F2 RNF43 POLE BRAF MNX1 SFTPA2 CDH23 ASCL1 APC ACVR1 PIGL BAX RAG2 RSPO1 MSH3 PGM3 FGF3 FANCE MPL TP53 COL7A1 BUB1 TET2 PALB2 ACTB PNP SDHC EDN3 XPA TMC6 NEK1 GNA11 KAT6B KRT1 RUNX1 PAX7 NOTCH1 ENG CTNNB1 ETV6 MPLKIP PARN CDKN2A PTPN3 STAG3 MDM2 TP53 LAMC2 NBEAL2 VAMP7 GNA14 DCLRE1C CBL GCDH FANCC AXIN2 PYGL SOS1 BLK WRAP53 IDH1 KRAS CCM2 APC ASXL1 ATP7B ERCC3 SF3B1 EP300 BRCA2 MGAT2 NRTN CDKN2A DICER1 PMS1 RPS10 TBC1D24 FAH BRCA2 ASXL1 BCR C2CD3 KRAS IDH1 IGLL1 RASA1 BRCA2 CHEK2 PTCH1 RNF113A BRAF MBTPS2 EDNRB IGHM PDGFRB RAF1 MEN1 FASLG TUBB NDUFAF6 FOXI1 TGFBR1 EPCAM CYLD SDHB APC CYP2D6 TAF1 KRT17 BRCA1 BUB1B BAP1 GDF2 BUB1B ERCC2 TP53 KRT5 GATA2 BRCA1 RAD54B MRE11 STAC3 DNMT3A MLH1 BCHE EDN3 CDKN1B AURKA NRAS FLCN IDH2 EDN1 ESCO2 USF3 IGH POT1 ACVRL1 JAK2 NBN NRAS SQSTM1 TMEM127 ZFPM2 SLC12A3 NTHL1 ADA CHIC2 STAT3 SETBP1 FANCB FIBP STAT3 STK11 MLLT10 SFTPC HDAC4 NUP214 GLI2 SLX4 TSC1 ERCC6 TP53 CLCNKB KLF6 OGG1 JAK2 PAX6 RECQL4 RPL31 MYO1H FH RPGRIP1L SLC45A2 RPL10 RPL10 HMBS GDF5 TNFRSF10B PIK3CA GABRD TP53 BRCA2 SEMA4A BCR PALB2 ASXL1 KRT6B CCDC22 SAMD9 DMPK DCC ERCC5 RPL5 CTNNB1 RPS27 TRNS2 PTCH1 PTEN TFAP2A RPS24 RPL35A RET AXIN1 HNF1B ARMC5 UBE2T SRP54 SSX2 DKC1 ERCC3 JAK2 GNA11 LAMB3 GJB2 NFKB1 KCNQ1 GLI3 PIK3CA KANSL1 CASP8 MYC RECQL4 ACAN CACNA1S BDNF KIF11 MDH2 MSL3 FGFR1 TERF2IP HFE NFKB2 TOP2A GFI1 SRD5A3 PHKA2 MAX POLE MAP2K1 EYA1 RNF43 ALX3 SETD2 ERCC4 CTLA4 SIX3 LEMD3 OCRL CDH23 DZIP1L MSH3 AR CDC73 PDGFRL TWIST1 POU2AF1 DKC1 CALR LIN28B KRT6A GATA1 MC1R DIS3L2 CD28 CDC73 ADA2 UROD CIB1 TSR2 WNT5A TET2 PHOX2B BMPER KIT DLC1 MSTO1 H19-ICR SLC25A13 ADAR TMEM67 BMPR1A MLH3 POLR1C KRT6B FH EFL1 TERC BUB3 FOXC2 NOTCH3 KIT NSD1 FGFR2 SLC6A17 MAP3K1 TRIP13 MEG3 RRAS2 BMPR1A NF1 DPM1 LIG4 PARN RHOH BRCA2 NF1 TAF15 RFWD3 VHL H19 BCR KRAS VANGL2 KRAS SDHD DVL3 BIN1 ABL1 GPC3 HAX1 FANCA GDNF NHP2 IGF2 VHL CCL2 EXTL3 RUNX1 PRKCD BLNK MSH6 SLC22A18 IL2RG PTH1R SDHB AIP WDPCP APC KCNJ10 ASPSCR1 OCA2 TP53 WT1 SPRTN TET2 TAL1 L2HGDH KIT SDHC ERCC4 GPR143 PRKN SMAD4 SEMA3C TRNS1 BRCA1 SHOX PCNA FANCG CREB1 TRNH VHL MYLK BAP1 SUFU ANTXR1 POLD1 NODAL IGH JAK2 MS4A1 MEN1 TSC2 GATA2 DHCR7 TINF2 F13B RB1 COL7A1 SCN4A BMPR1A DDB2 CDKN2A SDHD CYP11B2 IL7 ARID1B KIT FGFR1 RET CDKN2A LAMA3 CHEK2 TBX2 TBX18 HNF4A GPC4 SHH LMNA BMP2 YY1 AKT1 WT1 BAP1 FZD2 SH2B3 BTK GATA1 RAD54L ATM CTBP1 PTEN SRY RYR1 CTHRC1 MFN2 PTEN RAD21 PTEN MYC SLC26A2 TP53 CTNNB1 RAD51C NAB2 NLRP1 SUFU DLL1 PSAP SDHB REST TGFBR2 TRIP13 IGH ABCC8 IL6 CPLANE1 H19 FANCD2 FGFR2 RET PKD1 DNMT3A REST CHEK2 GNAQ MXI1 BRIP1 DYNC2LI1 GNAS TP53 GLI3 DIS3L2 NRAS PICALM WT1 BAP1 MEN1 TXNRD2 MGMT PTEN MYD88 GNAS POT1 AGGF1 BUB1 PTEN PORCN HFE NUTM1 PHOX2B MSX2 PMS2 SLX4 H19 USP9X RPL27 GNAS SEC23B CBL CD28 PKHD1 AXIN2 TRPV3 KLLN SSX1 TSC1 PPOX KRT17 CARD14 HRAS TCF3 RPL11 CC2D2A GREM1 CHEK2 AP2S1 NRAS TRNL1 ALX1 CREBBP TCTN3 TET2 ESCO2 DOCK8 NRAS STK11 GCM2 TTC37 WT1 SMAD4 DAXX MITF BCL2 DIS3L2 POLR1D TDGF1 KRAS TNFRSF13C KIT PHOX2B SF3B1 RPL15 NF1 TERT TNFRSF1B FANCD2 MLH3 IL7R GPC4 H19-ICR SLC17A9 MEN1 MST1R KIT RAD50 TJP2 DNAJC21 PDCD10 MUTYH IL12RB1 SH2D1A FGFR2 NBN KRAS KIT CASR ENPP1 SDHB HRAS IKBKG PNP EXT2 BRD4 SMARCB1 REST COL11A2 TG KIT LIG4 SUFU NBN RSPRY1 CYSLTR2 SDHD AAGAB BLM RAG1 RNF139 RB1CC1 ACD PTPN11 SLC26A2 TREX1 BMPR1B DDR2 ZAP70 MNX1 MAGT1 AIP GATA2 AR STAR IFIH1 IDH2 BRCA1 USP8 RB1 FGFRL1 SMO USP8 RMRP SLC25A11 MLH3 FUZ DOCK8 SUFU NF2 KDR KRAS RPS14 CASP10 SRP54 ZSWIM6 TBXT PTCH2 EWSR1 TNFRSF13C MTAP NQO2 RPL18 DNAJC21 GCK ERCC6 KDM6B EXT1 SBDS CCND1 SDHAF2 KCNH1 CYLD LMOD1 PDGFRA CAT CHRNG TRNQ ADA NRAS TLR2 SHOX FGFR3 BCL10 TYR KRAS COL2A1 PTCH2 SMO GBA MSTO1 TREM2 JAK2 TMEM231 MSH2 ASXL1 RET DHCR7 NBN PIK3CA NSD2 SDHB EIF2AK4 PALB2 KIF7 PTPN11 PIK3CA HLA-DRB1 STIM1 TMC6 KIF1B TNFSF15 RELA AKT1 NPM1 APC SDHA SDHB STAT6 CDKN1C CDC73 PTCH2 KANSL1 ZSWIM6 FLCN HBB LZTS1 FN1 TRAF7 ACP5 CTNNB1 MLH1 EXT2 RNASEL RNASEH2A IL2RG ATP7A CDK4 CYP11B1 MMP1 SDHB ATRX ACTG2 FOXH1 OFD1 NEK9 STS MUC5B PRKCD PTPN11 PTCH2 LRRC8A RPL26 MSH6 NNT LZTR1 CDC73 PTEN AKT1 AKT1 SASH1 HRAS ANAPC1 PTPN12 KCNJ11 TCF4 GATA2 MLH3 ERCC4 GNB1 DISP1 IDH1 BCR GANAB MSH6 NR5A1 TSC2 GFI1 TNFSF12 TRNP MAPK1 IFNG FLT4 MTM1 WWOX HABP2 RPS28 HRAS SLCO2A1 ND5 SDHB CHD7 BRIP1 SLC37A4 MC2R XRCC3 TNFRSF4 NAGS PHF21A ZIC2 PCGF2 SMARCE1 CTNNB1 SRP54 CDH1 CDK4 RPS20 KCNJ10 RAD21 RNF6 COL14A1 SMO CD19 WRN SRGAP1 CDKN2C AXIN2 GPC6 WWOX HSPA9 FOXI1 CPOX RPS17 APC2 MYH8 SERPINA1 ATM LMX1B ENG POLH TGFBR2 DHX37 VEGFC KIF1B KRT17 DDX41 SPIB CBFB HRAS BCL10 PIGL FGFR1 NSD1 F5 KCNN3 BAX PIEZO2 RECQL4 CREBBP KIT PDGFB PDE6D ABCA5 AKT1 KLHDC8B TNFSF12 EPCAM RARA MLH1 GINS1 EVC PIK3CA FANCE WIPF1 NF2 PDGFRA PRKAR1A CDH1 SDHD PRCC TRNF PTCH1 TNFRSF1B WNT10A WWOX MAD1L1 MTOR WDPCP RNASEH2C NSD2 SAMD9L FH LPP NF1 KRIT1 NTHL1 IL12A HNF1A CDH1 SMARCB1 SMARCE1 CD19 FH FDPS TRPS1 ERCC4 SMPD1 SMARCD2 BRCA1 MPL CRKL SEC23A EXT1 PERP ATM FOXE1 CDKN2B CTSC SIX1 FAM149B1 CDH1 RAD51C ALX3 DLST TRIP13 ING1 PDGFRB FLT3 COL18A1 MST1 TGIF1 TMEM107 SRSF2 TRIM28 BAP1 ANTXR2 CD79A PIK3R1 MAP3K1 NOP10 PIK3CA POLD1 KDSR CCND1 TP53 TMC8 ALK MAP2K1 CD79B SDHC ECE1 PALLD CTSA PRDM16 IVNS1ABP CALR FLNA GPR101 BRCA2 ERCC2 DYNC2H1 TFAP2A COL2A1 DVL1 TERT APC TERT TEK EXT2 TERC ALX4 OFD1 LMO1 PDGFRB RPS14 DCC RTEL1 INS TSC2 FAM20C MYH11 GPC3 SCN9A SMAD4 RASGRP1 HBB TGFBR2 RERE NDP PLA2G2A TCF4 MAD2L2 SKI AIP HMMR SDHC SNAI2 PIK3CA LMNA PGM3 ABCB11 TAL2 WT1 VHL PIK3CA TCTN3 SAMD9L ICOS GLI3 RB1 SLC25A13 SDHC DCLRE1C GCM2 VANGL1 SIX6 WT1 PMS2 KCNH1 BARD1 H19-ICR GNAS TERT CIB1 B3GALT6 GJB3 ERBB2 SDHA KRAS CDC73 TNFRSF13B TET2 FGFR3 WAS SEC23B TGFBR2 TP53 NF2 SMARCA4 NF2 SLC26A4 ANTXR2 WRAP53 FAS SAMHD1 TP53 TET2 ATP7A PTEN SH3KBP1 CARMIL2 MVD PDGFB ABCC6 G6PC1 TRNK KRAS GPC3 PTEN NF2 JAK2 DMRT3 GNAQ RAD51 GTF2H5 TMEM127 TERT RUNX1 FAT4 AR HABP2 NR4A3 EP300 MINPP1 OFD1 RASA1 DLEC1 BIRC3 AIP CD27 PHOX2B BMPR1A KCNE3 PLCD1 RAD51 KRT1 MSH3 MITF EPHB2 DHCR24 RABL3 KRT17 XRCC2 NRAS ITK VHL BICC1 RECQL4 SMARCAD1 MYCN RET CTC1 PTCH1 JAK2 SRC SDHB PHOX2B AKT1 KEAP1 JAG1 VHL LETM1 NLRP1 MEN1 BRCA2 FLCN C2CD3 RFWD3 XPA APC APC SDHD FOXO1 MAFA WHCR GPC4 MLH1 ICOS CDKN1B MTMR14 KIT DICER1 EP300 ZFHX3 MMP1 PRKAR1A KRT9 F13A1 CTNNB1 MPL INPP5E NF1 DKC1 TERT DLK1 SCN10A STS RPS29 PTEN FLCN LRBA ELANE GTF2E2 ATM PIK3CA GPR35 CYLD RAD51C CDKN1A WT1 DICER1 PIK3CA TERC PIK3CA SLC25A11 GNAS CEBPA ATP6V1B2 RET XPC EXT1 BRCA2 SH2B3 ERCC3 BRCA2 RTEL1 WASHC5 ERCC2 AKT1 KCNAB2 CYLD STK4 POLH ERCC5 CDH1 CEL XIAP MSR1 TP53 TET2 DHH PRKAR1A
HP:0000820: Abnormality of the thyroid gland
Genes 601
TGIF1 KMT2D UBR1 SLC16A2 MAGEL2 NODAL ND6 FOXE1 PIEZO1 TBL1X TREX1 NODAL MAGEL2 GTF2IRD1 INSR BRAF DUOXA2 APC SHH FGFR1 TSHR RET GNAS ARVCF CDKN2A TBX2 SHH CTNNB1 YY1 THRB PIK3C2A RREB1 MALT1 TF SOX3 OCA2 GATA1 USP9X TCF4 PTEN NKX2-5 SVBP NDN NKX2-1 GPC1 DLL1 BUB1B FGF8 GAS1 B3GLCT TGFBR2 SIM1 FOXH1 IGH CLIP2 BMP4 ELN TPO FOXD3 TTC7A HIRA DNAH1 GP1BB TP53 GLI3 SLC26A4 FDX2 BAP1 MEN1 COX1 DLL1 SEC24C TXNRD2 SIX3 NKX2-5 ELN PIK3CA TRH GLIS3 PMS2 DUOXA2 FOXH1 FOXP3 USP9X ADAMTSL1 SEC23B KATNIP CDON AKT1 TSC1 IGSF1 TNPO3 MEN1 TRMT10A HRAS XRCC4 HESX1 GREM1 CHEK2 PTRH2 GAS1 PDE4D PROP1 TRNW MRAP PRKCD SUFU TRNL1 CDH23 TTC37 DACT1 LIG4 PLAGL1 POLR1D FOXP1 TDGF1 KRAS CDON LHX4 GNE IGF2 HPD TMEM67 SHH DISP1 IL7R DUOX2 NKX2-1 PPP1R15B ZIC2 ARL6IP6 THRA IL12RB1 DISP1 SRY HSD17B3 FAS SLC25A4 PRKAR1A IL2RA ENPP1 FOXH1 TDGF1 AIP FAN1 EXOSC2 SEMA3D TG LIG4 MDM4 TRNS1 GLI2 POU1F1 FGF8 TRNH LHX4 RAG1 PAX8 DUOX2 PCSK1 SNRPN FMR1 FANCI TREX1 SCN4A FGFR1 PROP1 STAR DCAF17 IFIH1 IYD IDH2 DNM1L FOXE1 CCBE1 PDE4D CACNA1S EXT2 IRS4 ROBO1 GNAS WDR11 ND1 GATA6 KCNJ18 PAX8 ND4 SUFU CASP10 STAT1 SUGCT POLG DISP1 RMRP STAG2 BAP1 SIX3 TRNQ NKX2-1 RAI1 SNRPN ZBTB20 SMARCB1 LHX4 MSH6 HSD17B3 DICER1 NIN RET ADA RNASEH2B ZIC2 XRCC4 BCL10 SLC5A5 SKIV2L MSTO1 STAT1 MSH2 RET FGF8 TCOF1 SHH SDHB HBB MMP2 OCA2 PIK3CA NODAL FOXP3 CEP57 TNFSF15 CEP57 SLC26A4 PTCH1 AKT1 ZIC2 TRNF ALMS1 CDC73 KANSL1 FGF8 DLL1 RET HBB TRHR TRAF7 ACP5 CDON PTEN RNASEH2A TRNS2 CDON NLRP1 POLR3A DUOX2 HNF4A ZFP57 MMEL1 RASGRP1 FOXH1 CDON MARS1 GABRA3 CDKN1C TONSL KLLN TSHR NNT CDKN1B GAS1 CDC73 PTEN PTCH1 STUB1 SASH1 MINPP1 GLI2 C1S ANAPC1 APC TSHB IL18BP DISP1 THRB BCOR POLG2 IFNG APC IRF5 GDNF HABP2 NDN SLC26A4 ANAPC1 FGFR1 CHD7 ACP5 MC2R OCA2 PHF21A ZIC2 FLCN NNT LIFR PLVAP RPS20 ARNT2 KCNJ10 OTX2 TSHR WRN DDOST SMO INSR SRGAP1 CDKN2C WFS1 MMP14 LEP PROKR2 ADAT3 PMM2 FOXI1 RBM28 ITCH APC2 PTRH2 APC KAT6B PLCG2 NDN THRB SPIB RAG2 MSH3 JAK1 NSD1 TRHR SPOP CACNA1C JMJD1C GLI2 BUB1 CDH23 PDGFB TBX1 TSHR ATRX EPCAM EDN3 LEPR TBL2 TBX1 LHX3 FOXE1 FMR1 KAT6B CTNS FOXA2 PPP1R15B FOXP1 RFC2 FUCA1 MDM2 LEPR RNASEH2C PLAA TRNW LHX3 MADD DCLRE1C SGPL1 PROP1 RRM2B LIMK1 HESX1 IL12A TWNK WDR4 SMARCE1 APC SIX3 CACNA1S GLI2 NRTN SAA1 FARSA PMS1 FOXE1 CDKN2B TANGO2 TBC1D24 SIX1 TRAPPC9 PROP1 IDH1 MST1 TGIF1 SEMA3E CDON TBX1 HNRNPK EDNRB ALG8 MEN1 MCM8 FASLG ZFAT FOXI1 IQSEC2 OPA1 HYMAI ECE1 PRDM16 TRNS1 DEAF1 ZIC2 AFF4 MLH1 FOXE1 NPHS1 COX2 PAX8 NRAS FOXH1 STEAP3 ALX4 NKX2-5 TSC2 RAI1 COX3 SOX3 USF3 FGF8 HBB CASR HESX1 LRP4 RERE POLG MTTP SLC12A3 SKI TGIF1 SETBP1 PIK3CA LMNA STAT3 SMC1A WFS1 GLI3 GLI2 TDGF1 SDHC CLCNKB DCLRE1C ALMS1 POU3F4 HMGA2 PTCH1 LHX4 GNAS TERT PIK3CA GLI2 GABRD TSHR ITCH SEMA4A GAS1 GAS1 DMPK SEC23B NF2 PTCH1 POU1F1 DYRK1A PTEN RCBTB1 SLC26A4 FAS SAMHD1 UFD1 C1QBP PTEN TGIF1 TREX1 HNF1B ABCC6 PLAG1 GTF2I MAGEL2 TSHR TWNK TG SRD5A3 KISS1R KANSL1 PTCH1 EIF2AK3 KCNJ11 CLPB HABP2 DNAJC19 TDGF1 FUT8 TG GCH1 MINPP1 GPR161 RAI1 HFE BIRC3 HNRNPK TGIF1 BMPR1A SALL1 NSDHL EYA1 SETD2 TSHB SIX3 MSH3 TSHR POMC POU2AF1 TDGF1 TRNL2 TRNL1 CDC73 ADA2 DLL1 TRNN CTLA4 SNRPN SHH SLC5A5 AKT1 CTNS MSTO1 KEAP1 SIX3 JAG1 DMXL2 TBCK ADAR BMPR1A MLH3 CHD7 POLR1C STAT5B APC ND5 STAG2 CDKN1B TSHR BUB3 DICER1 PRKAR1A SLC6A17 KCNJ18 MAGEL2 TRIP13 MLXIPL HLA-DRB1 AIRE LIG4 PAX8 TPO NKX2-1 SDHD APOE FLCN NODAL GRM7 ABCC8 LRBA IYD POU1F1 GPR35 BAZ1B DLL1 CDKN1A COMT DMXL2 DICER1 TANGO2 GNAS FLII IL2RG KCNJ10 NODAL KCNAB2 CTNS PRKAR1A KDM6A SALL1 SEMA3C BTNL2 DISP1
SNP 0
HP:0008069: Neoplasm of the skin
Genes 287
FERMT1 TYR BAP1 TNFRSF4 MSH2 COL7A1 CDK4 RPS20 MC1R TINF2 WRN KRAS SMO COL7A1 DDB2 CDKN2A KRT16 PSENEN IL7 APC LAMA3 POLH VEGFC LMNA KRT17 FCN3 GJC2 MSH3 HPGD RECQL4 CREBBP COL7A1 KIT PDGFB PTEN KRT16 SDHC EPCAM PTEN XPA TMC6 GJB6 MLH1 HRAS SUFU TGFBR2 PTCH1 CTNNB1 TNFRSF1B WNT10A MPLKIP CDKN2A IL6 GJB2 TP53 LAMC2 TARS1 NF1 FH GNA14 DCLRE1C NF1 WRAP53 NTHL1 KRAS SMARCE1 FH BAP1 ERCC3 EP300 FDPS ERCC4 MVK PIK3CA PERP PMS1 CTSC PORCN ALX3 NUTM1 ING1 PMS2 KIT SLX4 IGLL1 SEC23B RASA1 CD28 HRAS TRPV3 KLLN AKT1 TSC1 PTCH1 KRT17 TCF3 RNF113A MBTPS2 IGHM PDGFRB MEN1 CD79A PIK3R1 FASLG KDSR NRAS IL7 CYLD TMC8 CD79B WNT10A KRT17 COL1A1 IVNS1ABP DOCK8 PRKCD PTCH1 NRAS ERCC3 KRT14 CXCR4 KRT5 ERCC2 MLH1 BLM MITF NRAS KRAS KIT APC TERC NF1 FLCN TERT TNFRSF1B CDKN2A DCC ERCC2 TSC2 SLC17A9 USF3 NF1 NTHL1 FAS PRKAR1A KIT SNAI2 PIK3CA LMNA HRAS IKBKG FAN1 BRD4 RSPO1 TP53 SDHC GJA1 BLM RNF6 FH MSH2 SLC45A2 TERT CIB1 GJB3 TNFRSF10B PIK3CA ECM1 ERCC2 SEMA4A KRT6B DMPK SEC23B PMVK ERCC5 GJB4 TGFBR2 SMO NF2 NF2 RMRP FAS MLH1 CARMIL2 MVD PDGFB SUFU NF2 DKC1 ERCC3 NRAS CASP10 STAT1 PTEN LAMB3 GJB2 BAP1 GTF2H5 RECQL4 DDB2 SMARCB1 CYLD FGFR1 MSH6 NOTCH3 CXCR4 BMPR1A TYR PLCD1 PTCH2 CTLA4 OCRL KRT1 MSH3 MSH2 KRT17 NRAS SDHB KRT6A MC1R CD28 CREBBP CIB1 PIK3CA SDHB STIM1 AKT1 TMC6 KEAP1 AKT1 CTLA4 NLRP1 MLH3 PTCH2 APC KRT6B MLH1 LZTS1 GJB2 CDKN1B KIT TRAF7 DICER1 PTEN MMP1 PRKAR1A KRT9 BMPR1A NF1 MMP1 CTNNB1 RASGRP1 NF1 SPRED1 FLT4 SDHD LRRC8A KLLN GTF2E2 PTEN SASH1 BLNK ANAPC1 PIK3CA GNAS XPC BRAF ERCC4 ERCC3 MSH6 ERCC2 OCA2 KIT ERCC4 IFNG APC GPR143 CYLD FLT4 STK4 POLH ERCC5 WWOX HRAS SLCO2A1 XPC TMC8
SNP 0
Protein Mutations 1
V600E
SNP 0
HP:0007378: Neoplasm of the gastrointestinal tract
Genes 375
BRIP1 SLC37A4 RPS7 PDGFRA MSH2 POLD1 CTNNB1 TREX1 JAK2 MS4A1 CASP8 MEN1 RPS20 RAD21 RNF6 RHBDF2 RTL1 WRN COL14A1 BMPR1A CDKN2C RPS26 SDHD AXIN2 POU6F2 RNF43 APC KIT CPOX RPS17 CDKN2A SERPINA1 CDKN2A HNF4A RPS15A ENG APC TGFBR2 SDHD BMP2 BAX SPIB BCL10 MSH3 F5 PMS1 PIEZO2 TP53 BUB1 TCF4 CTHRC1 SDHC TNFSF12 PAX4 SETBP1 EPCAM PTEN EDN3 TP53 CTNNB1 MLH1 NAB2 STK11 SUFU BUB1B PSAP SDHB REST TGFBR2 ENG ABCC8 WWOX MCC H19 PTPN3 MTOR BRCA1 MDM2 PDGFRL NF1 AXIN2 PYGL BARD1 BLK TP53 IL12A CDH1 APC CD19 IL1RN FH ATP7B MEN1 CD81 SMPD1 NRTN MGMT CDKN2A KLF11 BMPR1A PIK3CA SLC37A4 PMS1 RPS10 CDKN2B FAH BUB1 PTEN BRCA2 HFE TRIP13 PMS2 RPL27 MST1 SEC23B PKHD1 AXIN2 AKT1 PTCH1 PPOX TNPO3 TRIM28 BAP1 EDNRB NEUROD1 MEN1 RPL11 CC2D2A FASLG GREM1 CHEK2 POLD1 CCND1 EPCAM APC ECE1 IL1B GDF2 BUB1B DOCK8 PRKCD TP53 STK11 RAD54B TTC37 MRE11 SMAD4 DAXX MLH1 BLM DIS3L2 KRAS SDHD AURKA PDX1 APC RPL15 FLCN ADA2 RHBDF2 PHKG2 INS MLH3 GPC4 H19-ICR SMAD4 USF3 ACD CR2 MUTYH KIT HBB FAH RAD50 ACVRL1 MSH2 TGFBR2 TJP2 PLA2G2A CDKN2B MUTYH IL12RB1 NTHL1 POLE RPL35 NBN SDHC FAS SETBP1 KIT PIK3CA LMNA ABCB11 WT1 SDHB FAN1 ICOS SEMA3D SLC25A13 SDHC PIK3CA AAGAB RPL31 PMS2 RPGRIP1L MSH2 C11ORF95 GNAS HMBS ARSA SDHC BRCA2 SEMA4A TNFRSF13B PALB2 BRCA1 RAD51D POT1 FGFR3 DMPK FOXE1 SEC23B DCC TP53 RPL5 RPS27 RPS24 RPL35A FAS IGF2R PTEN ASCC1 SH3KBP1 AXIN1 G6PC1 APPL1 KRAS RPS19 IGF2 KRAS CASP10 STAT1 PTEN TNFRSF13C NFKB1 KCNQ1 RPL18 GCK EP300 BMPR1A RAD51 MINPP1 TERF2IP MSH6 DLEC1 HFE PDGFRA NFKB2 PHKA2 BMPR1A PALLD POLE TLR2 RNF43 SMAD4 AHCY PTCH2 SMAD4 SKIV2L MSH3 MITF HMBS MSH2 DZIP1L PDGFRL POU2AF1 SDHB NRAS GATA1 HBB HFE PALB2 UROD PIK3CA MET TSR2 SRC SDHB DLC1 KEAP1 JAG1 TNFSF15 CEP57 RELA AKT1 H19-ICR APC SLC25A13 TRIM28 SDHA TMEM67 BMPR1A MLH3 STAT6 FLCN CDKN1C SMAD7 APC APC RET HBB MLH1 CDKN1B BUB3 GPC3 DICER1 MLH1 PRKAR1A TRIP13 CDK4 MEG3 BMPR1A CTNNB1 MMEL1 INPP5E ATRX RASGRP1 CHEK2 TERT DLK1 SDHD CHEK2 RPS19 RPS29 RPL26 KLLN GPC3 HNF1A CDKN1B GPR35 IGF2 PTEN KCNQ1OT1 RAD51C CDKN1A MC1R PRKCD WT1 MSH6 PTPN12 PIK3CA GNAS KCNJ11 HNF1A MLH3 SDHB APC BRCA2 MSH6 TP53 SPRTN PTPRJ TNFSF12 AKT1 SDHC APC IRF5 SMAD4 GDNF SEMA3C HABP2 RPS28 CEL MSR1 SDHB
Protein Mutations 5
C10D G12D G12V G34A V600E
Protein Mutations 3
D89E S1009A V600E
SNP 0
HP:0001945: Fever
Genes 374
NLRP3 PSMB4 CHD7 NABP1 PTPN22 TRNK MTHFR ND6 GALC IGH SCYL1 LIFR TREX1 BCAP31 EIF2B5 G6PD NPM1 ZBTB16 ABCC2 EPB41 CTRC DDB2 CD247 ADAMTS13 POU6F2 ND2 IFNG NTRK1 LAMA3 SCNN1A IKZF1 ND1 SLC29A3 TNFRSF1A RAG2 NLRP3 CFTR CRLF1 TP53 MALT1 CD70 ATM CACNA1S TCF4 SLC19A3 PRSS1 IL12B HLA-DPA1 JAK2 XPA CPT2 PRSS2 CFTR IL10 NAB2 ATP13A2 NCF4 REST WIPF1 NLRP3 NCF2 IGH SPTA1 SCNN1B CHEK2 H19 PTPN3 CYBC1 HTR1A BCOR LAMC2 RYR1 RAG2 TMEM165 RNASEH2C RARA DST IL6 PMM2 NCF1 CYP11B2 CD3D COX1 UNC93B1 RB1 TRAF3 MPL PSMB8 EIF2B4 IL36RN MYD88 GCH1 TH TSC1 GAA CYBA HLA-DPB1 RIPK1 NLRP12 STAT4 SPTA1 MLX TRIP13 AVP CFHR1 ELANE MPL AVPR2 P4HTM ND4 IGLL1 MST1 SLC22A4 PTS LPIN1 TRIM28 TCF3 HNRNPK IGHM CD79A PIK3R1 NOD2 MTHFR RANBP2 RYR1 LACC1 AVPR2 STAT5B STXBP2 TRNW CD79B CTLA4 NLRP3 TET2 SPTB EIF2B2 HAVCR2 HLA-DRB1 ERCC3 CYBB CD3E BCL2 DIS3L2 FOXP1 IL23R COX2 SPINK1 STAT3 GLA PRKAR1A KCNJ1 RNF168 COX3 IL7R NLRP3 TRNV FBP1 STAT2 HBB IGH GALC STX11 MEFV SLC12A3 BACH2 LPIN2 STAT3 ATP1A2 CFH CALR SLC35C1 WT1 LIFR PEX6 TRNW PRTN3 EPB42 HMGCL MEFV NOD2 HLA-B TRNS1 DCLRE1C NGLY1 IBA57 TLR4 TRNH JAK2 RAG1 ORAI1 PMP22 CYBC1 MVK AQP2 PRNP ATP1A3 CACNA1A TREX1 MEFV GATA2 ERCC2 BRCA2 OTULIN BCR ND5 IRF2BP2 IFIH1 IFNGR1 WAS RYR1 CASK NLRC4 PSAP ERCC5 ZFHX2 NLRP3 SAMHD1 COL1A1 ND1 SH3KBP1 ASAH1 SLC29A3 LACC1 TCIRG1 ND4 TNFRSF1A MEFV ACAT1 STING1 STAT4 EDA SRP54 ELP1 LAMB3 VANGL2 RMRP IRF8 IRAK1 C4A QDPR TRNQ COL1A1 KLHL7 CCND1 CCR1 UNC13D EIF2B1 UBAC2 BTK BIRC3 HNRNPK MEFV CD27 TP53 ADA RNASEH2B FAS NLRC4 CFHR3 PSMB9 BCL10 TNFAIP3 PRF1 TICAM1 ND3 VANGL2 PSTPIP1 BCL6 SLC4A1 NUMA1 PADI4 CACNA1S JAK2 HMBS TRNT1 CYP21A2 SCNN1G F5 MIF NTRK1 EIF2B3 ALPL ITK CALR ERAP1 RAB27A WDR1 HBB SPP1 MYD88 TRNL1 TLR3 ADA2 LBR IRF8 HLA-DRB1 PTPN22 TET2 STIM1 KIF1B LYST PML TRIM28 TRNF ADAR NLRP3 GYPC FIP1L1 RAG1 STAT6 TBK1 ELANE ND5 HAVCR2 HMGCL TBL1XR1 COG6 KLRC4 PTPN22 AQP2 XIAP ND6 HLA-B RNASEH2A TRNS2 IL2RG SPTB NLRP1 POLR3A HLA-DRB1 LIG4 AK2 IL10 HLA-DRB1 PRKCD MVK NKX2-1 KRT18 LRRC8A SLC12A1 IL12A-AS1 ABL1 KRT8 GPC3 ELANE LPIN2 GPR35 CYP11B2 CIITA RUNX1 BLNK TSC2 WT1 IL2RG IL7R ERCC4 ATP6 ANK1 SH2B3 IL12A CD244 LIPA RAB27A GFI1 NGF SLC11A1 CYTB POMP NFKBIL1 BTNL2 XPC HLA-B TRNL1 PRKAR1A
HP:0001369: Arthritis
Genes 273
NLRP3 PSMB4 ACP5 SLC37A4 PTPN22 MIR140 LMNA HGD COL1A1 MMP13 FRZB MMP14 COL9A3 NTRK1 ARVCF PTPN22 LMX1B HPRT1 GBA HLA-C PFKM ABCG8 TNFRSF1A IL2RB RREB1 NLRP3 HPGD TF BTK JMJD1C COPA COL2A1 PIK3CD EXT1 COMP TBX1 IL12B STAT4 TNFRSF11B IL10 TBX1 GJB6 LRP6 IL2RA TRPV4 MUC1 WIPF1 COMP MMP13 GJB2 PSTPIP1 RNASEH2C HPRT1 DCLRE1C HIRA GP1BB TRAPPC2 IRF5 IL6 ATP7B EPCAM CLCN7 SEC24C HJV IL36RN COL3A1 KIF7 SLC37A4 GHR NLRP12 STAT4 SPTA1 MLX COL11A1 SLC40A1 HPGD PTPN2 SMAD3 IGLL1 COL9A1 PTPN22 SLC22A4 FGFR3 COL2A1 UMOD CCN6 IDS TCF3 PRPS1 IGHM MYH14 CD79A PIK3R1 FASLG COL1A1 HNF1B CD79B NLRP3 ASAH1 HLA-DRB1 PRKCD ANKRD55 HLA-B COL5A1 CCR6 DNAJB11 COL2A1 MATN3 IL23R KNSTRN GLA F8 PTPN22 RAG1 RNF168 COL5A1 PTPN2 COL11A2 TREX1 TFR2 COL11A2 SLC26A2 UMOD SLC12A3 FAS CD247 EPB42 VPS13A EXT2 NOD2 COL11A2 CLCN7 NOD2 HGD ZNF687 CLCNKB FCGR2B TLR4 IL2RA MVK COMP CTLA4 TREX1 MEFV CAV1 IFIH1 ANKRD55 WAS AGA MATN3 NLRP3 CFI FAS COL9A2 SAMHD1 UFD1 SH3KBP1 HNF1B ASAH1 LACC1 G6PC1 TNFRSF1A MEFV TRAPPC2 CASP10 ANKH STAT4 UFSP2 TRPV4 SMAD3 COL2A1 MYD88 GPR101 IRAK1 C4A HPRT1 ZMPSTE24 ACAN STAT4 CCR1 GCH1 UBAC2 BTK HFE CD247 AIP HPGD MEFV ACAN UFSP2 RNASEH2B FAS PSMB9 MTHFD1 COL2A1 GDF5 PSTPIP1 SLC4A1 RAG2 PADI4 OCRL PHEX COL9A1 COL9A3 MIF ANKH ERAP1 KIF22 SCARB2 SPP1 CANT1 MMP2 ADA2 LBR HLA-DRB1 PTPN22 FOXP3 PRPS1 CCN6 ADAR IL2RB NLRP3 GNAS COMP COL2A1 HPRT1 FBN1 KLRC4 DNASE1 ACP5 PHEX HLA-B RNASEH2A LEMD3 HOXD10 SPTB BTK HNF4A DNASE1L3 RASGRP1 ATP7B IL10 ASPN HLA-DRB1 PRKCD MVK LRRC8A IL12A-AS1 APOE ACAN LRBA AEBP1 CCN2 CIITA COMT BLNK SEC61A1 COL9A2 ANK1 COL5A2 CTLA4 PRG4 MATN3 IL12A CD244 TGFB3 FCGR2A F9 NFKBIL1 SLCO2A1 TRPS1 HLA-B IDS
Protein Mutations 4
A147T N363S R620W V600E