SNPMiner Trials by Shray Alag

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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation L861Q

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 92 clinical trials

Clinical Trials


1 A Phase II Study of Erlotinib and Chemotherapy for Patients With Stage IB-IIIA NSCLC With EGFR Mutations (ECON)

The purpose of this study is to try to improve the odds that your cancer may be cured. Pemetrexed and cisplatin are traditional chemotherapy drugs that have been shown to help some patients with non-small cell lung cancer. Many different types of cancer cells, including your type of lung cancer, have a protein on their surface called the epidermal growth factor receptor (EGFR). Stimulation of these receptors can result in growth of cancer cells and progression of cancer. In addition, your cancer has an EGFR mutation (a specific abnormality in the genetic code for EGFR). Erlotinib (TarcevaTM) is a newer drug which has shown benefit for patients with lung cancers that contain an EGFR mutation. Erlotinib works by blocking this receptor and depriving the cancer cells of this message to grow and multiply. In this research study, we plan to combine erlotinib with traditional chemotherapy drugs to see if the combination works better than chemotherapy alone. The main purpose of this research is to find out the good and bad effects that the combination of these 3 drugs (pemetrexed, cisplatin and erlotinib) has when given to patients with early stage non-small cell lung cancer before surgery. A secondary purpose is to find out the good and bad effects that occur when erlotinib is given to patients after surgery for 2 years.

NCT00577707
Conditions
  1. Non Small Cell Lung Cancer
  2. Lung Cancer
Interventions
  1. Drug: erlotinib
  2. Drug: Pemetrexed
  3. Drug: Cisplatin
  4. Procedure: Resection
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R --- --- L861Q ---

- Other serious illness or medical condition including unstable cardiac disease requiring treatment, history of significant neurologic or psychiatric disorders (including psychotic disorders, dementia, or seizures), or active uncontrolled infection - Women who are pregnant or breast-feeding - Psychiatric illness or social situation that would limit compliance with study requirements Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Complete Response (CR): Disappearance of all clinical evidence of tumor. Partial Response (PR): A 50% or greater decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Minor Response (MR): A > 25% and < 50% decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Stable Disease (SD): A less than 25% decrease. This includes a decrease of less than 25% in the sum of the products of the measured lesions, and any increase of less than 25% in the sum of the products of the measured lesions. There may be no appearance of new disease sites for this category. Progressive Disease (PD): A ≥25% increase in one or more lesions, or appearance of new lesions.

Measure: Number of Patients With Pathologic Complete Response Rate

Time: Patients will undergo a CT scan of chest every 3 months for year 1 and every 4 months for year 2. In years 3 and 4, a chest CT or chest x-ray every 6 months.

Secondary Outcomes

Measure: Number of Participants With Response After 21 Days of Single Agent Erlotinib for Stage IB-IIIA NSCLC With a Known EGFR Mutation

Time: calculate the response rate after 21 days of single agent erlotinib

Measure: Number of Patients With a Response Rate, 3-year Overall Survival and Median Survival of Patients With a Known EGFR Mutation Receiving Neoadjuvant Chemotherapy and Erlotinib (and Adjuvant Erlotinib).

Time: 3 years

2 A Phase Ib Open-label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Cetuximab (Erbitux®) in Patients With Non-small Cell Lung Cancer With Progression Following Prior Erlotinib (Tarceva®) or Gefitinib (Iressa®)

The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.

NCT01090011
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Cetuximab
  2. Drug: Cetuximab
  3. Drug: BIBW 2992
  4. Drug: BIBW 2992
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.. Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R --- --- L861Q ---

Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnancy or breast-feeding Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R --- --- L861Q ---

Primary Outcomes

Description: A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: CTCAE Grade 2 or higher decrease in cardiac left ventricular function CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days CTCAE Grade ≥3 rash despite standard medical management CTCAE Grade ≥3 fatigue lasting for more than 7 days CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.

Measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).

Time: from day 1 treatment until progression or undue toxicity, up to 28 days

Secondary Outcomes

Description: Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0

Measure: Highest CTCAE Grade

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Dose Reduction

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with adverse events leading to treatment discontinuation

Measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Death

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with drug-related serious adverse events

Measure: Frequency (%) of Patients With Related Serious Adverse Events

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy

Measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).

Measure: Concentration of Afatinib in Plasma for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.

Measure: Peak-trough Fluctuation (PTF)

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)

Measure: t1/2,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days

Measure: MRTpo,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)

Measure: CL/F,ss,15

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days

Measure: Vz/F,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.

Measure: Predose Plasma Concentrations of Afatinib for the Combination Arm

Time: Up to 57 days

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) 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; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.

Measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) 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; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.

Measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).

Measure: Duration of Objective Response (According to RECIST v1.1)

Time: up to 116 weeks

Description: Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.

Measure: Duration of Disease Control (According to RECIST v1.1)

Time: up to 116 weeks

Description: Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.

Measure: Progression-Free Survival (PFS) Time

Time: up to 116 weeks

3 A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors

Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.

NCT01259089
Conditions
  1. Adenocarcinoma of the Lung
  2. Non-small Cell Lung Cancer
Interventions
  1. Drug: erlotinib hydrochloride
  2. Drug: Hsp90 inhibitor AUY922
  3. Other: laboratory biomarker analysis
  4. Procedure: needle biopsy
  5. Genetic: mutation analysis
  6. Other: pharmacological study
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.. Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- T790M --- --- L858R --- --- L861Q ---

Gilbert's syndrome) Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- L858R --- --- L861Q ---

Primary Outcomes

Description: To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.

Measure: Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)

Time: During the first 4 weeks of treatment for each patient.

Description: Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions

Measure: Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922

Time: At 8 weeks from treatment initiation

Secondary Outcomes

Description: To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years

Description: Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Incidence of Reported Adverse Events in Phase I

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years

Description: Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show 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: Progression-free Survival (Phase II)

Time: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment

Description: Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.

Measure: Overall Survival (Phase II)

Time: From the time of first treatment with AUY922 to death, followed up to 2 years post treatment

Description: Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.

Measure: Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)

Time: From the time of first treatment with AUY922 to death, followed for up to 2 years

4 A Randomized Phase III Study of TaxoteRe Plus Cisplatin Versus AlImta Plus Cisplatin in 1st Line Non-squamous Cell Type Lung Cancer

This study is: - A multicenter, prospective, randomized, phase 3 trial. - To prove non-inferiority of Taxotere/Cisplatin compared to Pemetrexed/Cisplatin as a front line treatment of patients with non-squamous cell lung cancer. - 276 patients will be recruited.

NCT01282151
Conditions
  1. Carcinoma, Non Small Cell Lung
Interventions
  1. Drug: Taxotere
  2. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Inclusion Criteria: - Age >= 18 years old - ECOG performance status 0-2 - Non-squamous cell type non-small cell lung cancer (NSCLC) - Stage IV, Stage IIIB cannot be treated with curative intent or Relapsed after surgery or radiation therapy - No prior chemotherapy except adjuvant chemotherapy and concurrent chemoradiation treatment. --- L858R --- --- L861Q ---

Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Carcinoma, Non Small Cell Lung Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung Docetaxel is being used in 60mg/m2 3 weekly dosage in Japan and several east Asian institutions. --- L858R --- --- L861Q ---

Primary Outcomes

Description: months after beginning of first cycle chemotherapy

Measure: Progression Free Survival

Time: one year

Secondary Outcomes

Description: months from the beginning of first cycle chemotherapy

Measure: Overall Survival (months from the beginning of first cycle chemotherapy)

Time: three years

Description: Toxicity using CTCAE version 4.0

Measure: Safety Profile

Time: four months

Description: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Measure: Response rate

Time: 6-7th week

5 A Phase 1, Open-Label, Multiple-Ascending-Dose Study of DS-2248, an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Subjects With Advanced Solid Tumors

This phase 1 clinical trial is intended to understand the safety and tolerability of a new anticancer drug in subjects with advanced solid tumors. The patients who qualify for the study will receive a once daily dose of the drug taken by mouth and will undergo several tests to measure the drug in the blood and to understand the safety, tolerability and any effect of the drug on the tumor. The antitumor effect of the drug is not known in human.

NCT01288430
Conditions
  1. Solid Tumors
  2. Non-small Cell Lung Carcinoma
Interventions
  1. Drug: DS-2248
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

- Either of the following: A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) -OR- Prior objective clinical benefit from EGFR-TKI, as evidenced by complete response (CR), partial response (PR), or stable disease (SD) ≥6 months as defined by RECIST or World Health Organization criteria. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Objective response rate was defined as the sum of complete response (CR) and partial response (PR) rates. CR was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had 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.

Measure: Summary of Objective Response Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Secondary Outcomes

Description: Complete response (CR) was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to <10 mm. Partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Objective response rate (ORR) was defined as the sum of CR and PR rates.

Measure: Summary of Best Overall Response Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Description: Disease control rate (DCR) was defined as the sum of complete response (CR) and partial response (PR) rates, and stable disease (SD) rate for a minimum of 12 weeks. Complete response (CR) was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to <10 mm. Partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions), taking as reference the smallest sum diameters while on study.

Measure: Summary of Disease Control Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Description: Duration of response measured from the time at which criteria were first met for complete (CR) or partial response (PR) until the first date that progressive disease (PD) was objectively documented. Participants who had not progressed at the data cut-off date were censored at their last evaluable tumor assessment date. Duration of stable disease (SD) measured from the date of enrollment until the first date that criteria for disease progression were met. The minimum time interval for the duration of SD was 6 weeks. Participants who had not progressed at the data cut-off date were censored at their last evaluable tumor assessment date.

Measure: Duration of Stable Disease Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Description: Progression-free survival (PFS) defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of radiographic disease progression (as per RECIST V1.1) or death due to any cause. Participants who were alive with no objective documentation of (radiographic) disease progression by the data cut-off date were censored at the date of their last evaluable tumor assessment. Participants who were lost to follow-up or withdrew early from the study with no documented disease progression were censored at the last evaluable tumor assessment.

Measure: Summary of Progression-free Survival Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Measure: Summary of Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Infinity Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Maximum Concentration Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Time at Maximum Concentration Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Terminal Half-life Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Total Body Clearance Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Description: A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during treatment, having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the AE is continuous. A DS-2248-related TEAE is an TEAE that is related to DS-2248 in the relationship.

Measure: Summary of Drug Related Treatment Emergent Adverse Events Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to 30 days post last dose, up to 2 years 11 months

6 Phase II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Preclinical data in lung cancer cell lines showed that EGFR mutation can potentially be a positive predictor for sensitivity to BKM120. Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). Therefore, combining BKM120 with erlotinib could potentially down-modulate PI3K-Akt activity resulting in a synergistic effect on cell growth inhibition and enhancing the response to erlotinib.

NCT01487265
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: BKM120 and Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

These include, but are not limited to mutations in L858R (Exon 21); Exon 19 deletion; G719S, G719A, G719C mutations (Exon 19);or L861Q (laboratory report required at enrollment). --- L858R --- --- G719S --- --- G719A --- --- G719C --- --- L861Q ---

Primary Outcomes

Description: Percentage of patients who are alive and progression-free at 3 months (APF3) from first treatment.

Measure: Progression Free Survival at 3 Months

Time: 3 months

Secondary Outcomes

Description: Defined as the time from first treatment until death from any cause.

Measure: Overall Survival

Time: every 3 months after study treatment, projected 24 months

Description: Defined as the time from complete or partial response (CR or PR) until objective tumor progression. Tumor measurements will be obtained using CT scans of chest, abdomen and pelvis and assessed per RECIST v 1.1. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Duration of Response

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Defined as the percentage of complete and partial responses (CR + PR) among all patients. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Objective Response Rate

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Adverse events will be graded using CTCAE v4.3. and will be collected until 30 days after the discontinuation of study treatment for each participant. A non-serious adverse event is any untoward medical occurrence. A serious adverse event (SAE) is an event that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; requires intervention to prevent permanent impairment or damage. Specific AE and SAE terms are provided in the Adverse event module.

Measure: Number of Participants With Serious and Non-serious Adverse Events as a Measure of Safety.

Time: Every 2 weeks for 8 weeks, then every 8 weeks thereafter, estimated 24 months

7 Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) in Lung Adenocarcinoma Patients With Acquired Resistance to 1st Generation EGFR Tyrosine Kinase Inhibitors

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a 2nd line monotherapy agent in lung adenocarcinoma patients with acquired resistance to prior EGFR tyrosine kinase inhibitors (TKIs).

NCT01718847
Conditions
  1. Increased Drug Resistance
Interventions
  1. Drug: NOV120101 (Poziotinib)

Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R --- --- L861Q ---

Patients who cannot participate in this trial by investigator's judgment Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R --- --- L861Q ---

Primary Outcomes

Description: The length of time during and after medication or treatment during which the disease being treated (usually cancer) does not get worse.

Measure: Progression free survival (PFS)

Time: By 1 year after enrollment of the last subject

Secondary Outcomes

Description: The proportion of Patients maintaining progress-free status at 16 weeks

Measure: PFS rate at 16 weeks

Time: 16 weeks

Description: The proportion of patients with partial response or complete response at their best tumor treatment evaluation

Measure: Objective response rate (ORR)

Time: By 1 year after enrollment of the last subject

Description: The proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: By 1 year after enrollment of the last subject

Measure: Overall survival (OS)

Time: By 1 year after enrollment of the last subject

Measure: Time to progression (TTP)

Time: By 1 year after enrollment of the last subject

Measure: Time to objective response

Time: By 1 year after enrollment of the last subject

Measure: Duration of objective response

Time: By 1 year after enrollment of the last subject

Measure: Duration of disease control

Time: By 1 year after enrollment of the last subject

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: baseline and the end of treatment, by 1 year after enrollment of the last subject

Other Outcomes

Description: The study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a study drug. Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: By 3 months after enrollment of the last subject

Description: Subgroup analysis, in the context of design and analysis of study drug, refers to looking for pattern in a subset of the subjects according to genotype

Measure: Subgroup analyses with the genetic information

Time: by 1 year after enrollment of the last patient

8 Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of Simotinib Hydrochloride in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

The primary objective is to assess the safety and tolerability of multiple doses of Simotinib Hydrochloride in NSCLC patients. The secondary objective is to determine the pharmacokinetic (PK) profile and explore the preliminary anti-tumor activity.

NCT01772732
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Simotinib Hydrochloride
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC, who were previously treated with at least one platinum-based chemotherapy regimen, but had disease relapse; - Patients have ended their chemotherapy or radiotherapy at least 4 weeks prior to study entry and have recovered from any previous toxicity; - EGFR mutation positive (such as E19del, L858R, L861Q, G719X, etc.); - Patients with at least one measurable lesion meeting RECIST; - ECOG performance status 0-2; - Life expectancy ≥12 weeks; - Adequate bone marrow function: ANC ≥1.5 × 109/L, PLT≥80 ×109/L, HB ≥90 g/L; - Adequate hepatic function: serum bilirubin ≤ 2 × ULN, AST and ALT ≤ 2.5 × ULN, and ≤ 5 × ULN are acceptable if the liver has tumor involvement; - Adequate renal function: endogenous creatinine clearance rate (CrCl) ≥ 60 mL/min or serum creatinine ≤ 1.5 × ULN; - Females with childbearing potential must have a negative pregnancy test within 7 days prior to treatment and use an approved contraceptive method during the study; - Males must be surgically sterile or use an approved contraceptive method during the study. --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD)

Time: 28 days

Secondary Outcomes

Measure: The maximum plasma concentration (Cmax)

Time: d1,d8,d9,d10,d15

Measure: The time to Cmax (tmax)

Time: d1,d8,d9,d10,d15

Measure: Area under the plasma concentration-time curve (AUC)

Time: d1,d8,d9,d10,d15

Measure: Overall Response Rate (ORR)

Time: 1 year

Measure: Progression-free Survival (PFS)

Time: 1 year

9 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.

NCT01802632
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Advanced (Inoperable) Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients (with the exception of 1st line expansion cohort) must fulfil one of the following: - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR - Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI. - Previous treatment with a single-agent EGFR TKI (e.g. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for Dose Escalation Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for 80mg AZD9291 Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

10 A Randomized, Controlled Phase 2 Study Evaluating LY2875358 Plus Erlotinib Versus Erlotinib as First-Line Treatment in Metastatic Non-Small Cell Lung Cancer Patients With Activating EGFR Mutations Who Have Disease Control After an 8-Week Lead-In Treatment With Erlotinib

The primary purpose of this study is to compare the efficacy of the study drug LY2875358, given together with erlotinib, against erlotinib, alone. Participants will have Non-Small Cell Lung Cancer (NSCLC) that has advanced to Stage IV. Participants should not have been treated with drugs for Stage IV NSCLC, previously. All participants will get erlotinib alone, for approximately 8 weeks. Participants with radiographic disease control at the end of the erlotinib lead-in study period will be randomly assigned to receive LY2875358 plus erlotinib or erlotinib alone. Participants, who were chosen to receive erlotinib, alone, may cross over to the combination treatment at the time of progression.

NCT01897480
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Biological: LY2875358
  2. Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Progression Free Survival (PFS)

Time: Randomization to Objective Disease Progression or Death Due to Any Cause (Estimated 3 Years)

Secondary Outcomes

Measure: Change in Tumor Size (CTS)

Time: Baseline to Measurement with Smallest Tumor Size (Estimated 3 Years)

Measure: Proportion of Participants Exhibiting a Confirmed Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])

Time: Baseline to Objective Disease Progression or Start of New Anticancer Therapy (Estimated 3 Years)

Measure: Duration of Response (DoR)

Time: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Estimated 3 Years)

Measure: Time to Progressive Disease (TTPD)

Time: Randomization to Objective Disease Progression (Estimated 3 Years)

Measure: Proportion of Participants Exhibiting a Stable Disease (SD) or a confirmed CR or PR (Disease Control Rate [DCR])

Time: Baseline to Objective Disease Progression or Participant Stops Study (Estimated 3 Years)

Measure: Overall Survival (OS)

Time: Randomization to Death Due to Any Cause (Estimated 5 Years)

Measure: Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ) C30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13)

Time: Baseline, Objective Disease Progression or Participants Stops Study (Estimated 3 Years)

Measure: Pharmacokinetics (PK): Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) of LY2875358 and Erlotinib

Time: Baseline through Cycle 4 (28 Day Cycle)

Measure: Proportion of Participants with Anti-LY2875358 Antibody Response

Time: Baseline through 30 Day Follow Up (Estimated 3 Years)

11 Phase I Study of INC280 Plus Erlotinib in Patients With C-Met Expressing Non-Small Cell Lung Cancer

This phase I trial studies the side effects and best dose of c-Met inhibitor INCB028060 and erlotinib hydrochloride when given together in treating patients with previously treated non-small cell lung cancer. C-Met inhibitor INCB028060 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01911507
Conditions
  1. Recurrent Non-small Cell Lung Cancer
Interventions
  1. Drug: INC280
  2. Drug: erlotinib hydrochloride
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

G719X, exon 19 deletion, L858R, L861Q) - Systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or World Health Organization [WHO]) while on continuous treatment with gefitinib or erlotinib - Patients must have measurable disease; disease in previously irradiated sites is considered measurable if there is clear disease progression following radiation therapy - Failed 1-2 prior chemotherapies for advanced disease; prior erlotinib is allowed in the dose finding phase and expansion cohort A (Patients in expansion cohort B must be erlotinib naïve and have v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS] wild type tumor) - Patients must be willing to be off therapy for a minimum of two weeks (In expansion cohort A patients on erlotinib do not have to discontinue treatment) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Life expectancy greater than 3 months - Hemoglobin > 9 g/dL (International System [SI] units: 90 g/L) without transfusion support or growth factors within 10 days of starting INC280 - Platelet count >= 75 x 10^9/L - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L without growth factor support - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) - Serum creatinine =< 2 x ULN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting serum triglyceride level =< 500 mg/dL Exclusion Criteria: - Patients who have had major surgery within 4 weeks of initiation of study medication, excluding the placement of vascular access - Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data - Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia - Severely impaired lung function - Active (acute or chronic) or uncontrolled infection - Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy - Liver disease (i.e. --- L858R --- --- L861Q ---

Primary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Maximum tolerated dose (MTD) of c-Met inhibitor INCB028060 and erlotinib, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4

Time: Up to 28 days after a full course of therapy

Secondary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Toxicities as measured by NCI CTCAE V4

Time: Up to 30 days

Description: Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.

Measure: Overall response rate among patients with measurable disease, measured by RECIST 1.1

Time: Up to 30 days

Measure: Disease control rate, measured by RECIST 1.1

Time: Up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Progression-free survival

Time: Duration of time from start of treatment to time of progression or death, assessed up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Overall survival

Time: Duration of time from the start of treatment to death from any cause, assessed up to 30 days

Measure: Concentrations of c-Met inhibitor INCB028060 in plasma, measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay

Time: Days 15-16 of course 1, days 1 and 15 of course 2, and day 1 of courses 3-4

12 A Phase IB/II, Open Label, Multicenter Study of Selumetinib Administered Orally in Combination With Gefitinib in Patients With EGFR-mutated Non-small Cell Lung Cancer Who Have Developed Acquired Resistance of EGFR Inhibitor Treatment

This is an open-label, non-randomized, multicenter phase Ib/II study, which is composed of a phase Ib dose escalation part and a phase II dose expansion part. Patients will receive selumetinib in combination with gefitinib 250mg daily. This study will enroll EGFR-mutated NSCLC patients who have developed acquired resistance to EGFR TKI treatment.

NCT02025114
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: selumetinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A tumor harboring an EGFR mutation known to be associated with drug sensitivity (ie, exon 19 deletion , L858R, L861Q, G719X etc.). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Frequency and characteristics of DLTs to the selumetinib and gefitinib combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. (an expected average of 18 weeks) If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, then dose escalation may occur.

Measure: To determine the MTD and/or RP2D

Time: an expected average of 18 weeks

Secondary Outcomes

Description: to estimate overall clinical activity of selumetinib combined with gefitinib in EGFR-mutated NSCLC patients who have acquired resistance to EGFR TKIs

Measure: Overall Response Rate (ORR)

Time: Patients will be followed up for 2 years(post disease progression)

13 An Open-label, Randomized, Phase II Study of Erlotinib Monotherapy Versus Docetaxel and Cisplatin as Neoadjuvant Therapy in Patients of Stage IIIA Lung Adenocarcinoma With Epidermal Growth Factor Receptor Gene Mutation.

To compare clinical response (complete response and partial response) by RECIST) rates by RECIST between erlotinib monotherapy and docetaxel plus cisplatin chemotherapy

NCT02036359
Conditions
  1. Non-small Cell Lung Cancer(NSCLC)
Interventions
  1. Drug: erlotinib
  2. Drug: docetaxel
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Life expectancy > 12 weeks - Tumor specimen with EGFR gene mutation of exon 19 deletion and L858R, G719X, L861Q mutation - Adequate hematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL - Data of INR and PTT should be available in patients taking anticoagulants concomitantly, with INR ≤ 1.5 and PTT ≤ 1.5 times the upper limit of normal (x ULN ) within 7 days prior to starting study treatment - Adequate liver function: serum bilirubin ≤ 1.5 x ULN; transaminases ≤ 2.5 x ULN - Adequate renal function: 24-hour urine creatinine clearance or creatinine clearance measured and calculated according to the formula of Cockroft and Gault ≥ 60ml/min - Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women - Written informed consent. --- L858R --- --- L861Q ---

Those with exon 19 deletion and L858R, G719X, L861Q mutation were randomized as erlotinib monotherapy or docetaxel plus cisplatin chemotherapy. --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Number of Adverse Event

Time: Within 28 days of last study dose

14 Phase I, Open-label, Safety, Tolerability and Preliminary Efficacy Study of Tremelimumab in Combination With Gefitinib in EGFR Mutant NSCLC Patients

This is an open-label phase 1, safety, PK, and preliminary efficacy study of oral Gefitinib and IV Tremelimumab in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as Erlotinib or Gefitinib. The primary objective of this phase I, is to determine the safety and tolerability of oral Gefitinib in combination with escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Secondary objectives include evaluation of, pharmacokinetics, immunogenicity, antitumor activity of Gefitinib and Tremelimumab combination. The exploratory objectives are to evaluate biomarkers that may correlate with activity or prospectively identify patients likely to respond to Tremelimumab and Gefitinib. The biological rationale for such a study is that even though the disease is progressing it is likely that EGFR sensitive clones, although diminished under the pressure from the EGFR TKI, are still present. Therefore, withdrawing the inhibitory pressure of the EGFR TKI can potentially allow regrowth of the EGFR sensitive cells. On the other hand, the proliferation of EGFR resistant clones needs to be suppressed by another therapeutic approach. Until today no association of chemotherapy and TKI EGFR has demonstrated clinical benefit. Moreover, patients may have received chemotherapy and the likelihood of chemosensitivity is very low. So, the association of Gefitinib with immune checkpoint blockade is very attractive and may result in clinical benefit in NSCLC with EGFRmut.

NCT02040064
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Tremelimumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R --- --- L861Q ---

- Previous allogenic bone marrow transplant Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R --- --- L861Q ---

Primary Outcomes

Description: The primary objective of this phase 1 study is to determine the safety and tolerability of oral Gefitinib in combination with three escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Overall safety profile will be characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCICTCAE] Version 4.03), timing of adverse events and laboratory abnormalities in the first and in the following cycles

Measure: safety and tolerability of the association between Gefitinib (fixed dose) and Tremelimumab (dose escalation)

Time: Up to 42 days

Secondary Outcomes

Description: To obtain a preliminary assessment of the anti-tumour activity of Gefitinib + Tremelimumab by evaluation of tumour response using modified Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and evaluation of Disease control rate and PFS

Measure: Anti-tumour activity of Gefitinib + Tremelimumab

Time: From day 1 cycle 1 every 8 weeks for 24 weeks and then every 6 weeks until progression or death whichever comes first assessed up to 30 months

Description: Immunogenicity results will be analyzed descriptively by summarizing the number and percentage of subjects who develop detectable anti-Tremelimumab antibodies. The immunogenicity titer will be reported for samples confirmed positive for the presence of anti-Tremelimumab antibodies.

Measure: Immunogenicity of Tremelimumab in combination with Gefitinib

Time: At day 1 cycle 1 and then every 8 weeks from day 1 cycle 2 until progression or death whichever comes first assessed up to 30 months

Description: Gefitinib pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)

Measure: Pharmacokinetics of Gefitinib

Time: At first Tremelimumab administration and then every 4 weeks until progression or death whichever comes first assessed up to 30 months

Description: Tremelimumab pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)

Measure: Pharmacokinetics of Tremelimumab

Time: Before and after injection of Tremelimumab at day 1 cycle 1 and at day 8 and day 15 of cycle 1 and then before and after injection at day 1 for every cycle (4 weeks) until progression or death whichever comes first assessed up to 30 months

15 Erlotinib Treatment Beyond Progression in EGFR Mutant or Patients Who Have Responded EGFR TKI in Stage IIIB/IV NSCLC

The purpose of this study is to determine whether continuing erlotinib beyond disease progression in combination with chemotherapy is beneficial for NSCLC patients who have EGFR mutant disease or who have responded to EGFR TKI.

NCT02064491
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Chemotherapy
MeSH:Carcinoma, Non-Small-Cell Lung Disease Progression
HPO:Non-small cell lung carcinoma

- Investigator confirmed progression according RECIST 1.1 during EGFR TKI treatment within 28 days of the randomization - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Performance status: WHO 0-2 - Measurable disease according to RECIST 1.1 - Patients must be able to comply with study treatments - Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study - Neutrophils ≥ 1'000/μl, Platelets ≥ 100'000/μl, Alanine amino transferase ≤ 2.5 × Upper limit of normal (ULN) (< 5 × ULN if liver metastases), Alkaline phosphatase ≤ 2.5 × ULN (< 5 × ULN if liver metastases), Serum bilirubin ≤ 1.5 × ULN, Serum Creatinine ≤ 1.5 × ULN. - Patient must be able to comply with the protocol Exclusion Criteria: - RECIST 1.1 defined disease progression for more than 28 days while on previous EGFR TKI treatment. --- G719A --- --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Progression-free survival of the whole study population and in the strata 1-2

Time: An expected average of 36 weeks after last subject enrolled into our study

Secondary Outcomes

Measure: Overall Survival

Time: An expected average of 52 weeks after last subject enrolled into our study

Measure: Overall Response Rate

Time: An expected average of 36 weeks after last subject enrolled into our study

Measure: Rate of non-progression at 9 and 18 weeks

Time: 18 weeks after date of randomization of a last patient

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety and toxicity

Time: An expected average of 52 weeks after last subject enrolled into our study

16 Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

NCT02094261
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

17 An Open-label, Phase 1 Dose Escalation Study of Oral ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations

The purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.

NCT02113813
Conditions
  1. Non-Small-Cell Lung Cancer (NSCLC)
  2. Epidermal Growth Factor Receptor Mutations
Interventions
  1. Drug: naquotinib
  2. Drug: midazolam
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.. Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q ---

Exclusion Criteria: - Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment - Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days - Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV) - Symptomatic Central Nervous System (CNS) metastasis - Active infection requiring systemic therapy within 14 days - Severe or uncontrolled systemic diseases including uncontrolled hypertension - History of or active interstitial lung disease - Screening QTcF >450 msec or current medication known to prolong QT - ≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months - History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction - Concurrent corneal disorder or ophthalmologic condition making subject unsuitable - RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days - Any other malignancy requiring treatment Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03.

Measure: Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)

Time: up to 18 months

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Measure: Safety and tolerability as assessed by adverse events (AEs)

Time: up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.

Measure: Safety and tolerability as assessed by laboratory tests

Time: up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature.

Measure: Safety and tolerability as assessed by vital signs

Time: up to 18 months

Measure: Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)

Time: up to 18 months

Secondary Outcomes

Description: Maximum concentration (Cmax), the time after dosing when Cmax occurs (tmax), area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast), area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf), apparent terminal elimination half-life (t1/2), apparent oral systemic clearance (CL/F), Apparent volume of distribution (Vz/F)

Measure: Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3

Measure: Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2

Description: Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.

Measure: Best overall response rate

Time: Up to 18 months

Description: Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.

Measure: Disease control rate

Time: Up to 18 months

Description: Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.

Measure: Progression free survival

Time: Up to 18 months

18 A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of a Single Oral Dose of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2 part study in patients with EGFRm+ non small cell lung cancer (NSCLC), whose disease has progressed on an EGFRm TKI, who are refractory or resistant to standard therapy. Part A will assess the effect of multiple oral doses of itraconazole on the single dose pharmacokinetic (PK) parameters of AZD9291. On completion of Part A, patients may continue to take AZD9291 tablets (Part B) following the collection of the 216 hour sample on Day 19 if they and the Investigator deem it appropriate, until such time as their disease progresses, the Investigator believes they are no longer deriving clinical benefit, or they stop taking AZD9291 for any other reason.

NCT02157883
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Advanced (Inoperable) Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling
  2. Drug: AZD9291
  3. Drug: Itraconazole
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. ECOG performance status 0-1 with no deterioration over the previous 2 weeks. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Secondary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours

Measure: AUC(0-120) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration curve from time zero to last quantifiable dose

Measure: AUC(0-t) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax

Measure: Tmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life

Measure: t1/2 of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution

Measure: Vz/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of maximum plasma AZ5104 concentration

Measure: Cmax of AZ5104

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of maximum plasma AZ7550 concentration

Measure: Cmax of AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

19 An Open-label, Randomised, Phase I, Study to Determine the Effect of Food on the Pharmacokinetics of Single Oral Doses of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2-part study in patients with epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung cancer (NSCLC) whose disease has progressed on treatment with an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI): Part A will determine the effect of food on the pharmacokinetics (PK) of AZD9291; Part B will allow patients further access to AZD9291 and will provide for additional safety data collection. Part A is a randomised, open-label, 2 treatment period crossover study in which patients will each receive a single oral dose of AZD9291 (1 x 80 mg tablet) at breakfast time (approximately 0800) in each of 2 treatment periods (once immediately following a high fat meal [fed], and once in the fasted state [fasted]), with a washout period of 9 days between doses. Approximately 38 patients are planned to be enrolled and dosed; at least 30 evaluable patients will be required to complete Part A (ie, the last PK sample in Treatment Period 2 [TP 2] has been collected). Additional patients may be enrolled to allow for at least 30 evaluable patients.

NCT02163733
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Advanced (Inoperable) Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291 tablets
  2. Procedure: Pharmacokinetic sampling - AZD9291
  3. Other: Dietary Fasted
  4. Other: Dietary High Fat
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 72 hours.

Measure: AUC(0-72) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration.

Measure: Cmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Secondary Outcomes

Description: Area under the plasma concentration curve from zero extrapolated to infinity.

Measure: AUC of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Area under the plasma concentration curve from time zero to last quantifiable dose.

Measure: AUC(0-t) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours.

Measure: AUC(0-120) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax.

Measure: Tmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life.

Measure: t1/2 of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration.

Measure: CL/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution.

Measure: Vz/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 72 hours.

Measure: AUC(0-72) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of maximum plasma concentration.

Measure: Cmax of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Area under the plasma concentration curve from time zero to last quantifiable dose for AZ5104 and AZ7550 (metabolites to AZD9291).

Measure: AUC(0-t) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 120 hours.

Measure: AUC(0-120) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of time to Cmax.

Measure: Tmax of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of the terminal half-life.

Measure: t1/2 of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

20 A Multicenter Randomized Phase III Study Comparing Second-line Treatment With Chemotherapy Associated or Not to Erlotinib in NSCLC Patients With Secondary Resistance to TKI-EGFR

The current first line treatment of patients with EGFR activating mutation lung cancer is EGFR TKI. Compared to platinum-based chemotherapy, EGFR-TKIs are superior in terms of response rate and progression-free survival. However, an acquired resistance occurs almost constantly. The second-line treatment includes platinum-based chemotherapy in the absence of contraindication. This chemotherapy is then administered after discontinuing EGFR TKIs. However, a rebound phenomenon of the disease was described in patients who discontinued EGFR TKIs. Some clinical teams therefore recommend, as a precaution, in order to avoid any withdrawal phenomenon, to never discontinue EGFR TKIs in patients developing an EGFR TKI acquired resistance. It seems therefore useful to conduct a study to better define the therapeutic strategy to adopt in patients developing an acquired resistance after having received EGFR TKIs as first line treatment.

NCT02178397
Conditions
  1. NSCLC Patients With EGFR Activating Mutation
Interventions
  1. Drug: ERLOTINIB WITH CHEMOTHERAPY
  2. Drug: CHEMOTHERAPY ONLY
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Presence of one of the EGFR activating mutations in the tumor (exon 19 deletion or L858R, G719X or L861Q) - One additional line of previous chemotherapy is allowed if administered in adjuvant or neoadjuvant setting and received more than six months before. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Efficacy will be assessed by the PFS, define as time between randomization of the patient in the study and disease progression (local, regional, distant and second cancer) or death (all causes). Alive patients free of progression will be censored at the last follow-up.

Measure: Efficacy by PFS

Time: From date of randomization until the date of first documented progression evaluated every 6-9 weeks

Secondary Outcomes

Description: difference between the scores of QoL at baseline and at 4 months after inclusion for the three targeted dimensions of EORTC QLQ-C30 (global quality of life, fatigue and physical functioning). A difference or 10 points or more at 4 months after inclusion for one score between the 2 arms will be considered as clinically relevant.

Measure: scores of QoL

Time: at 4 months after inclusion

Description: Overall survival defined as time interval between randomization and death (all causes). Alive patients will be censored at the last date of news or data cut off

Measure: Overall survival

Time: From date of randomization until the date of death from any cause, whichever came first, assessed up to 100 months

Description: Tumoral response (complete response, partial response, stable disease, progression) according to RECIST 1.1

Measure: Tumoral response

Time: every 6-9 weeks

Description: Toxicities according to NCI-CTC-AE v.4

Measure: Toxicities

Time: From date of randomization until study participation, assessed up to 100 months

Description: Rebound phenomenon (flare) defined by a hospitalization or a death within 3 weeks for disease progression after the end of TKI EGFR treatment (in the arm without EGFR TKI) and date of onset

Measure: Rebound phenomenon (flare)

Time: within 3 weeks after disease progression before inclusion

21 An Open-label Study of the Oral Administration of ASP8273 in Patients With Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

Purpose of the study is to determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. - the safety and tolerability of ASP8273. - the pharmacokinetics (PK) of ASP8273. - the antitumor activity of ASP8273.

NCT02192697
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: ASP8273
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the del ex19, L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R --- --- L861Q ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using the Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE ver 4.0 - JCOG)

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by Dose Limiting Toxicities (DLTs)

Time: Up to Day 23

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR) at Week 24

Time: Week 24

Secondary Outcomes

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Measure: Phase I: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase I: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase I: Overall response rate (CR+PR)

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase I: Disease control rate (CR+PR+SD)

Time: Up to 18 months

Measure: Phase II: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase II: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase II: Disease control rate

Time: Up to 18 months

Measure: Phase II: Progression-free survival (PFS)

Time: Up to 18 months

Measure: Phase II: Overall survival (OS)

Time: Up to 18 months

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR)

Time: Up to 18 months

22 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Simvastatin (a Sensitive CYP3A4 Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197234
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling - AZD9291
  2. Drug: Simvastatin
  3. Drug: AZD9291 tablet dosing
  4. Procedure: Pharmacokinetic sampling - simvastatin
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration

Measure: Cmax of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Secondary Outcomes

Description: Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax

Measure: Tmax of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration

Measure: CL/F of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration

Measure: Cmax of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose

Measure: AUC(0-t) of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

23 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of Rifampicin (a CYP3A4 Inducer) on the Pharmacokinetics of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of rifampicin on the pharmacokinetic (PK) parameters of AZD9291 and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients who complete Part A will be able to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197247
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling - AZD9291
  2. Drug: Rifampicin
  3. Drug: AZD9291 tablet dosing
  4. Procedure: Pharmacokinetic sampling - rifampicin
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of Css,Max for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of AUCtau for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of AUCtau for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Tss,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Min for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of CLss/F for AZD9291

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of CLss/F for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

24 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Rosuvastatin (a Sensitive BCRP Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of rosuvastatin, following multiple oral dosing of AZD9291 in the fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily as a single agent until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02317016
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling - AZD9291
  2. Drug: AZD9291 tablet dosing
  3. Drug: Rosuvastatin
  4. Procedure: Pharmacokinetic sampling - rosuvastatin
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 [Period 1] and Day 32 [Period 3], respectively).

Measure: Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC0-t. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration at Time "t" (AUC0-t) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of CL/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance (CL/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of Vz/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Volume of Distribution (Vz/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of t1/2(lambda_z). Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Terminal Elimination Half-life (t1/2[lambda_z]) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of AUCtau. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUCtau) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Maximum Plasma Concentration at Steady State (Css,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of tss,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,min over the dosing interval. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Minimum Plasma Concentration at Steady State (Css,Min) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291 by assessment of CLss/F after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance at Steady State (CLss/F) for AZD9291 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRCss,max for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of Css,Max (MRCss,Max) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRAUCtau for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of AUCtau (MRAUCtau) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

25 A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.

The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

NCT02335944
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: INC280
  2. Drug: EGF816
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

L861Q, G719X, S768I) - Presence of at least one measurable lesion according to RECIST v.1.1 - ECOG performance status ≤1 - Patients must be screened for HBV. --- L861Q ---

Primary Outcomes

Measure: Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D)

Time: First 28 days of treatment

Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1

Time: At least 24 weeks

Description: Frequency of treatment-emergent adverse events

Measure: Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity

Time: At least 24 weeks

Secondary Outcomes

Description: Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II)

Time: At least 24 weeks

Description: Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II)

Time: At least 24 weeks

Description: ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Overall Response Rate (Phase Ib and Phase II Group 4)

Time: At least 24 weeks

Description: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Disease Control Rate (Phase I/II)

Time: At least 24 weeks

Description: Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Progression Free Survival (Phase I/II)

Time: At least 24 weeks

Description: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Duration of Response (Phase I/II)

Time: At least 24 weeks

Description: OS is defined as the time from first dose of the study treatment to the date of death due to any cause.

Measure: Overall Survival (Phase I/II)

Time: At least 24 weeks

Measure: Plasma concentration versus time profiles

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Description: TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Time to Response (Phase I/II)

Time: At least 24 weeks

26 A Phase I/Ib Trial of MK-3475 (Pembrolizumab) and Afatinib in EGFR-Mutant Non-small Cell Lung Cancer With Resistance to Erlotinib

This phase I/Ib trial studies the side effects and best dose of pembrolizumab when given together with afatinib dimaleate in treating patients with non-small cell lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or has come back and does not respond to erlotinib hydrochloride. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and afatinib dimaleate together may be an effective treatment for non-small cell lung cancer.

NCT02364609
Conditions
  1. Recurrent Non-Small Cell Lung Carcinoma
  2. Stage IIIA Non-Small Cell Lung Cancer
  3. Stage IIIB Non-Small Cell Lung Cancer
  4. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib Dimaleate
  2. Biological: Pembrolizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.. Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R --- --- L861Q ---

Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) - Subjects that require treatment with a strong inhibitor of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) will be excluded; they may be included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and they are willing to switch prior to enrollment; if a subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug administration - Receiving drugs known to be strong inducers or inhibitors of permeability (P)-glycoprotein that are known to interact with afatinib including, but not limited to: ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone; 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; the subject must stop the strong inducer or inhibitor of P-glycoprotein 7 days before or 5 half lives before study drug administration (whichever timepoint is longer) - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study - Hormonal treatment within 2 weeks prior to start of study treatment - Radiotherapy within 4 weeks prior to enrollment, except as follows: - Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to enrollment, and - Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor-investigator prior to enrolling - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of study Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Descriptive summaries will be provided for number and proportion with specific type and grade of toxicities.

Measure: Maximum tolerated dose (MTD) recommended dose of pembrolizumab in combination with lead in pembrolizumab and afatinib dimaleate

Time: Day 21

Description: Will be determined by the overall assessment of the MTD and toxicities observed in the dose de-escalation portion of this study.

Measure: Recommended phase II dose

Time: Day 21

Secondary Outcomes

Description: Descriptive summaries will be provided for numbers and proportion of patients responding.

Measure: Overall response rate per RECIST 1.1

Time: Up to 3 years

Description: Kaplan-Meier plot and life-table summary will be used.

Measure: Progression free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years

Other Outcomes

Description: Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in plasma EGFR-mutant DNA levels

Time: Baseline to up to 3 years

Description: Descriptive associations with response rate and PFS will be performed. Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in PDL1 expression by immunohistochemistry

Time: Baseline to up to 3 years

27 T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry

The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin).

NCT02368990
Conditions
  1. Non Small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation prior to enrolment into the study that the tumour harbours the following EGFR mutations known to be associated with EGFR-targeted TKI sensitivity: Ex19Del, L858R, L861Q, and G719X. --- L858R --- --- L861Q ---

There are Epidermal Growth Factor Receptor (EGFR) mutations known to be associated with EGFR-targeted TKI sensitivity ( Ex19Del, L858R, L861Q, and G719X). --- L858R --- --- L861Q ---

Primary Outcomes

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause or censoring (at end of 24 months).To assess efficacy of permetrexed + cisplatinum/carboplatin as the 2nd line of treatment of NSCLC.

Measure: Overall Survival

Time: 24 months from last subject in

Secondary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visits

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the date of complete or partial response until the first date of recurrence or progression. To assess the efficacy of 2nd line treatment and beyond.

Measure: Duration of Response as defined by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause. This will be done to assess efficacy of pemetrexed + cisplatin/carboplatin as the 2nd line treatment of NSCLC.

Measure: Progression Free Survival

Time: 24 months from last subject in

28 A Phase Ib, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumour Activity of Volitinib in Combination With Gefitinib in Patients With Epidermal Growth Factor Receptor-mutated Non-small Cell Lung Cancer Who Have Progressed on Epidermal Growth Factor Receptor Inhibitor Treatment

This is a Phase 1b, open-label, multicentre study of AZD6094 in combination with gefitinib in patients with epidermal growth factor receptor (EGFR) mutation positive (m+) and progressed on EGFR Tyrosine kinase inhibitor (TKI) treatment.

NCT02374645
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Volitinib
  2. Drug: gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed locally advanced or metastatic NSCLC patients who are harbouring an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X). --- L858R --- --- L861Q ---

Primary Outcomes

Description: the grade of AE event according to CTC AE 4.0

Measure: Number of adverse events and serious adverse events

Time: From ICF signed to within 28 days after the last dose

Secondary Outcomes

Description: Peak Plasma Concentration (Cmax)

Measure: The Pharmacokinetics (PK) profiles of AZD6094

Time: Cycle 1 Day1 and Day 15

Description: Area under the plasma concentration versus time curve (AUC)

Measure: The Pharmacokinetics (PK) profiles of AZD6094

Time: Cycle 1 Day1 and Day 15

Description: 6-months PFS, 12 months PFS and 24 month PFS

Measure: Progression-free survival (PFS)

Time: from enrolled until progression or death due to any cause, assessed up to 2 year

Description: CR+PR+SD

Measure: Disease control rate(DCR)

Time: 12 weeks and 24 weeks

29 Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study

The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure.

NCT02418234
Conditions
  1. Non-small Cell Lung Cancer Stage III
  2. Non-Small-Cell Lung Cancer Metastatic
Interventions
  1. Other: mutation detection
  2. Other: ARMS and ddPCR
  3. Genetic: ctDNA analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Investigator confirmed progression according RECIST 1.1 during EGFR-TKI treatment within 28 days of the enrollment - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Patient must be able to comply with the protocol Exclusion Criteria: - Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined disease progression for more than 28 days while on previous EGFR-TKI treatment. --- G719A --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).

Measure: Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay

Time: up to 2 years

Description: The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.

Measure: Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient

Time: up to 2 years

Secondary Outcomes

Description: The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure

Time: up to 2 years

Description: The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure

Time: up to 2 years

30 A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02442349
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, N Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---

Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, N Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in Asia Pacific patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) sensitising mutation positive (ie, G719X, exon 19 deletion, L858R, L861Q) and T790M mutation positive (hereafter referred to as EGFRm+ and T790M+) un-resectable, locally advanced or metastatic NSCLC (Stage IIIB-IV), who have progressed on an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(EGFR-TKI), either as first line treatment or following one line of EGFR-TKI and one line of platinum containing doublet chemotherapy. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time of first dose until objective disease progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time first dose until date of progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

31 Pilot Study of Local Therapies for Oligometastatic Non-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations

This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.

NCT02450591
Conditions
  1. Oligometastatic Lung Adenocarcinoma
Interventions
  1. Drug: Erlotinib
  2. Other: Local Therapies
MeSH:Adenocarcinoma of Lung

At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.. Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---

- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---

Primary Outcomes

Description: At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.

Measure: Feasibility as Measured by at Least Five Patients Will Need to Complete Local Therapy.

Time: 2 years

32 A Single Arm, Open-label, Phase 2 Study Evaluating the Efficacy, Safety and PK of HM61713 in Patients With T790M-positive NSCLC After Treatment With an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor

The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT02485652
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: HM61713
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: To assess the anti-tumor efficacy of HM61713 as measured by objective response rate (ORR).

Measure: Objective response rate (ORR)

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Secondary Outcomes

Description: To assess clinical efficacy of HM61713 regarding disease control rate (DCR).

Measure: Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Duration of overall tumor response (DR).

Measure: Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Progression-free survival (PFS).

Measure: Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Overall survival (OS).

Measure: Overall survival (OS), defined as the time from first administration of study drug until death from any cause

Time: From first dose to end of study or date of death from any cause whichever came first, assessed up to 48 months

Description: To assess clinical efficacy of HM61713 regarding Time to progression (TTP).

Measure: Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding tumor shrinkage.

Measure: Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST tumor response

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Peak concentration (Cmax) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Trough plasma concentration (Ctrough) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Area under the plasma concentration time curve over the 24-hour dosing interval (AUC) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status.

Measure: Patient reported outcomes (PROs)

Time: At baseline and every 6 weeks from time of discontinuation, assessed up to 24 months

Description: To evaluate the effect of HM61713 on the QT interval.

Measure: ECG/QTc (absolute values and change from baseline)

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: Incidence of reported AEs and abnormal laboratory tests (AEs will be assessed using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4).

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: QTc interval as assessed by digital ECG with central reading. The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.

Time: Adverse events will be collected from baseline until 28 days after the last dose

33 A Phase I Trial of AZD9291 and Necitumumab in EGFR-Mutant Non-Small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be a better treatment for EGFR-mutant non-small cell lung cancer.

NCT02496663
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Necitumumab
  2. Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); 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 - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); 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 - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); 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 - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); 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 - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 5.0. The recommended phase II dose (RP2D) will be the MTD, pending review of other safety/tolerability considerations. The RP2D will be determined based upon the MTD in the dose escalation portion as well as other considerations such as toxicities at additional courses. After completing the 4 expansion cohorts, the dose level will be re-reviewed to confirm that the RP2D is in fact well tolerated.

Measure: Maximum tolerated dose (MTD) of necitumumab combined with osimertinib

Time: 21 days

Description: Will be graded according to NCI CTCAE version 5.0. Grade and attribution will be summarized by dose level, cycle, organ system and type.

Measure: Incidence of toxicity

Time: Up to 1 year

Secondary Outcomes

Description: Will be graded according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR). Point estimates and associated 90% confidence intervals will be calculated.

Measure: Objective response rate (ORR) in patients treated at the recommended phase II dose

Time: Up to 1 year

Description: Kaplan-Meier plots will be used to summarize the progression-free survival. Medians and associated 95% confidence intervals will be calculated.

Measure: Progression-free survival (PFS)

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

Description: DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease. Point estimates and associated 90% confidence intervals will be calculated.

Measure: Disease control rate (DCR) with combination osimertinib and necitumumab

Time: Up to 1 year

Other Outcomes

Description: The PK analyses will be descriptive and will permit comparison of the plasma levels of osimertinib and its metabolites in the presence of necitumumab (in this trial) with levels in other studies where osimertinib is given alone or combined with other drugs. We will estimate mean PK parameters as well as the between-patient variability. Results will be listed and plotted, by dose as well as by objective response, qualitative patterns will be described, and means and standard deviations will be calculated for use in planning follow-up studies.

Measure: Pharmacokinetic (PK) parameters of osimertinib in combination with necitumumab

Time: Prior to dosing on day 1 of course 2, 1, 2, 4, 6, 8, and 24 hours after dosing in course 2 (dose escalation and cohort A); prior to treatment on day 1 of course 2 for up to 4 courses (cohorts B, C, and D)

Description: Will study biopsied tumor tissue as well as serial plasma deoxyribonucleic acid specimens. For each cohort alone, Fisher's exact test, and in a stratified analysis including all cohorts, an exact logistic regression model, will be used to examine the association with objective response and a Cox proportional hazards model will be used to examine the association with PFS. Odds ratio's and hazard ratio's will be estimated and associated 90% two-sided confidence intervals will be constructed. Testing will be one-sided, at the 0.05-level.

Measure: Presence of biomarkers of response and resistance to previous EGFR-tyrosine kinase inhibitors

Time: Up to 1 year

34 Phase II Study of ASP8273 - An Open-Label, Study of the Oral Administration of ASP8273 in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-NaïvePatients With Non-Small Cell Lung Cancer Harboring EGFR Mutations

The purpose of this study is to determine the safety, the antitumor activity and the pharmacokinetics of ASP8273 in EGFR tyrosine kinase inhibitor (EGFR-TKI)-naïve patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations.

NCT02500927
Conditions
  1. EGFR-TKI-naïve Patients With NSCLC Harboring EGFR Activating Mutations
Interventions
  1. Drug: ASP8273 Capsules
  2. Drug: ASP8273 Capsules A
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the deletion of exon 19 (del ex19), L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Safety assessed by AEs

Time: Up to 18 months

Measure: Safety assessed by Laboratory tests

Time: Up to 18 months

Measure: Safety assessed by Vital signs

Time: Up to 18 months

Measure: Safety assessed by Percutaneous oxygen saturation (SpO2)

Time: Up to 18 months

Measure: Safety assessed by Body weight

Time: Up to 18 months

Description: ECG: Electrocardiogram

Measure: Safety assessed by 12-lead ECG

Time: Up to 18 months

Measure: Safety assessed by Ophthalmologic examination

Time: Up to 18 months

Measure: Safety assessed by Chest X-ray examination

Time: Up to 18 months

Measure: Safety assessed by Chest computed tomography (CT) examination

Time: Up to 18 months

Measure: Safety assessed by ECOG Performance Status

Time: Up to 18 months

Secondary Outcomes

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR) or Partial Response (PR)among all analyzed subjects

Measure: Overall response rate

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR), Partial Response (PR), or Stable disease (SD) among all analyzed subjects

Measure: Disease control rate

Time: Up to 18 months

Measure: Plasma concentrations of unchanged ASP8273

Time: Up to Day1 of Cycle 3

35 A Phase 1B Study of AZD9291 in Combination With Navitoclax in EGFR-Mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor

This phase Ib trial studies the side effects and best dose of osimertinib and navitoclax when given together and to see how well they work in treating patients with previously treated epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer that has spread to other places in the body (metastatic) or has not responded to previous treatment with initial EGFR kinase inhibitor. Osimertinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02520778
Conditions
  1. Advanced Lung Non-Squamous Non-Small Cell Carcinoma
  2. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  3. Stage III Lung Non-Small Cell Cancer AJCC v7
  4. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  5. Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  6. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Navitoclax
  2. Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R --- --- L861Q ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - 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 - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; 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 - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have 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 AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. 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: Incidence of toxicity (dose escalation)

Time: Up to 2 years

Description: Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with > 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).

Measure: Feasibility of the combination therapy in T790M+ lung cancer (dose expansion)

Time: Up to 12 weeks (3 cycles of treatment)

Secondary Outcomes

Description: Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.

Measure: Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax

Time: Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2)

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.

Measure: Objective response rate

Time: Baseline up to 30 days after completion of study drug

Description: Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.

Measure: Change in plasma concentration of EGFR T790M and other EGFR mutations

Time: Baseline to up to 2 years

Description: Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.

Measure: Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue

Time: Baseline

36 Phase I, Open-Label, Two Parts Study in Chinese Patients With Advanced NSCLC Who Have Progressed Following Prior Therapy With an EGFR Tyrosine Kinase Inhibitor Agent

A Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291 administered orally once daily in Chinese patients with locally advanced or metastatic non small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent. 2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

NCT02529995
Conditions
  1. Carcinoma, Non-Small-Cell Lung With EGFR Mutation Positive
Interventions
  1. Drug: AZD9291 40 mg
  2. Drug: AZD9291 80 mg
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

In addition other lines of therapy may have been given - Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6. World Health Organisation (WHO) performance status 0-1 7. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Rate and extent of absorption of single dose AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of apparent plasma clearance at steady state

Measure: CL(ss)/F of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: Treatment discontinuation plus 28 days or 12 months after last subject first dose (LSFD). Results are based on data cut off of 2 Nov 2016.

37 A Phase 1/2 Trial of Erlotinib and Onalespib Lactate in EGFR-Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02535338
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Erlotinib Hydrochloride
  2. Other: Laboratory Biomarker Analysis
  3. Drug: Onalespib Lactate
  4. Other: Pharmacological Study
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q ---

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - 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 and for the duration of study participation; 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; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; 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 - 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 from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - 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 and for the duration of study participation; 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; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; 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 - 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 from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: Will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Measure: Incidence of dose-limiting toxicities from onalespib lactate in combination with erlotinib hydrochloride (Phase I)

Time: Up to 28 days

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase II)

Time: Up to at least 1 year

Secondary Outcomes

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase I)

Time: Up to at least 1 year

Description: Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to at least 1 year

38 A Phase II, Open-Label, Multicentre Study to Assess the Anti-tumour Activity of Afatinib in Patients With Activating Epidermal Growth Factor Receptor Mutation in Circulating Tumor DNA

Treatment efficacy of afatinib will be assessed in patients with lung cancer harboring EGFR mutations which were detected from circulating tumor DNA.

NCT02629523
Conditions
  1. Lung Neoplasms
  2. EGFR Gene Mutation
Interventions
  1. Drug: Afatinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: 1. Stage IIIB or IV lung cancer diagnosed radiologically with or without pathologic diagnosis 2. Age> 18 year-old 3. ECOG performance status 0~2. 4. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from circulating DNA 5. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Efficacy evaluation RECIST v1.1

Measure: Efficacy evaluation RECIST v1.1

Time: 2 months

Secondary Outcomes

Measure: Progression Free Survival

Time: 2 years

39 A Phase 1b/2 Study of the Safety and Efficacy of Rociletinib (CO-1686) Administered in Combination With MPDL3280A in Patients With Activating EGFR Mutation-positive (EGFRm) Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

This clinical research study is being carried out in two parts, Phase 1 and Phase 2. The primary purpose of the Phase 1 portion of the study is to observe the safety of the combination of rociletinib and MPDL3280A in EGFR-mutant NSCLC patients. The primary purpose of the Phase 2 portion of the study is to evaluate the safety and anti-tumor effects of the combination of rociletinib and MPDL3280A, at the best doses for the combination determined in Phase 1, in patients with EGFR-mutant NSCLC.

NCT02630186
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
  2. Drug: MPDL3280A
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Given the limited sample size, no formal statistical analysis is planned.. Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R --- --- L861Q ---

- For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve Exclusion Criteria: - Unresolved toxicities from prior therapy - Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases - Previous treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1) - Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4 therapeutic antibodies - Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures - Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (bisphosphonate use for prevention of skeletal events allowed) - Known hypersensitivity to any component of the MPDL3280A or rociletinib formulations or history or hypersensitivity to chimeric humanized antibodies or fusion proteins - History of autoimmune disease - History of prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation - Treatment with systemic immunosuppressive medications within 2 weeks prior to first day of study treatment (inhaled corticosteroids and mineralocorticoids allowed) - Live attenuated vaccine within 4 weeks prior to first day of study treatment - Active tuberculosis, active hepatitis, or positive HIV status - Class II to IV heart failure as defined by the New York Heart Association functional classification system - Untreated or uncontrolled cardiovascular disease or other symptomatic cardiac dysfunction - QTCF > 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan (history of radiation pneumonitis in radiation field may be allowed) - Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R --- --- L861Q ---

Primary Outcomes

Description: The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A.

Measure: Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03

Time: Continuously, up to approximately 18.5 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of Rociletinib and Its Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of Rociletinib and Metabolites

Time: Approximately every 6 weeks up to 24 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 8

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of MPDL3280A

Time: Cycle 1 Day 1

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of MPDL3280A

Time: Approximately every 6 weeks up to 24 months

Description: To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI.

Measure: Objective Response Rate Per RECIST v1.1 in Phase 2

Time: Approximately every 6-9 weeks

Secondary Outcomes

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study.

Measure: Number of Patients Alive at Study Termination

Time: Up to approximately 18.5 months

Description: Tumor tissue, plasma, and blood specimens will be used for pharmacodynamic assessment of rociletinib and/or MPDL3280A activity, to evaluate the concordance of mutant EGFR detection between tissue and plasma, and to explore biomarkers that may be predictive of response or resistance to rociletinib and/or MPDL3280A. Biomarkers and changes in biomarker status will be investigated for associations with rociletinib and/or MPDL3280A exposure, safety, and clinical activity. Given the limited sample size, no formal statistical analysis is planned.

Measure: Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA

Time: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months

40 A Randomized Open-label Phase 3 Trial Comparing Bevacizumab + Erlotinib vs Erlotinib Alone as First Line Treatment of Patients With EGFR Mutated Advanced Non Squamous Non Small Cell Lung Cancer

The purpose of this study is to test whether the combination of bevacizumab and erlotinib can prolong progression free survival as compared with erlotinib alone as first-line treatment in patients with non small cell lung cancer (NSCLC) with activating mutation of EGFR.

NCT02633189
Conditions
  1. Non-squamous Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Age ≥18 years 2. Histological documentation of primary non squamous lung carcinoma 3. Stage IV or IIIB disease with supraclavicular metastatic nodes (according to TNM 7th edition) 4. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21 L858R mutation or other activating/sensitizing mutations, such as exon 21 L861Q, exon 18 G719S, G719A and G719C, exon 20 S768I and V769L). --- L858R --- --- L861Q ---

Primary Outcomes

Description: as determined by investigator

Measure: progression free survival

Time: up to 2 years

Description: as determined by an independent central review board blinded to study treatment

Measure: progression free survival

Time: up to 2 years

Secondary Outcomes

Measure: overall survival

Time: 1 year

Measure: changes in quality of life scores from baseline

Time: up to 2 years

Measure: number of patients with complete and partial responses , investigator assessed

Time: 6 months

Measure: number of patients with complete and partial responses , centrally reviewed

Time: 6 months

Measure: worst grade toxicity per patient

Time: up to one year

Measure: progression free survival according to type of EGFR mutation (exon 19del, exon 21L858R, other)

Time: 2 years

Other Outcomes

Description: samples taken at baseline, 6 weeks, 6 months, and at progression

Measure: number and type of EGFR mutations in plasma samples

Time: up to 2 years

41 A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 (AP32788) in Non-Small Cell Lung Cancer

The purpose of this phase 1/2 study is to evaluate the safety, recommended phase 2 dose (RP2D), dose limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics of oral TAK-788, anti-tumor activity of TAK-788 in participants with NSCLC with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) and anti-tumor activity of TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations, and to explore relationship between tumor and/or plasma biomarkers, and TAK-788 efficacy, safety, and/or cytochrome P450 3A (CYP3A) induction. The study will also determine the efficacy of TAK-788 in participants with locally advanced or metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations who have received at least 1 prior line of therapy for locally advanced or metastatic NSCLC.

NCT02716116
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: TAK-788
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Part 2: Expansion Cohort 4 Specific Inclusion Criteria: 1. Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R. --- L858R --- --- T790M --- --- S768I --- --- L861Q ---

Primary Outcomes

Measure: Dose Escalation Cohort: RP2D of Orally Administered TAK-788

Time: Day 1 to 28 (Cycle 1)

Measure: Expansion Cohorts 1, 2, 4, 5 and 7: Confirmed Objective Response Rate (ORR) Assessed by the Investigator

Time: up to 36 months after first dose

Measure: Expansion Cohort 3: Intracranial ORR (iORR) Assessed by Independent Review Committee (IRC)

Time: up to 36 months after first dose

Measure: Extension Cohort: Confirmed ORR Assessed by IRC

Time: up to 36 months after first dose

Measure: Expansion Cohort 6: Confirmed ORR Assessed by IRC

Time: up to 36 months after first dose

Secondary Outcomes

Measure: Dose Escalation and Expansion Cohorts: Safety Analysis of TAK-788 Assessed by Adverse Events, Toxicity Grades, and Laboratory Test Results

Time: up to 36 months after first dose

Measure: Dose Escalation Cohort: Identify DLTs and MTD of TAK-788

Time: Day 1 to 28 in Cycle 1 (Cycle length is equal to [=] 28 days)

Measure: Dose Escalation and Expansion Cohorts: Tmax: Time of First Occurrence of Maximum Plasma Concentration (Cmax)

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: AUC 24: Area Under the Concentration-time Curve from Time Zero to 24 hours for TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: AUCt: Area Under the Concentration-time Curve from Time Zero to Time t for TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: RAC (Cmax): Accumulation Ratio Based on Cmax of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: Ctrough: Observed Concentration at the end of a Dosing Interval of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: RAC (AUC): Accumulation Ratio Based on AUC of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: Cmax: Maximum Observed Concentration of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Expansion Cohorts 1, 2, 3, 4, 5, and 7: Confirmed ORR as Assessed by IRC

Time: up to 36 months after first dose

Measure: Expansion Cohorts: Best Overall Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion Cohorts: Best Target Lesion Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Duration of Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Time to Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion Cohort 3: Duration of Intracranial Response (iDOR)

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Disease Control Rate (DCR) as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Progression Free Survival (PFS) as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion Cohort 3: Intracranial PFS (iPFS)

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Overall Survival (OS)

Time: up to 36 months after first dose

Measure: Extension Cohort: Confirmed ORR as Assessed by the Investigator

Time: up to 36 months after first dose

Measure: Dose Escalation and Expansion Cohorts: Cmax: Dose Linearity for TAK-788 Exposure

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: AUC: Dose Linearity for TAK-788 Exposure

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and Health-related Quality of Life (HRQoL) Based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30)

Time: up to 30 days after last dose of drug (approximately up to 37 months)

Measure: Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and health-related Global Quality of Life (HRQoL) Based on Quality of Life Questionnaire Lung Cancer Module-13 (QLQ-LC13)

Time: up to 30 days after last dose of drug (approximately up to 37 months)

Measure: Expansion Cohorts 6: Confirmed ORR as Assessed by the Investigator

Time: up to 36 months after first dose

42 Phase II Study Evaluating the Combination of Cetuximab With Afatinib as First-line Treatment for Patients With EGFR Mutated Non Small Cell Lung Cancer

Until recently, the first line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) was a platine-based chemotherapy. It has been changed by the discovery of EGFR (Epidermal Growth Factor Receptor) mutations and associated treatment with Tyrosine Kinase Inhibitor (TKI) of EGFR. The superiority of EGFR TKI over chemotherapy for EGFR mutated patients has been proved in several phase III trials with gefitinib, erlotinib or afatinib. Nevertheless, all patients will progress after 9 to 12 months of treatment due to the appearance of a treatment resistance. Afatinib is an irreversible EGFR TKI. It binds to its receptor permanently.Contrary to erlotinib and gefitinb which inhibits only EGFR, afatinib inhibits the kinase activity of all HER family (Human Epidermal growth factor Receptor). Nevertheless, there is no proof that afatinib delay the appearance of resistance. Cetuximab is a monoclonal antibody which binds specifically with EGFR. The double inhibition of EGFR by afatinib and cetuximab has demonstrated its efficacy in pre-clinical models. The hypothesis of this study is that the combination between cetuximab and afatinib will permit to delay or decrease the appearance of resistances.

NCT02716311
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib
  2. Drug: Cetuximab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q ---

Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- S768I --- --- T790M --- --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Time to Treatment Failure

Time: 9 months

Secondary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 1 month

Measure: Response Rate

Time: 9 months

Measure: Overall survival

Time: 6 months

Measure: Overall survival

Time: 9 months

Measure: Overall survival

Time: 12 months

Measure: Progression-Free Survival

Time: 6 months

Measure: Progression-Free Survival

Time: 9 months

Measure: Progression-Free Survival

Time: 12 months

Measure: Progression-Free Survival

Time: 18 months

43 Using Next Generation Sequencing (NGS) Method to Detect Circulating Free DNA (Cf-DNA) and Explore the Resistance and Prognosic Mechanism of Third Generation Epidermal Growth Factor Receptor (EGFR) Tyrosine-kinase Inhibitor (TKI) in Advanced Non-small Cell Lung Cancer (NSCLC) Patients: a Single Center Study

third generation of EGFR-TKIs is the newest target therapy for NSCLC. However, we did not known the specific mechanisms for those non-responders and patients grow resistance.Next generation sequencing is current the most sensitive and specific method to exam gene mutation, diversion etc. By consistently detect the cf-DNA, we could possibly find out the mechanisms of response and resistance.

NCT02738593
Conditions
  1. Non-small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- harboured with positive EGFR mutation (19 exon deletion, L858R, G719X, L861Q mutation) - reliable patients history data. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Using next generation sequencing (NGS) method to detect circulating free DNA (cf-DNA) in patients receive third generation EGFR-TKI, periphereal blood sample were collected at baseline and every 2 months to disease progression.

Measure: cf-DNA change from baseline

Time: baseline and every 2 months up to 36 months or first documented progression disease.

44 Phase II Trial of AZD9291 in First Line Treatment of Lung Cancer Harboring Activating EGFR Mutation From Circulating Tumor DNA and Second Line Treatment After Acquired Resistance With T790M Mutation Detected From Circulating Tumor DNA

Treatment efficacy of osimertinib will be assessed in patients with lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations (cohort 1) and those harboring T790M (cohort 2) which were detected from circulating tumor DNA

NCT02769286
Conditions
  1. Lung Neoplasms
  2. EGFR Gene Mutations
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

5. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test. --- L858R --- --- L861Q ---

6. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from tumor tissue or cytology specimen. --- L858R --- --- L861Q ---

5. Patients must fulfil one of the following: 5.1) Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) from tumor tissue or cytology or circulating tumor DNA 5.2) Must have experienced clinical benefit from prior EGFR-TKI, according to the Jackman criteria (Jackman 2010) followed by systemic objective progression (RECIST) while on continuous treatment with EGFR-TKI 6. T790M mutation detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test. --- L858R --- --- L861Q ---

Primary Outcomes

Description: RECIST v1.1

Measure: Response rate

Time: 2 months

Secondary Outcomes

Description: Percentage of positive cases among cases tested with Mutyper or Cobas

Measure: Sensitivity of testing methods

Time: 2 weeks

Measure: Progression free survival

Time: 2 years

Measure: Duration of response

Time: 2 years

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 2 years

45 A Multi-centre Observational Study on Dynamic Changes of Circulating Tumor DNA in Late Stage NSCLC Patients Under Gefitinib Treatment

A multi-centre observational, non-interventional study is to dynamically monitor the changes of circulating tumor DNA (ctDNA) in late stage NSCLC patients under Gefitinib treatment.

NCT02804100
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Bronchial Neoplasms
  3. Carcinoma, Bronchogenic
  4. Lung Diseases
  5. Lung Neoplasms
MeSH:Carcinoma Neoplasms Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Lung Diseases
HPO:Abnormal lung morphology Bronchial neoplasm Carcinoma Neoplasm Neoplasm of the lung Non-small cell lung carcinoma

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Inclusion Criteria: - Provision of informed consent - Histologically confirmed stage IIIB/IV NSCLC. --- G719A --- --- L858R --- --- L861Q ---

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Carcinoma, Non-Small-Cell Lung Bronchial Neoplasms Carcinoma, Bronchogenic Lung Diseases Lung Neoplasms Carcinoma Neoplasms Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Lung Diseases null --- G719A --- --- L858R --- --- L861Q ---

Primary Outcomes

Measure: dynamic changes of circulating tumor DNA in late stage NSCLC patients under Gefitinib treatment

Time: 2 years

46 A Phase IIa Clinical Trial to Evaluate the Safety and Efficacy of Osimertinib (AZD9291) in First-line Patients With EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer and Concomitant EGFR T790M Mutation at Time of Diagnosis

The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.

NCT02841579
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally. --- L858R --- --- L861Q ---

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Defined as the rate of complete responses [CR] or partial responses [PR] to treatment in accordance to the guidelines of RECIST version 1.1 criteria

Measure: Objective response rate

Time: Baseline up to 78 weeks after patient entry

Secondary Outcomes

Description: Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4

Measure: Grade 3 or 4 adverse events and SAEs

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time of death due to any cause

Measure: Overall survival

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time at which the patient discontinues treatment due to any cause

Measure: Time to treatment failure

Time: Baseline up to 78 weeks after patient entry

Description: Time from the first documented response to documented disease progression or death

Measure: Duration of response

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks after patient entry

Measure: Disease control rate

Time: Baseline up to 78 weeks after patient entry

Measure: Tumor shrinkage

Time: Baseline up to 78 weeks after patient entry

Description: Correlation ratio of mutational status and documented clinical response

Measure: Correlation ratio between mutational status and clinical response

Time: Baseline up to 78 weeks after patient entry

Measure: Tumour EGFR mutation status by histology

Time: Baseline up to 78 weeks after patient entry

Description: Measured by Percentage of patients with a positive EGFR mutation in plasma

Measure: Overall plasma EGFR mutation status

Time: Baseline up to 78 weeks after patient entry

Measure: BIM mRNA levels

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in tumour tissue

Measure: Acquired resistance to osimertinib (AZD9291) by histology

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in plasma

Measure: Overall plasma acquired resistance to osimertinib (AZD9291)

Time: Baseline up to 78 weeks after patient entry

47 Tyrosine-kinase Inhibitor (TKI) With or Without SBRT in Newly Diagnosed EGFRm Advanced Staged Lung Adenocarcinoma

To tested if the adding of consolidative SBRT to TKI in EGFR mutated patients with less than or equal to 5 metastatic sites (primary + 5) will improve progression free survival (PFS) compared to TKI alone.

NCT02893332
Conditions
  1. Stage IV EGFR Mutated Non-Small Cell Lung Cancer
Interventions
  1. Radiation: Radiation: SBRT
  2. Drug: TKI (Gefitinib or Tarceva )
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---

- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---

Primary Outcomes

Description: Evaluate the effect of TKI with or without SBRT on progression free survival,to describe local control and out-of-field disease progression

Measure: Progression free survival

Time: 4 years

Secondary Outcomes

Description: To evaluate overall survival after SBRT followed by maintenance chemotherapy in comparison to maintenance chemotherapy alone.

Measure: Overall survival

Time: 4 years

Description: Using CTCAE system to evaluate toxicity profile

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])

Time: 4 years

48 An Open-Label Phase 1/2 Study of Itacitinib in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

The purpose of this study is to evaluate the safety and tolerability of itacitinib in combination with osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC).

NCT02917993
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Itacitinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Documented evidence of somatic activating mutation in EGFR (eg, G719X, exon 19 deletion, L858R, L861Q) in a tumor tissue sample. --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Phase 1: Frequency, severity, and duration of adverse events (AEs)

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

Measure: Phase 1: Number of subjects with dose-limiting toxicities (DLTs)

Time: Day 1 through Day 28

Description: ORR defined as the percentage of subjects who have a confirmed best overall response of complete response (CR) or partial response (PR).

Measure: Phase 2: Objective response rate (ORR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Secondary Outcomes

Measure: Phase 1 and Phase 2: Maximum plasma concentration (Cmax) of itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Measure: Phase 1 and Phase 2: Area under the plasma concentration-time curve (AUC) of Itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Description: Defined as the percentage of maximal tumor shrinkage observed at the lowest point (nadir) compared with baseline.

Measure: Phase 2: Depth of response (DpR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Measure: Phase 2: Progression-free survival (PFS)

Time: Interval from the first day of study treatment until disease progression or death due to any cause, approximately 3 years.

Measure: Phase 2: Overall survival (OS)

Time: Interval from the first day of study treatment until death due to any cause, approximately 3 years.

Measure: Phase 2: Frequency, severity, and duration of AEs

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

49 A Phase I/II, Open-Label, Safety, Pharmacokinetic and Efficacy Study of Ascending Doses of Oral CK-101 in Patients With Advanced Solid Tumors

CK-101 is a novel, potent, small molecule tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral CK-101; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral CK-101; to assess the safety and efficacy of CK-101 in treatment-naive NSCLC patients known to have activating EGFR mutations and previously treated NSCLC patients known to have the T790M EGFR mutation.

NCT02926768
Conditions
  1. Lung Neoplasms
  2. Carcinoma, Non-Small-Cell Lung
  3. Lung Diseases
  4. Adenocarcinoma
Interventions
  1. Drug: CK-101
MeSH:Carcinoma, Non-Small-Cell Lung Lung Neoplasms Lung Diseases
HPO:Abnormal lung morphology Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Measureable disease according to RECIST Version 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Minimum age of 18 years - Adequate hematological, hepatic and renal function - Written consent on an Institutional Review Board-approved informed consent form prior to any study-specific evaluation - Histologically or cytologically confirmed diagnosis of one of the following: 1. Metastatic or unresectable locally advanced NSCLC with documented evidence that the tumor harbors one of the two common EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (exon 19 deletion, L858R), either alone or in combination with other EGFR mutations, determined by PCR-based testing of the tumor tissue or plasma sample, and without prior exposure to an EGFR-TKI therapy; OR 2. Metastatic or unresectable locally advanced NSCLC: 1. with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and 2. with evidence of radiological disease progression while on a previous continuous treatment with a first-generation EGFR TKI. --- L858R --- --- L858R --- --- L861Q ---

- Refusal to use adequate contraception for fertile patients (females and males) - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection Inclusion Criteria: - Measureable disease according to RECIST Version 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Minimum age of 18 years - Adequate hematological, hepatic and renal function - Written consent on an Institutional Review Board-approved informed consent form prior to any study-specific evaluation - Histologically or cytologically confirmed diagnosis of one of the following: 1. Metastatic or unresectable locally advanced NSCLC with documented evidence that the tumor harbors one of the two common EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (exon 19 deletion, L858R), either alone or in combination with other EGFR mutations, determined by PCR-based testing of the tumor tissue or plasma sample, and without prior exposure to an EGFR-TKI therapy; OR 2. Metastatic or unresectable locally advanced NSCLC: 1. with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and 2. with evidence of radiological disease progression while on a previous continuous treatment with a first-generation EGFR TKI. --- L858R --- --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Phase I: Incidence of dose-limiting toxicities (DLTs)

Time: From baseline (first dose) to 28 days after last dose, expected average 6 months

Measure: Phase II: Objective response rate (ORR): Defined as the rate of complete responses [CR] or partial responses [PR] per RECIST Version 1.1 as assessed by an independent central review

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Secondary Outcomes

Measure: Phase II: Evaluation of tumor response based on disease control rate as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on duration of response as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on tumor shrinkage as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on progression free survival as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase I: Change from baseline in QT/QTc interval

Time: Cycle 1 Day 1 until disease progression or withdrawal from study, expected average 10 months

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by area under the curve

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by maximum concentration

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by elimination half-life

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

50 Phase I/II Study of Dasatinib and Osimertinib (AZD9291) in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations

This is a study for patients with advanced non-small cell lung cancer with changes to their cancer cells called EGFR mutations. Mutated EGFR is important in the growth of cancer cells. Medical studies have shown that patients with EGFR mutation-positive lung cancer gain more benefit from targeted therapy drugs such as EGFR inhibitors than with standard chemotherapy. However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first-generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through activation of the SRC oncogene. They have also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a Src inhibitor are synergistic in Cripto-1 overexpressing tumors in the laboratory. This study will be testing a combination of two drugs, dasatinib and osimertinib, to overcome resistance to EGFR-TKIs. Osimertinib (AZD9291) is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants, but spares that of wild type. The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors. The first part of the study will involve finding the highest dose of dasatinib that can be given with osimertinib without causing severe side effects, finding out the side effects seen by giving dasatinib at different dose levels with osimertinib, and measuring the levels of dasatinib and osimertinib in blood at different dose levels. The second part will determine the effects of the combination of dasatinib and osimertinib and determine if the amount of Cripto-1 protein in your tumor or blood makes you more likely to have a good response to the combination of dasatinib and osimertinib.

NCT02954523
Conditions
  1. EGFR Gene Mutation
  2. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: Dasatinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Number of patients with drug related adverse events and number of patients who can tolerate dosing of dasatinib when given in combination with osimertinib

Measure: Phase I : Number of patients with drug-related adverse events as assessed by CTCAEv4.0

Time: 9 months

Description: The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib

Measure: Phase II : Number of patients that do not progress according to RECIST v1.1

Time: 9 months

Secondary Outcomes

Description: Number of patients with treatment-related adverse events in the phase II study, who are treated at the same dose that has been selected based on the phase I part

Measure: Number of patients with treatment-related adverse events in the phase II study

Time: 18 months

Description: To describe the concentration of osimertinib when administered with dasatinib. Blood is obtained from patients before each cycle and 4 hours after start of the first 2 cycles.

Measure: Concentration of orimertinib in blood

Time: 18 months

Description: Determination of the time between the start of the experimental treatment and progression of the tumor

Measure: Progression-free survival

Time: 3 years

Description: Determination of the time between start of the experimental treatment and death

Measure: Overall survival

Time: 3 years

Description: Determination of the duration of the response to the treatment, calculated from start of treatment in case of partial response and from the declaration of complete response in case of complete response. The end of the response will be when the tumor progresses

Measure: Duration of response

Time: 3 years

51 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Alflutinib in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

Alflutinib Mesylate Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT02973763
Conditions
  1. NSCLC
Interventions
  1. Drug: Alflutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) 5. Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Secondary Outcomes

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out Cmax.

Measure: Maximum Plasma Concentration [Cmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out tmax.

Measure: Peak Plasma Time [tmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day1 to figure out AUC.

Measure: Area under the plasma concentration versus time curve (AUC) of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out terminal rate constant.

Measure: Terminal rate constant of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out clearance.

Measure: Clearance of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out half life.

Measure: Half life of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out volume of distribution.

Measure: Volume of distribution of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out mean resistance time.

Measure: Mean resistance time of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state tmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state AUC of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.

Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Time dependency of Alflutinib and 2 metabolites following multiple doses.

Measure: Time dependency of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease progression rate

Measure: Disease progression rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1

Measure: Clinical benefit rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

52 A Phase 1/2, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10296 in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

This is a Phase 1/2, open-label, multicenter study of HS-10296 with dose escalation, dose expansion and extension cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent. The study is designed to evaluate safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of once-daily and orally (PO) administered HS-10296. The overall study design is shown in the flow chart below, which consists of 3 phases: dose escalation, dose expansion and extension cohort.

NCT02981108
Conditions
  1. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: HS-10296
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5. Patients must fulfill one of the following: - Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (followed by systemic objective progression (RECIST or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 6. --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Incidence of Dose Limiting Toxicity (DLT) Phase I Part

Time: 4 weeks

Measure: Overall Response Rate (ORR) Phase II Part

Time: 12 months

Measure: Progression-free survival (Phase I Part)

Time: 12 months

Measure: Overall Response Rate (Phase I Part)

Time: 6 weeks

Measure: Incidence and severity of AEs, changes in laboratory values, vital signs & ECGs

Time: 12 months

Measure: Area under the plasma concentration versus time curve (AUC) of HS-10296

Time: 4 weeks

Measure: Elimination half-life(T1/2) of HS-10241

Time: 4 weeks

53 A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI

A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI.

NCT03058094
Conditions
  1. NSCLC
Interventions
  1. Drug: Pemetrexed
  2. Drug: Cisplatin 75mg/m2
  3. Drug: AC0010
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

6. Confirmation of tumor EGFR sensitive mutation positive in previous tumor samples, including G719X, exon 19 deletion, L858R, L861Q. --- L858R --- --- L861Q ---

Primary Outcomes

Description: To assess the Progression-Free Survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Progression-Free Survival (PFS)

Time: From the date of randomization until the date of first documented progression or the date of death from any cause, whichever came first, assessed up to 24 months.

Secondary Outcomes

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Objective Response Rate (ORR)

Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Duration of Response (DoR)

Time: From occurring of CR or PR until progression or the date of death from any cause, whichever came first, assessed up to 24 months.

Description: To assess the Disease Control Rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Disease Control Rate (DCR)

Time: From the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

Description: To assess the Overall Survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Overall Survival (OS)

Time: From the date of randomization to death or end of study, which is assessed up to 36 months.

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Patient Reported Outcomes by EORTC QLQ-C30 Questionnaire

Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.

Other Outcomes

Description: Clinical chemistry, hematology, urinalysis, vital signs, physical examination, weight, ECG and ECOG Performance status and adverse event will be used to assess safety endpoints.

Measure: Incidence of toxicity, grading with CTCAE 4.03

Time: From the date of randomization until end of treatment,which is assessed up to 24 months

54 Multiple-Centered Study of AST2818 in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations

This study is conducted to assess the safety, tolerability and preliminary efficacy of AST2818 in patients with advanced Non Small Cell Lung Cancer (NSCLC).

NCT03127449
Conditions
  1. Advanced NSCLC
Interventions
  1. Drug: Alflutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Secondary Outcomes

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1

Measure: Clinical benefit rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease control rate

Measure: Disease control rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses

Measure: Steady state Maximum Plasma Concentration [Cmax] of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state peak plasma time [tmax] of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state area under the plasma concentration versus time curve [AUC] of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.

Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

55 Phase II, Multicenter, Single-arm, Open-label Study to Evaluate the Efficacy of Olmutinib(Olita®) in Patients With NSCLC Who Harboring T790M Mutation Confirmed Using DNA Extracted From Extracellular Vesicles in Bronchoalveolar Lavage Fluid

The purpose of this study is to evaluate the efficacy of Olmutinib(Olita®) in patients with T790M-positive non-small cell lung cancer (NSCLC) confirmed using DNA extracted from extracellular vesicles of bronchoalveolar lavage fluid.

NCT03228277
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Olmutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumor harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group performance status of 0 to 2 6. --- L858R --- --- L861Q ---

Primary Outcomes

Description: defined as the proportion of patients who achieved complete remission(CR) or partial remission(PR) based on RECIST version 1.1

Measure: Objective response rate (ORR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Secondary Outcomes

Description: defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Measure: Disease control rate (DCR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Description: defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Measure: Progression-free survival (PFS)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

56 Phase II Trial to Evaluate Trametinib in Patients With Advanced NF1-mutant Non-small Cell Lung Cancer

Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.

NCT03232892
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Trametinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

bevacizumab, ipilumimab) 4. Patients with a known activating mutation in epidermal growth factor receptor (EGFR) (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase inhibitor (TKI) (erlotinib, afatinib, or gefitinib). --- G719A --- --- S768I --- --- V769L --- --- T790M --- --- L833F --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: For participants receiving at least one dose of study treatment, the ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% using the Fisher's exact test.

Measure: Objective Response Rate (ORR)

Time: Up to 1 year

Secondary Outcomes

Description: The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Duration of Response (DR)

Time: Up to 4 years

Description: DCR will be defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Disease Control Rate (DCR) According to RECIST Version 1.1 Criteria.

Time: Up to 4 years

Description: PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1 Criteria.

Time: Up to 1 year

Description: OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.

Measure: Overall Survival (OS)

Time: Up to 1 year

57 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

3. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 4. Is currently receiving, and is able to discontinue erlotinib, gefinitib, or afatinib; or is currently receiving osimertinib at the prescribed 80 mg dose and is able to interrupt osimertinib. --- L858R --- --- L861Q ---

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)

58 A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer

This study is designed to evaluate safety and antitumor activity of U3-1402 in two parts: Dose Escalation and Dose Expansion. In Dose Escalation, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy. In Dose Expansion, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without EGFR-activating mutations) with disease progression during/after systemic treatment for locally advanced or metastatic disease.

NCT03260491
Conditions
  1. Non-Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: U3-1402
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q ---

3. Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q. --- L858R --- --- L861Q ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q Non-Small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of U3-1402 in the study population and to determine the recommended dose for expansion (RDE) of U3-1402 in the study population - For Dose Expansion, to investigate the antitumor activity of U3-1402 The number of treatment cycles is not fixed in this study. --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Dose-limiting toxicities (DLTs) in the dose escalation period

Time: 21 days of Cycle 1

Measure: Summary of adverse events in the dose escalation period

Time: By the global end of trial date, approximately within 36 months

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee in the dose expansion period

Time: Approximately within 36 months

Secondary Outcomes

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose escalation period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose escalation period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose escalation period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose escalation period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose escalation period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose escalation period

Time: Approximately within 36 months

Measure: Summary of adverse events in the dose expansion period

Time: By the global end of trial date, approximately within 36 months

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose expansion period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose expansion period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose expansion period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose expansion period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose expansion period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose expansion period

Time: Approximately within 36 months

59 Retreatment With 1st Generation EGFR TKIs in Sensitizing EGFR Mutation Positive Non-Squamous Cell Carcinoma Patients Who Previously Treated With EGFR TKI and Cytotoxic Chemotherapy

In this trial, treatment efficacy and safety of retreatment with 1st generation epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI)s(Gefitinib/Erlotinib), will be assessed in patients with sensitizing EGFR mutation positive Non-Squamous Cell Carcinoma patients who previously treated with EGFR TKI and cytotoxic chemotherapy

NCT03382795
Conditions
  1. EGFR Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: EGFR
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Males or females ≥ 19 years of age 2. Non Small Cell Lung Cancer(Non-Squamous Cell Carcinoma) patients who had shown clinical benefits (Complete response(CR) or Partial response(PR) or Stable disease(SD) ≥6 months) from EGFR-TKIs as first line treatment and developed progressive disease, and then received cytotoxic chemotherapy more than 4 cycles and developed progressive disease, and then confirmed T790 negative and sensitizing EGFR mutation(E19Del, L858R, L861Q, G719X, E19insertion) positive in Histologic, cytologic specimen or blood. --- L858R --- --- L861Q ---

Patients who are difficult to include in this study in accordance with the investigator's judgment due to severe adverse effects during previous EGFR TKI treatment Inclusion Criteria: 1. Males or females ≥ 19 years of age 2. Non Small Cell Lung Cancer(Non-Squamous Cell Carcinoma) patients who had shown clinical benefits (Complete response(CR) or Partial response(PR) or Stable disease(SD) ≥6 months) from EGFR-TKIs as first line treatment and developed progressive disease, and then received cytotoxic chemotherapy more than 4 cycles and developed progressive disease, and then confirmed T790 negative and sensitizing EGFR mutation(E19Del, L858R, L861Q, G719X, E19insertion) positive in Histologic, cytologic specimen or blood. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Assessed on based of RECIST 1.1.

Measure: Objective Response Rate(ORR) including rage of CR&PR

Time: Through study completion (5 years)

Secondary Outcomes

Description: Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause

Measure: Progression Free Survival, PFS

Time: Through study completion (5 years)

Description: Overall Survival (OR) the time from first dose of the study drug until the date of death by any cause

Measure: Overall Survival

Time: Through study completion (5 years)

Description: Assessment on the base of NCI-CTCAE (version 4.03)

Measure: The incidence of Adverse Events(including Serious Adverse Events and Adverse Drug Reactions)

Time: Through study completion (5 years)

60 An Open-label, Single Arm, Phase I/IIa Study to Evaluate Safety, Dose Escalation Tolerability, Pharmacokinetics and Antineoplastic Activity of the BPI-7711 Capsule in Patients With EGFR Mutation Advanced or Recurrent NSCLC

Lung cancer has the highest incidence rate in China and is also a very common cancer in the world. BPI-7711 is a new drug developed for patients with non-small cell lung cancer. The purpose of this study is to evaluate the safety, efficacy and PK profile of BPI-7711. The first part of the study will recruit 3~6 patients for different dose levels to evaluate safety. The dose will increase from the lowest level. The second part of the study is the dose expansion. Once efficacy is observed in the dose increasing process, additional 20~30 patients will be enrolled to further evaluate the anti-tumor efficacy. A recommended dose will be selected for Phase II study.

NCT03386955
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: BPI-7711 Capsule
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Prior to enrollment, a central laboratory testing report confirmed the tumor has EGFR positive gene mutation sensitive to EGFR-TKI treatment (including G719X, exon 19 loss, L858R, L861Q etc.). --- L858R --- --- L861Q ---

Primary Outcomes

Description: DLT to be evaluated according to NCI CTCAE V4.03

Measure: Number of patients with dose limiting toxicity ( DLT).

Time: From first dosing ( Day -7) to the last dosing of Cycle 1 ( Day 28).

Secondary Outcomes

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Maximum plasma concentration (Cmax) of BPI-7711 and its main metabolites.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Peak Plasma Time (tmax) of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Area under the plasma concentration versus time curve (AUC) of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Clearance of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Half life of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Cycle 1 Day1, Cycle Day 8, Cycle 1 Day 15 and Cycle 2 Day1 at designated time. points.

Measure: Blood concentration of BPI-7711 and its main metabolites after single dose under steady state.

Time: Pre-dose of Cycle1 Day1, 8, 15. Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h post dose on Cycle 2 Day1

Description: Objective response rate evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Objective response rate (ORR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Best objective response evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Best objective response (BOR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Disease control rate evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Disease control rate ( DCR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Duration of response evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Duration of response ( DoR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Progression free survival evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Progression free survival (PFS) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Other Outcomes

Description: To test EGFR mutation in plasma circulating tumor DNA (ctDNA).

Measure: EGFR mutation testing.

Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: To test T790M mutation in plasma circulating tumor DNA (ctDNA).

Measure: T790M mutation testing.

Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

61 A Phase II Study for Evaluating Anti-tumor Efficacy of TAGRISSO (Osimertinib) in NSCLC Patients in Whom T790 Mutations Are Detected by Liquid Biopsy Using Bronchoalveolar Lavage Fluid, Plasma or Pleural Effusion

In this trial, anti-tumor efficacy of TAGRISSO in NSCLC patients in whom T790 mutations are detected by liquid biopsy.

NCT03394118
Conditions
  1. NSCLC
Interventions
  1. Drug: Osimertinib
MeSH:Pleural Effusion
HPO:Pleural effusion

AE/SAE assessement on the base of NCI-CTCAE (version 4.03).. Inclusion Criteria: 1. Age ≥ 20, and patients who understand information about the trial and voluntarily agree to participate in the trial 2. Histological or cytological confirmation diagnosis of NSCLC and inoperable stage IIIB or IV at the time of study enrolment 3. Patients with EGFR sensitizing mutation (E19Del, L858R, L861Q, G719X) positive, who had shown clinical benefits (responders (CR or PR) and SD ≥6 months) from EGFR-TKIs and had developed progressive disease following those therapy - Patients who have histories of previous exposure to EGFR-TKIs or other systemic chemotherapies are permitted (regardless of the order of treatment) - Treated with at least one of KGFR-TKIs (regardless of treatment with or without systemic chemotherapies) - In case the patient previously received any of the treatments including systemic chemotherapy, radiation therapy, surgery, and hormonal therapy, there should be at least 2 weeks of time interval between the last day of the previous treatment and the start of TAGRISSO™, and the remaining toxicity should be ≤ CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2, prior platinum-therapy related neuropathy) 4. ECOG performance status 0-2 5. Patients in whom T790 mutations are detected in at least one of the samples including tumor tissues, BALF (cell-free DNA), plasma (cell-free DNA), and pleural effusion (cell-free DNA) 6. --- L858R --- --- L861Q ---

Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry Inclusion Criteria: 1. Age ≥ 20, and patients who understand information about the trial and voluntarily agree to participate in the trial 2. Histological or cytological confirmation diagnosis of NSCLC and inoperable stage IIIB or IV at the time of study enrolment 3. Patients with EGFR sensitizing mutation (E19Del, L858R, L861Q, G719X) positive, who had shown clinical benefits (responders (CR or PR) and SD ≥6 months) from EGFR-TKIs and had developed progressive disease following those therapy - Patients who have histories of previous exposure to EGFR-TKIs or other systemic chemotherapies are permitted (regardless of the order of treatment) - Treated with at least one of KGFR-TKIs (regardless of treatment with or without systemic chemotherapies) - In case the patient previously received any of the treatments including systemic chemotherapy, radiation therapy, surgery, and hormonal therapy, there should be at least 2 weeks of time interval between the last day of the previous treatment and the start of TAGRISSO™, and the remaining toxicity should be ≤ CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2, prior platinum-therapy related neuropathy) 4. ECOG performance status 0-2 5. Patients in whom T790 mutations are detected in at least one of the samples including tumor tissues, BALF (cell-free DNA), plasma (cell-free DNA), and pleural effusion (cell-free DNA) 6. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Objective response rate (ORR) including rate of CR and PR on based of RECIST 1.1

Measure: ORR

Time: through study completion (43 months)

Secondary Outcomes

Description: Disease control rate (DCR) including rate of CR, PR and SD on based of RECIST 1.1

Measure: DCR

Time: through study completion (43 months)

Description: Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause.

Measure: PFS

Time: through study completion (43 months)

Measure: T790M postive rate in Plasma cell free DNA

Time: through study completion (43 months)

Measure: T790M postive rate in BALF free DNA

Time: through study completion (43 months)

Measure: T790M postive rate in tissue

Time: through study completion (43 months)

Measure: Concordance rate of T790M positivity between plasma & BALF

Time: through study completion (43 months)

Measure: T790M sensitivity & specificity in Plasma & BALF (gold standard: tissue biopsy)

Time: through study completion (43 months)

Description: AE/SAE assessement on the base of NCI-CTCAE (version 4.03).

Measure: The frequency of occurrence of grade 3 or higher AE/SAEs

Time: through study completion (43 months)

62 A Single Arm Phase II Study Osimertinib in Patients With Stage 4 Non-small Cell Lung Cancer With Uncommon EGFR Mutations

This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. Patients on the study will not have had previous tyrosine kinase inhibitor (TKI) treatment.

NCT03434418
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Study Osimertinib in Patients With Stage 4 Non-small Cell Lung Cancer With Uncommon EGFR Mutations This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. --- L861Q ---

Overall survival as noted by follow-up via composite of telephone or medical record review.. Overall survival as defined as time from starting study therapy until death from any causes.. Inclusion Criteria: - EGFR mutations as performed on a CLIA certified laboratory demonstrating EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q. --- S768I --- --- L861Q ---

- Grade ≥ 2 blurred vision, conjunctivitis, corneal ulcer, dry eye, or keratitis Inclusion Criteria: - EGFR mutations as performed on a CLIA certified laboratory demonstrating EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q. --- S768I --- --- L861Q ---

- Grade ≥ 2 blurred vision, conjunctivitis, corneal ulcer, dry eye, or keratitis Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. --- L861Q ---

Patients who have one of the following EGRF mutations: exon 18 G719X, exon 20 S7681, or exon 21 L861Q) may be eligible to participate in this study. --- L861Q ---

Primary Outcomes

Description: RECIST 1.1 will be used to measure confirmed partial or complete responses to the study drug.

Measure: Objective response rate as assessed by the investigator using Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name)

Time: Up to 3 years

Secondary Outcomes

Description: Progression will be defined as time from starting study therapy to disease progression or death (whichever occurs first)

Measure: Progression free survival as measured by Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name) as assessed by the investigator.

Time: Up to 5 years

Description: Evaluation of safety using the National Cancer Institute (NCI) CTCAE version 4.03

Measure: AEs as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Time: Up to 3 years

Description: Overall survival as defined as time from starting study therapy until death from any causes.

Measure: Overall survival as noted by follow-up via composite of telephone or medical record review.

Time: Up to 5 years

63 A Phase 1/2 Open Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of ZN-e4 (KP-673) in Patients With Advanced Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor (EGFR) Mutations

This is a Phase 1/2, open-label, multicenter, sequential dose-escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ZN-e4 administered orally in subjects with advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations who have progressed while on treatment with an EGFR tyrosine kinase inhibitor (TKI) agent (other lines of treatment are allowed, except for other epidermal growth factor receptor inhibitors [EGFRis]) for Phase 1; and for Phase 2, subjects who have T790M+ and are osimertinib naïve (Cohort 1), and also those who have not been treated with an EGFR Inhibitor (EGFRi) (Cohort2).

NCT03446417
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: ZN-e4
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Phase 1 only: Confirmation that the tumor harbors an EGFR mutation known to be associated with aberrations that are amenable to EGFRi therapy including but not limited to: G719X, exon 19 deletion, exon 21 L858R, and L861Q. --- L858R --- --- L861Q ---

- Measurable disease meeting the criteria specified by RECIST v1.1 - Phase 2, Cohort 1 only: Subjects must have confirmation of tumor T790M mutation status (confirmed positive) and are osimertinib naïve - Phase 2, Cohort 2 only: EGFR aberrations that are amenable to EGFRi therapy, including but not limited to: G719X, exon 19 deletion, exon 21 L858R, and L861Q, and be EGFRi naïve EXCLUSION CRITERIA - Subjects who have received only neoadjuvant or adjuvant therapy for NSCLC. --- T790M --- --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Observed dose limiting toxicities

Time: 1 Cycle (21 days)

Secondary Outcomes

Measure: Safety and tolerability as measured by incidence of treatment emergent adverse events

Time: Through study completion, approximately 2 years

64 An Open-label PET Study to Determine Brain Exposure of Osimertinib After IV Microdose Administration of [11C]Osimertinib and Therapeutic Oral Doses of Osimertinib to Patients With EGFR Mutated NSCLC With Brain Metastases

This is an open-label, single centre, Phase I study to determine the brain exposure of [11C]osimertinib in patients with EGFRm NSCLC with brain metastases.

NCT03463525
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: [11C]osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or T790M EGFR resistance mutation as assessed by local laboratory/or central laboratory via tissue/cytology or in plasma. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 1

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 2

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 29

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Secondary Outcomes

Description: Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax)

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.

Measure: Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Other Outcomes

Description: Collection and assessment of adverse events graded using CTCAE (version 4.03).

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with IV [11C]osimertinib administration

Time: From study Day 1 and until 30 days after the study drug is discontinued.

Description: Collection and assessment of adverse events using CTCAE (version 4.03)

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with continuous oral osimertinib

Time: From study Day 1 and until 30 days after the study drug is discontinued.

65 A Randomized Phase II Trial of Nivolumab, Cabozantinib Plus Nivolumab, and Cabozantinib Plus Nivolumab Plus Ipilimumab in Patients With Previously Treated Non-Squamous NSCLC

This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better than cabozantinib s-malate alone in treating patients with stage IV non-small cell lung cancer.

NCT03468985
Conditions
  1. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  3. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Cabozantinib
  2. Drug: Cabozantinib S-malate
  3. Biological: Ipilimumab
  4. Other: Laboratory Biomarker Analysis
  5. Biological: Nivolumab
  6. Other: Questionnaire Administration
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.. Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R --- --- L861Q ---

- Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration - History of organ transplant - Concurrent symptomatic untreated hypothyroidism within 7 days prior to registration - History of surgery as follows: - Major surgery (as an example, surgery requiring anesthesia and a > 24 hour hospital stay) within 3 months prior to registration, with wound healing at least 28 days prior to registration - Minor surgery within 28 days prior to registration with complete wound healing at least 10 days prior to registration - Minor procedures within 7 days prior to registration such as thoracentesis, paracentesis, or 18 g or smaller needle biopsy of tumor - Patients with clinically relevant ongoing complications from prior surgery are not eligible - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - No currently active other malignancies which require systemic treatment - No patients that 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 - No patients with known active autoimmune disease or known history of autoimmune disease for which recurrence may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; 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, autoimmune hepatitis; patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including type I diabetes mellitus or thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren'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 - No ongoing major illness or psychosocial issues that would limit compliance with the protocol - Women must not be pregnant or breast-feeding due to contraindications with the study agents - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy - A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP - Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral therapy are excluded because there are no safety data with the combination of antiretroviral therapy and cabozantinib or ipilimumab or nivolumab with ipilimumab - Patients with known chronic active hepatitis B (defined as a positive hepatitis B surface antigen and/or hepatitis B viral load in the last Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R --- --- L861Q ---

Primary Outcomes

Description: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparison of PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Other comparisons of groups will be made using the logrank test and Cox modeling.

Measure: Progression-free survival (PFS)

Time: From randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 years

Secondary Outcomes

Description: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios.

Measure: Overall survival

Time: From randomization to death from any cause, assessed up to 5 years

Description: According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response and partial response) will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Best objective response evaluated

Time: Up to 5 years

Description: Evaluated according to Common Terminology Criteria for Adverse Events version 5 criteria. Toxicity will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Incidence of toxicity

Time: Up to 5 years

Other Outcomes

Description: As measured by RECIST 1.1 criteria.

Measure: Time to tumor response

Time: Up to 5 years

Measure: Comparison of RECIST 1.1 imaging response assessment measurements

Time: Up to 5 years

Description: A combined analysis of the data from the selected Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco on provider-reported cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose modifications

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco on patient-reported physical symptoms and psychological symptoms

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Assessment of quitting behaviors, behavioral counseling/support and cessation medication utilization

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit

Time: Up to 5 years

66 A Phase I/II Study to Assess the Safety,Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Patients With Locally Advanced or Metastatic T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed Following Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

ASK120067 Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT03502850
Conditions
  1. Locally Advanced or Metastatic NSCLC
Interventions
  1. Drug: ASK120067
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R --- --- L861Q ---

- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Secondary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Evaluation of Disease control rate assessed by RECIST 1.1

Measure: Disease control rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: defined as the time from date of first dose until date of death due to any cause

Measure: Overall survival

Time: Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Collect plasma concentrations of ASK120067 and 1 metabolites following single dose at designated time points of Day 1 to figure out Cmax

Measure: Maximum Plasma Concentration [Cmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out tmax

Measure: Peak Plasma Time [tmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day1 to figure out AUC

Measure: Area under the plasma concentration versus time curve (AUC) of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out terminal rate constant

Measure: Terminal rate constant of single dose single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out clearance

Measure: Clearance of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out half life

Measure: Half life of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of f ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out volume of distribution

Measure: Volume of distribution of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out mean resistance time

Measure: Mean resistance time of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Cmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Tmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state tmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Cmin of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: AUC of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state AUC of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Clearance of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state clearance of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Accumulation ratio of ASK120067 and 1 metabolite following multiple doses

Measure: Accumulation ratio of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Time dependency of ASK120067 and 1 metabolite following multiple doses

Measure: Time dependency of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

67 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

Inclusion Criteria: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 3. Has acquired resistance to EGFR tyrosine kinase inhibitor (TKI) according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression [Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 4. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib 5. Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day 6. Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib 7. Has at least one measurable lesion per RECIST version 1.1 8. --- L858R --- --- L861Q ---

Has history of pancreatitis within the past 6 months Inclusion Criteria: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 3. Has acquired resistance to EGFR tyrosine kinase inhibitor (TKI) according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression [Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 4. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib 5. Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day 6. Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib 7. Has at least one measurable lesion per RECIST version 1.1 8. --- L858R --- --- L861Q ---

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

68 A Phase I, Open-label Study to Assess the Safety, Tolerability and Pharmacokinetics of Ascending Doses of SH-1028 Tablets in Patients With Advanced Non-small Cell Lung Cancer

This is a Phase 1, open-label study of SH-1028 with dose escalation and dose expansion cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent.

NCT03603262
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: SH-1028
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria while on continuous treatment with an EGFR TKI(PR/CR, or SD continued ≥6 months). --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD)

Time: Within the first 28 days of treatment

Measure: Incidence of Dose Limiting Toxicity (DLT)

Time: Within the first 28 days of treatment

Measure: Area under the plasma concentration versus time curve (AUC) of SH-1028

Time: 4 weeks

Measure: Elimination half-life(T1/2) of SH-1028

Time: 4 weeks

Measure: Maximum (or peak) concentration of SH-1028

Time: 4 weeks

Secondary Outcomes

Measure: Overall Response Rate (ORR)

Time: 12 months

Measure: Progression-free survival (PFS)

Time: 12 months

Measure: Disease control rates(DCR)

Time: 12 months

Measure: Overall survival(OS)

Time: 12 months

69 A Multicentre, Open-Label, Exploratory Phase Ib Clinical Study to Assess Safety and Efficacy of an EGFR Tyrosine Kinase Inhibitor in Combination With EGF Pathway Targeting Immunisation (EGF-PTI) in Treatment-Naïve Patients With EGFR Mutant NSCLC. The EPICAL Study

This is a multicentre, open-label, uncontrolled, Phase Ib clinical study. Patients who give informed consent will be screened for the study, including genotyping of the tumour and baseline characteristics. Eligible patients will receive a single pre-treatment of low dose of intravenous cyclophosphamide 200 mg/m2 (Day -3). Patients will commence daily oral therapy with the EGFR TKI afatinib as soon as possible, preferably on the same day as low dose cyclophosphamide. Afatinib will be prescribed according to the Summary of Product Characteristics (SmPC) of the product, and will continue in nominal 21-day cycles for as long as clinically indicated. The first day of dosing with EGF-PTI will be designated Day 1. Immunisation with EGF-PTI will commence 3 days after low dose cyclophosphamide and commencement of EGFR TKI, and will be repeated on Day 14, Day 28, Day 43, and Day 92. After the 5 th vaccination, patients will be followed up every 6 weeks for basic safety data and every 3 months for complete efficacy data, safety data, and maintenance (reduced) doses of EGF-PTI. Patients will continue in the study until disease progression, death, safety concerns (in the opinion of the investigator), non-compliance with the protocol, the patient withdraws from the study, 1 year after randomisation of the last patient, or the study is stopped the sponsor, whichever occurs sooner

NCT03623750
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: EGFR-TK Inhibitor
  2. Biological: EGF-PTI
  3. Drug: Cyclophosphamide
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Centrally confirmed EGFR exon 19 deletion, exon 21 (L858R, L861Q) or exon 18 (G719X) mutation before treatment (concomitant T790M pre-treatment mutation is permitted). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Evaluate the safety and tolerability of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in newly diagnosed patients with advanced or metastatic non-squamous NSCLC with EGFR mutations who are not candidates for local curative treatment throughout the patient's participation in the study.

Measure: Frequency and severity of Adverse Events

Time: 36 months

Secondary Outcomes

Description: Evaluate the anti-tumor activity of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in terms of clinical response. Every 3 months after the first dose of EGF-PTI and throughout the patient's participation in the study.

Measure: Clinical response efficacy assessments

Time: 36 months

70 Anlotinib Combined With Pemetrexed And Carboplatin Followed by Maintenance Therapy With Anlotinib Plus Pemetrexed as the First-line Treatment in Patients With Advanced Nonsquamous NSCLC

In recent years, with the progress in the treatment field, Non-Small Cell Lung Cancer(NSCLC) has become the most successful cancer species in precision medicine. Patients with positive driving genes such as EGFR, ALK, ROS1, BRAF and so on have clearly targeted drugs, which bring survival benefits to patients.However, about 50% of patients still lack a clear driving gene target, which has become the focus of current research.In the field of wild-type NSCLC with negative driver genes, the classic first-line treatment regimen is the two-drug regimen containing platinum.The study by Kimura T in the first-line treatment of 54 wild-type advanced NSCLC patients with carboplatin and pemetrexed showed that the ORR, mPFS and mOS of patients with wild-type non-squamous NSCLC treated with carboplatin permetrexine were 35.8%, 5.4 months and 12.7 months respectively. Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and development.In the phase Ⅲ study, patients who failed at least two kinds of systemic chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib or placebo, the anlotinib group PFS and OS were 5.37 months and 9.46 months, the placebo group PFS and OS were 1.4 months and 6.37 months. The efficacy and safety of Anlotinib combined with Pemetrexed and Carboplatin followed by maintenance therapy with Anlotinib plus Pemetrexed as the first-line treatment in patients with advanced nonsquamous NSCLC deserve further exploration.

NCT03790228
Conditions
  1. Non-squamous Cell Non-Small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib Combined With Pemetrexed And Carboplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer),Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis of non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; - Medical history and combined history: 1. Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); 2. The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; 3. Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with cervical carcinoma in situ , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); 4. Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy;Note: Under the premise of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; 5. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; 6. --- S768I --- --- L858R --- --- L861Q ---

Primary Outcomes

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: each 42 days up to PD or death(up to 24 months)

Secondary Outcomes

Description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.

Measure: Objective Response Rate,ORR

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate,DCR

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).

Description: Defined as the time until death due to any cause.

Measure: Overall Survival,OS

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months) .

Description: Number of Participants with Adverse Events.

Measure: Safety(Number of Participants with Adverse Events )

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).

71 to Evaluate SCT510 Compared to Avasitin Respectively Combined Paclitaxel and Carboplatin First-line Treatment of Locally Advanced and Metastatic or Recurrent Squamous Cell Non-small Cell Lung Cancer Efficacy and Safety

To evaluate the safety, efficacy and immunogenicity of SCT510 combined with paclitaxel and carboplatin compared with bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of locally advanced metastatic or recurrent squamous cell non-small cell lung cancer.

NCT03792074
Conditions
  1. Non-squamous Cell Non-small Cell Lung Cancer
Interventions
  1. Drug: SCT510
  2. Drug: Bevacizumab
  3. Drug: Paclitaxel
  4. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

21 (L858R, L861Q)) and ALK fusion.Subjects who have not previously undergone EGFR and ALK gene testing will need to undergo genetic testing during the screening period.Among them, subjects whose EGFR or ALK gene status cannot be determined for various reasons can be enrolled;Subjects who are known to have EGFR sensitive mutations and/or ALK fusion may also be enrolled if they are currently unable to obtain the corresponding targeted drugs (including the rejection of the subjects) and chemotherapy is standard treatment at the research center; 5. --- L858R --- --- L861Q ---

Primary Outcomes

Description: the proportion of subjects whose CR(complete response) and PR(partial response)combined , according to RECIST 1.1 criteria

Measure: Objective response rate

Time: 12 weeks

Secondary Outcomes

Description: the proportion of subjects whose CR(complete response) and PR(partial response)combined , according to RECIST 1.1 criteria

Measure: Objective response rate

Time: 18 week

Description: the proportion of subjects with CR(complete response), PR(partial response) and SD(Stable disease) combined,according to RECIST 1.1 criteria

Measure: Disease control rate

Time: 12 weeks and 18 weeks

Description: The time from the first assessment of CR(complete response) or PR(partial response) to the first assessment of PD(progressive disease) or any cause of death,according to RECIST 1.1 criteria

Measure: Duration of Response

Time: 3 years

Description: The time from randomization to PD(progressive disease) or any cause of death,according to RECIST 1.1 criteria

Measure: Progression free survival

Time: 3 years

Description: The proportion of subjects who survived longer than 1 year after randomization

Measure: 1-year overall survival rate

Time: 1 year

Description: Defined as the time from randomization of subjects to death from any cause

Measure: Overall survival

Time: 3 years

72 A Single Arm, Multi-center Study to Assess the Efficacy and Safety of Docetaxel Combined With Carboplatin Plus Anlotinib as First Line Treatment in Non-squamous Non-small-cell Lung Cancer (NSCLC)

Anlotinib which has shown an affirmatory efficacy in ALTER0303 controlled trial as a 3rd-line treatment on advanced NSCLC is a tyrosine kinase inhibitor with a favorable safety profile in phase I trial which mainly targets VEGFR1/2/3, FGFR, PDGFR and c-kit. The purpose of this trail is to establish whether advanced non-squamous NSCLC patients could benefit from the combination treatment of docetaxel, carboplatin and anlotinib as the first-line and maintenance treatment.

NCT03799601
Conditions
  1. NSCLC
Interventions
  1. Drug: Anlotinib
  2. Drug: Docetaxel
  3. Drug: Carboplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer), Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis induced by non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; Medical history and combined history: - Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); - The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; - Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with carcinoma in situ of the cervix , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); - Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy; Note: Under the condition of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; - Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; - The effects of surgery or trauma have been eliminated for less than 14 days before enrollment in subjects who have undergone major surgery or have severe trauma; - Severe acute or chronic infections requiring systemic treatment; Suffering from severe cardiovascular disease: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including men with QTc interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV Insufficient function, or cardiac color Doppler ultrasound examination indicates left ventricular ejection fraction (LVEF) <50%; - There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for trauma; - Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including pleural effusion, ascites, pericardial effusion) requiring surgical treatment; Long-term unhealed wounds or fractures; - Decompensated diabetes or other ailments treated with high doses of glucocorticoids; - Factors that have a significant impact on oral drug absorption, such as inability to swallow, chronic diarrhea, and intestinal obstruction; - Clinically significant hemoptysis (daily hemoptysis greater than 50ml) within 3 months prior to enrollment; or significant clinically significant bleeding symptoms or defined bleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood ++ and above, or suffering from vasculitis; - Events of venous/venous thrombosis occurring within the first 12 months prior to enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism; - Physical examination and laboratory findings: 1. --- S768I --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (PFS, progression-free survival)

Measure: progression-free survival

Time: Estimated about 24 months.

Secondary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (OS, overall survival)

Measure: Overall Survival

Time: Estimated about 24 months.

Description: Clinical response of treatment according to RESIST v1.1 criteria (DCR, disease control rate)

Measure: Disease Control Rate

Time: Estimated about 24 months.

Description: Clinical response of treatment according to RESIST v1.1 criteria (ORR, Overall Response Rate)

Measure: Overall Response Rate

Time: Estimated about 24 months.

73 A Phase IIb, Open-label, Single-arm Study to Assess the Safety and Efficacy of BPI-7711 Capsule in Patients With Metastatic or Recurrent Non-small Cell Lung Cancer With EGFR Mutation and T790M Mutation Positive.

A phase IIb, open-label, single-arm study to assess the safety and efficacy of BPI-7711 capsule in patients with metastatic or recurrent non-small cell lung cancer with EGFR mutation and T790M mutation positive.

NCT03812809
Conditions
  1. NSCLC
Interventions
  1. Drug: BPI-7711
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by an Independent Central Review (ICR)

Time: up to 52 weeks

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by investigators

Time: up to 52 weeks

Description: DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease control rate (DCR) according to RECIST 1.1

Time: up to 104 weeks

Description: PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from BPI-7711 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression free survival(PFS) according to RECIST 1.1

Time: up to 104 weeks

74 A Multicenter, Open-label, Phase II Study to Evaluate the Safety and Efficacy of SH-1028 in Locally Advanced or Metastatic NSCLC

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of SH-1028 with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene.

NCT03823807
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: SH-1028
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X or dual mutation) for treatment-naive NSCLC patients (without systemic therapy or with relapse after previous surgery; patients with locally treatment for non-target lesions are accepted ).(This criteria applies to treatment-naïve NSCLC patients in Part B). - Patients must have confirmation of T790M+ mutation status, which have experienced disease progression while on a previous continuous treatment with an EGFR-TKI or clinical benefit from EGFR-TKI according to the Jackman criteria while on continuous treatment with an EGFR-TKI (PR/CR, or SD continued ≥6 months); Patients can receive more than one line of systemic therapy. --- L858R --- --- L861Q ---

Primary Outcomes

Measure: Objective Response Rate (ORR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Secondary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time: From Baseline up to 30 days after the last dose, an average of 1 year.

Measure: Maximum Plasma Concentration (Cmax)

Time: Part A: Day 1 of Cycle 1 and 2 (21 days for 1 cycle).

Measure: Area Under the Curve [AUC]

Time: Part A: Day 1 of Cycle 1 and 2 (21 days for 1 cycle).

Measure: Progression-free survival (PFS)

Time: Every 2 cycles (21 days for 1 cycle) until end of follow-up, an average of 1 year.

Measure: Duration of Response(DOR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Measure: Disease Control Rates(DCR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Measure: Overall survival(OS)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment; Every 12 weeks until end of follow-up, an average of 2 years.

Other Outcomes

Description: optional,use NGS to analyse the gene associated with NSCLC and to determine the reason of SH-1028-resistance.

Measure: Biomakers (eg. AF value of KRAS,MET mutation or other gene mutations ) of drug-resistance measured by next-generation sequencing (NGS).

Time: at end of treatment,an average of 1 years.

Measure: Minimum Plasma Concentration (Cmin)

Time: Before administration in Day 1 of cycle 2, 3 and 5 (21 days for 1 cycle).

75 A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Study to Evaluate the Efficacy and Safety of Toripalimab Injection (JS001) or Placebo Combined With First-line Standard Chemotherapy in Treatment-naive Advanced Non-small Cell Lung Cancer (NSCLC)

This is one randomized, double-blind, placebo-controlled, multi-center, phase III clinical study to evaluate the efficacy and safety of Toripalimab injection (JS001) or placebo combined with standard 1st-line chemotherapy in treatment-naïve advanced non-small cell lung cancer (NSCLC); and evaluate the population with the best predictive biomarkers, i.e., positive diagnosis population. About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. The stratification will be based on the following factors: PD-L1 expression (TC≥1% vs TC<1%); Smoking state (often smoking vs no smoking or infrequent smoking); Pathological type (squamous cell carcinoma vs non-squamous cell carcinoma).

NCT03856411
Conditions
  1. Treatment-naive Advanced Non-small Cell Lung Cancer
Interventions
  1. Drug: TORIPALIMAB INJECTION (JS001 ) combine with chemotherapy
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Progression free survival (PFS) evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST 1.1)

Measure: PFS

Time: Up to 2 approximately years

Secondary Outcomes

Description: Overall survival (OS)

Measure: OS

Time: Up to 2 approximately years

Description: PFS evaluated by the Blinded Individual Review Committee (BIRC) based on RECIST1.1 criteria

Measure: PFS

Time: Up to 2 approximately years

Description: Objective response rate (ORR) evaluated by investigators and BIRC based on RECIST1.1

Measure: ORR

Time: Up to 2 approximately years

Description: Duration of response (DOR) evaluated by investigators and BIRC based on RECIST1.1

Measure: DOR

Time: Up to 2 approximately years

Description: Disease control rate (DCR) evaluated by investigators and BIRC based on RECIST1.1

Measure: DCR

Time: Up to 2 approximately years

Description: Time to response (TTR) evaluated by investigators and BIRC based on RECIST1.1

Measure: TTR

Time: Up to 2 approximately years

Description: Overall incidence of adverse events (AEs); incidence of grade 3 and above AEs; incidence of serious adverse events (SAEs); incidence of AEs leading to termination of the investigational drug; incidence of AEs interruption of the investigational drug

Measure: Incidence of AEs/SAEs

Time: From date of consent informed until 60 days after the last investigational product administration. Up to 2 approximately years

76 A Phase Ib Clinical Study With Extension Phase to Evaluate Safety and Efficacy of Genolimzumab (GB226) in Combination With Fruquintinib in the Treatment of Relapsed or Metastatic NSCLC Patients

This study is a multi-center, open-label, dose-finding phase Ib clinical study with extension phase, which is aimed at evaluating the efficacy and safety of GB226 combined with fruquintinib in treatment of relapsed or metastatic NSCLC patients with EGFR-sensitive mutations who have failed to respond to EGFR-TKI treatment,evaluating the pharmacokinetic characteristics of GB226 and fruquintinib, and the immunogenicity of GB226, and preliminarily evaluating the antitumor activity of GB226 and fruquintinib.

NCT03976856
Conditions
  1. Metastatic Non-small Cell Lung Cancer
Interventions
  1. Drug: GB226
  2. Drug: Fruquintinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

To evaluate the immunogenicity of GB226 in Chinese patients with lung cancer.. Inclusion Criteria: 1. Aged 18-75 years, male or female; 2. Understanding the procedures and contents of the study, and voluntarily signing the written informed consent form; 3. Histologically or cytology confirmed relapsed or metastatic NSCLC; 4. EGFR gene sensitive mutation is confirmed positive, any of following is met: exon 19 deletion (19DEL), exon 21 point mutation (L858R / L861Q), 18 exon point mutation (G719X), 20 exon point mutation (S768I). --- L858R --- --- L861Q ---

Inclusion Criteria: 1. Aged 18-75 years, male or female; 2. Understanding the procedures and contents of the study, and voluntarily signing the written informed consent form; 3. Histologically or cytology confirmed relapsed or metastatic NSCLC; 4. EGFR gene sensitive mutation is confirmed positive, any of following is met: exon 19 deletion (19DEL), exon 21 point mutation (L858R / L861Q), 18 exon point mutation (G719X), 20 exon point mutation (S768I). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Assessment of serious adverse events (SAEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Serious Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Incidence of Dose Limited Toxicity

Measure: Dose Limited Toxicity

Time: Day 1 to Day 28 after first dose

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 4.03

Measure: Maximum Tolerated Dose

Time: Day 1 to Day 28 after first dose

Secondary Outcomes

Description: Cmax

Measure: Cmax

Time: up to 90 days after the last administration

Description: Tmax

Measure: Tmax

Time: up to 90 days after the last administration

Description: AUC0-t

Measure: AUC0-t

Time: up to 90 days after the last administration

Description: AUC0-∞

Measure: AUC0-∞

Time: up to 90 days after the last administration

Description: MRT

Measure: MRT

Time: up to 90 days after the last administration

Description: Vd

Measure: Vd

Time: up to 90 days after the last administration

Description: CL

Measure: CL

Time: up to 90 days after the last administration

Description: AUC 0-τ

Measure: AUC 0-τ

Time: up to 90 days after the last administration

Description: C avg

Measure: C avg

Time: up to 90 days after the last administration

Description: C min

Measure: C min

Time: up to 90 days after the last administration

Description: CL ss

Measure: CL ss

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by objective response rate in patients with lung cancer.

Measure: Objective Response Rate, ORR

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by disease control rate in patients with lung cancer.

Measure: Disease control rate,DCR

Time: up to 90 days after the last administration

Description: To evaluate the duration of response (DOR) of GB226 in patients with lung cancer

Measure: Duration of response, DOR

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by progression-free survival in patients with lung cancer

Measure: Progression-free survival, PFS

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by overall survival in patients with lung cancer.

Measure: Overall survival, OS

Time: up to 90 days after the last administration

Description: To evaluate the immunogenicity of GB226 in Chinese patients with lung cancer.

Measure: Concentration of AntiDrug Antibody, ADA

Time: up to 90 days after the last administration

77 A Study of Nivolumab +/- Docetaxel in Patients Previously Treated With Advanced or Metastatic Non Small Cell Lung Cancer

This study is a randomized, single-center, open-label, phase II clinical trial designed to evaluate non-small cell lung cancer that has failed to undergo excessive platinum-based chemotherapy and has not received excessive statin chemotherapy and has not received immunotherapy. The efficacy and safety of Nivolumab in combination with docetaxel and Nivolumab in patients. Qualified patients were stratified by histological type (squamous cell carcinoma vs. non-squamous cell carcinoma) randomized to receive the following regimen in a 1:1 ratio: Group A: Nivolumab 300mg + docetaxel 75mg/m2 IV q3w Group B: Nivolumab 200mg IV q2w All patients were evaluated for tumor at baseline, and tumor evaluations were performed every 6 weeks within 48 weeks after randomization (regardless of whether dosing was delayed). After the 48th week of assessment, a tumor assessment is required every 9 weeks until disease progression, withdrawal of informed consent, sponsor termination study, or patient death.

NCT04023617
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Docetaxel
  3. Nivolumab
Interventions
  1. Drug: Nivolumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

3. The patient's tumor must be free of EGFR gene-sensitive mutations (including but not limited to exon 19 deletion mutation or exon 21 L858R mutation, exon 21 L861Q, exon 18 G719X or exon 20 S768I site Mutation) and ALK gene rearrangement. --- L858R --- --- L861Q ---

Primary Outcomes

Description: progression-free survival

Measure: PFS

Time: 24 months

Secondary Outcomes

Description: overall survival

Measure: OS

Time: 24 months

78 A Phase I/Ib Study of Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer

This is a phase I/Ib, open-label, single-center, single-arm study of alisertib and osimertinib for patients with stage IV EGFR-mutated lung cancer, incorporating both a dose escalation and dose-expansion phase

NCT04085315
Conditions
  1. Lung C
  2. Lung Cancer Metastatic
  3. EGFR Gene Mutation
Interventions
  1. Drug: Osimertinib
  2. Drug: Alisertib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

2. Male or female patients ≥18 years of age 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (see Appendix 1). 4. Documented activating EGFR mutation (Exon 19 deletion, Exon 19 insertion, E709K, G719X, S768I, V769L, T790M, L833F, L833V, V834L, H835L, L858R, A859S, K860I, L861Q, A871E, V843I, or H870R) on tumor sample or cell-free DNA sample performed in Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory. 5. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. --- E709K --- --- S768I --- --- V769L --- --- T790M --- --- L833F --- --- L833V --- --- V834L --- --- H835L --- --- L858R --- --- A859S --- --- K860I --- --- L861Q ---

Primary Outcomes

Description: ≤1 out of 6 at highest dose level below the maximal administered dose. If 0 of these 3 additional participants experience a dose limiting toxicity (DLT) (1 of 6), proceed to the next dose level. If 1 or more of the 3 additional participants experience DLT (2 of 6), then dose escalation is stopped, and this dose is declared the maximal administered dose (highest dose administered). Three (3) additional participants will be entered at the next lowest dose level if only 3 participants were treated previously at that dose.

Measure: Maximum Tolerated Dose (MTD)

Time: First 28 days of study treatment

Secondary Outcomes

Description: defined as the best overall response recorded from the start of the treatment until disease progression from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined based on RECIST 1.1 criteria. We will compute a 95% confidence interval using a binomial distribution.

Measure: Overall Response Rate (ORR)

Time: Up to 2 years

Description: The DR for CR and PR will be measured from the date that the best response if first recorded until the date that PD is documented over the period of 2 years. For patients who continue treatment post-progression, the date of PD documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum)

Measure: Duration of Response (DR)

Time: Up to 2 years

Description: The depth of response will be assessed by RECIST 1.1 criteria. The DOR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Depth of response (DOR)

Time: Up to 2 years

Description: Defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Disease Control Rate (DCR)

Time: Up to 2 years

Description: PFS will be calculated as 1+ the number of days from the first dose of alisertib to documented radiographic progression or death due to any cause over a period of 2 years. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the mean PFS with 95% confidence interval.

Measure: Progression Free Survival (PFS)

Time: Up to 2 years

Description: OS will be calculated as 1+ the number of days from the first dose of alisertib to death due to any cause over a period of 2 years. The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.

Measure: Overall Survival (OS)

Time: Up to 2 years

Description: Defined as the percentage of patients who have achieved CR, PR, or SD in the CNS for at least 12 weeks. The CNS disease control rate will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Central Nervous System (CNS) disease control rate

Time: Up to 2 years

Description: Pre-treatment tumor biopsy formalin-fixed paraffin-embedded (FFPE) samples will be stained for TPX2 expression by IHC. TPX2 IHC staining will be scored using the following scale: 0, 0-10% of tissue stained positive; 1, 10-20% stained positive; 2, 20-40% stained positive; 3, 40-70% stained positive; and 4, > 70% positive cells. The sum of staining score index (intensity + extent) will be designated as follows: 0-2, negative expression; 3-4, strong expression. The IHC score will be generated from three different areas of the slides and an average score will be calculated for each sample. We will determine whether there is a difference in TPX2 staining between responders and non-responders to alisertib + osimertinib treatment by the Fisher's exact test.

Measure: Intratumoral TPX2 expression by Immunohistochemistry (IHC)

Time: From pretreatment biopsy to time of response, up to 2 years

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and area under curve (AUC) 0-24 hours. The area under the curve (AUC) is the definite integral in a plot of drug concentration in blood plasma vs. time

Measure: Area Under Curve (AUC)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Cmax will be calculated. It is a standard measurement in pharmacokinetics

Measure: Maximum (or peak) serum concentration (Cmax)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Tmax will be calculated. It is a standard measurement in pharmacokinetics

Measure: Amount of time (maximum) drug concentration in serum (Tmax)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

79 A Randomized Phase 3 Multicenter Open-label Study to Compare the Efficacy of TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations

The purpose of this study is to compare the efficacy of TAK-788 as first-line treatment with that of platinum-based chemotherapy in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

NCT04129502
Conditions
  1. Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: TAK-788
  2. Drug: Pemetrexed
  3. Drug: Cisplatin
  4. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Higher scores represent a high level of symptomatology/problems.. Inclusion Criteria: - Histologically or cytologically confirmed nonsquamous cell locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) non-small cell lung cancer (NSCLC) - Documented epithelial growth factor receptor (EGFR) in-frame exon 20 insertion mutation assessed by a clinical laboratory improvements amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laboratory The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR mutations for which there are approved anti-EGFR TKIs (ie, exon 19 del, L858R, T790M, L861Q, G719X, or S768I, where X is any other amino acid) - Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR exon 20 insertion mutation - At least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 - Life expectancy ≥3 months - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Exclusion Criteria: - Received prior systemic treatment for locally advanced or metastatic disease - Received radiotherapy ≤14 days before randomization or has not recovered from radiotherapy-related toxicities - Received a moderate or strong cytochrome P-450 (CYP)3A inhibitor or moderate or strong CYP3A inducer within 10 days before randomization - Have been diagnosed with another primary malignancy other than NSCLC - Have current spinal cord compression or leptomeningeal disease - Have uncontrolled hypertension. --- L858R --- --- T790M --- --- L861Q ---

Participants with hypertension should be under treatment on study entry to control blood pressure - Received a live vaccine within 4 weeks before randomization per Summary of product characteristics (SmPCs) for pemetrexed, cisplatin, and carboplatin Inclusion Criteria: - Histologically or cytologically confirmed nonsquamous cell locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) non-small cell lung cancer (NSCLC) - Documented epithelial growth factor receptor (EGFR) in-frame exon 20 insertion mutation assessed by a clinical laboratory improvements amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laboratory The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR mutations for which there are approved anti-EGFR TKIs (ie, exon 19 del, L858R, T790M, L861Q, G719X, or S768I, where X is any other amino acid) - Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR exon 20 insertion mutation - At least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 - Life expectancy ≥3 months - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Exclusion Criteria: - Received prior systemic treatment for locally advanced or metastatic disease - Received radiotherapy ≤14 days before randomization or has not recovered from radiotherapy-related toxicities - Received a moderate or strong cytochrome P-450 (CYP)3A inhibitor or moderate or strong CYP3A inducer within 10 days before randomization - Have been diagnosed with another primary malignancy other than NSCLC - Have current spinal cord compression or leptomeningeal disease - Have uncontrolled hypertension. --- L858R --- --- T790M --- --- L861Q ---

Primary Outcomes

Description: PFS is defined as the time interval from the date of randomization until the first date at which the criteria for PD according to RECIST version 1.1 are met or death, whichever occurs first.

Measure: Progression Free Survival (PFS) as Assessed by Blinded Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Time: Up to approximately 40 months after the first participant is randomized

Secondary Outcomes

Description: Confirmed ORR is defined as the proportion of participants who are confirmed to have achieved complete response (CR) or partial response (PR). Confirmed responses are responses that persist on repeat imaging ≥4 weeks after initial response.

Measure: Confirmed Objective Response Rate (ORR) as Assessed by Blinded Independent Review Committee (IRC) per RECIST Version 1.1

Time: Up to approximately 40 months after the first participant is randomized

Description: OS is defined as the interval from the date of randomization until death.

Measure: Overall Survival (OS)

Time: Up to approximately 40 months after the first participant is randomized

Description: PFS is defined as the time interval from the date of randomization until the first date at which the criteria for progressive disease (PD) according to RECIST version 1.1 are met or death, whichever occurs first.

Measure: Progression Free Survival (PFS) as Assessed by the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Confirmed ORR is defined as the proportion of participants who are confirmed to have achieved CR or PR. Confirmed responses are responses that persist on repeat imaging ≥4 weeks after initial response.

Measure: Confirmed Objective Response Rate (ORR) as Assessed by the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that PD is objectively documented.

Measure: Duration of Response, as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Time to response is defined as the time interval from the date of randomization until the initial observation of CR or PR.

Measure: Time to Response, as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: DCR is defined as the percentage of participants who have achieved CR, PR, or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks) after the initiation of study drug.

Measure: Disease Control Rate (DCR) as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: EORTC QLQ-C30 is a cancer-specific questionnaire which comprises of 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and a global health status/quality-of-life (QoL) scale. Six single-item scales are also included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores will be converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QoL scale, higher scores represent better HRQoL, whereas for the symptom scales lower scores represent better HRQoL (i.e., a low level of symptomatology/problems).

Measure: Patient-reported Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30

Time: Up to approximately 40 months after the first participant is randomized

Description: EORTC QLQ-LC13 is a cancer-specific questionnaire which comprises of 13 questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Raw scores will be converted into scale scores ranging from 0 to 100. Higher scores represent a high level of symptomatology/problems.

Measure: Participant-reported Symptoms as Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, Lung Cancer Module (QLQ-LC13)

Time: Up to approximately 40 months after the first participant is randomized

80 A Phase II Study of Atezolizumab in Combination With Bevacizumab, Carboplatin or Cisplatin, and Pemetrexed for EGFR-mutant Metastatic Non-small Cell Lung Cancer Patients After Failure of EGFR Tyrosine Kinase Inhibitors.

using Atezolizumab, a PD-L1 inhibitor, in combination with bevacizumab, platinum and pemetrexed to treat patients with EGFR mutated, advanced non-small cell lung cancer (NSCLC) after failure of EGFR tyrosine kinase inhibitors.

NCT04147351
Conditions
  1. NSCLC Stage IIIB~IV
Interventions
  1. Drug: Atezolizumab Injection; bevacizumab Injection
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

EGFR activating mutations include exon19 deletion, L858R, G719X, L861Q, or S768I. --- L858R --- --- L861Q ---

Primary Outcomes

Description: The percentage of patients with radiologically complete or partial response as determined by the investigator according to RECIST version 1.1.

Measure: Objective response rate (ORR)

Time: 9 MONTHS

Secondary Outcomes

Description: PFS is measured from the date of study enrollment to radiographically documented progression according to RECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment.

Measure: Progression-free Survival (PFS)

Time: about 9 months

81 A Phase 2 Study of Poziotinib in Patients With EGFR or HER2 Activating Mutations in Advanced Malignancies

This is a Phase 2, open-label, multicenter study to evaluate the efficacy and the safety/tolerability of poziotinib in five patient cohorts for up to 150 previously treated patients with any systemic therapy (Cohort 1: 30 Patients that have HER2-positive or HER2-negative breast cancer with HER2 activating mutations, Cohort 2: 30 Patients that have colorectal cancer with HER2 activating mutations, Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal cancer) with HER2 activating mutations, Cohort 4: 30 Patients that have high-grade glioma with EGFR activating mutations, and Cohort 5: 30 Patients that have solid tumors (except NSCLC or high-grade glioma) with EGFR activating mutations.

NCT04172597
Conditions
  1. Breast Cancer
  2. Colorectal Cancer
  3. Solid Tumor
  4. High Grade Glioma
Interventions
  1. Drug: Poziotinib Hydrochloride
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

EGFR Activating Mutations (at least one of the following) Extracellular & Transmembrane: EGFRvIII, R108K, R222C, A289T, P596L, G598V Kinase Domain: Exon 20 insertion, E709K, G719X, V742I, E746_A750del, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V 5. Patient has measurable disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and/or RANO Criteria for Cohort 4. These target lesion(s) must be radiographically measurable. --- R108K --- --- R222C --- --- A289T --- --- P596L --- --- G598V --- --- E709K --- --- V742I --- --- S768I --- --- V769M --- --- V774M --- --- R831C --- --- R831H --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: Proportion of patients whose best overall response is confirmed CR or PR

Measure: Objective Response Rate (ORR)

Time: 24 months

Secondary Outcomes

Description: Time from the first CR or PR until progressive disease or death

Measure: Duration of Response (DoR)

Time: 24 months

Description: Proportion of patients whose best overall response is CR, PR, or SD

Measure: Disease Control Rate (DCR)

Time: 24 months

82 Randomized Phase III Study of Combination AZD9291 (Osimertinib) and Bevacizumab Versus AZD9291 (Osimertinib) Alone as First-Line Treatment for Patients With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase III trial compares the effect of bevacizumab and AZD9291 (osimertinib) combination vs. osimertinib alone for the treatment of non-small cell lung cancer that has spread outside of the lungs (stage IIIB-IV) and has a change (mutation) in a gene called EGFR. The EGFR protein is involved in cell signaling pathways that control cell division and survival. Sometimes, mutations in the EGFR gene cause EGFR proteins to be made in higher than normal amounts on some types of cancer cells. This causes cancer cells to divide more rapidly. Osimertinib may stop the growth of tumor cells by blocking EGFR that is needed for cell growth in this type of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with bevacizumab may control cancer for longer and help patients live longer as compared to osimertinib alone.

NCT04181060
Conditions
  1. Advanced Lung Non-Squamous Non-Small Cell Carcinoma
  2. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  3. Recurrent 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
Interventions
  1. Biological: Bevacizumab
  2. Drug: Osimertinib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

All staging is via the American Joint Committee on Cancer (AJCC)/International Association for the Study of Lung Cancer (IASLC) 8th edition staging criteria - Patient must have somatic activating sensitizing mutation in EGFR (e.g. but not limited to Exon 19 deletion, L858R, G709X, G719X, exon 19 insertions, L861Q, S768I). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 2.5%.

Measure: Progression-free survival (PFS)

Time: From randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first, assessed up to 10 years

Secondary Outcomes

Description: Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. OS will be tested at the one-sided 10% level.

Measure: Overall survival (OS)

Time: From randomization to death from any cause, assessed up to 10 years

Description: Best objective response will be evaluated via RECIST 1.1 criteria. Will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Best objective response rate

Time: Up to 10 years

Description: Will be estimated using competing risks methodology, adjusting for death and progression as competing events. Regular central nervous system imaging will occur when patients are on treatment. After they discontinue study treatment, central nervous system imaging will be symptom-prompted during follow up.

Measure: Time to central nervous system progression

Time: From study randomization to evidence of central nervous system progressive disease, with death and progression as competing events, assessed up to 10 years

Description: Will be estimated using the Kaplan-Meier method.

Measure: Central nervous system progression-free survival

Time: From study randomization to evidence of central nervous system progressive disease or death from any cause, whichever occurs first, assessed up to 10 years

Description: Toxicity will be determined using the Common Terminology Criteria for Adverse Events (CTCAE). Will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Incidence of adverse events

Time: Up to 30 days after the last administration of investigational agent

Other Outcomes

Description: Preliminary analyses of these data will utilize tests for association comparing the frequency of a particular genomic aberration at baseline and at progression (for example, using McNemar's test) and association between alterations and baseline characteristics (for example, using Fisher's exact test). More sophisticated analyses may include multivariable logistic regression modeling and/or competing risks analysis.

Measure: Mechanisms of resistance to AZD9291 (osimertinib) and AZD9291 (osimertinib) with bevacizumab first-line therapy through post-progression circulating tumor-derived deoxyribonucleic acid (ctDNA)

Time: Up to 10 years

Description: Will assess ctDNA clearance on study treatment and associate ctDNA clearance with clinical outcomes. Cox regression analysis will be used to assess whether EGFR ctDNA clearance is an independent predictor for PFS (and OS), adjusted by treatment effect, the presence of brain metastasis (yes versus [vs.] no), EGFR exon 19 deletion/L858R vs other, Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2) and other possible clinical and biological risk factors.

Measure: ctDNA clearance on study treatment

Time: Up to 10 years

83 Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of WSD0922-FUFU

This phase I trial studies the side effects and best dose of WSD0922-FU for the treatment of glioblastoma, anaplastic astrocytoma, or non-small cell lung cancer that has spread to the central nervous system (central nervous system metastases). WSD0922-FU is a targeted treatment which blocks the EGFR protein - a strategy that has led to a lot of benefit in patients with many different cancers. WSD0922-FU may also be able to get into cancers in the brain and spinal cord and help patients with brain and spinal cord cancers.

NCT04197934
Conditions
  1. Anaplastic Astrocytoma, IDH-Wildtype
  2. Glioblastoma, IDH-Wildtype
  3. Lung Non-Small Cell Carcinoma
  4. Metastatic Malignant Neoplasm in the Central Nervous System
  5. Metastatic Malignant Neoplasm in the Leptomeninges
Interventions
  1. Drug: EGFR/EGFRvIII Inhibitor WSD0922-FU
  2. Procedure: Therapeutic Conventional Surgery
MeSH:Neoplasms Glioblastoma Astrocytoma Neoplasms, Second Primary Carcinoma, Non-Small-Cell Lung
HPO:Astrocytoma Glioblastoma multiforme Neoplasm Non-small cell lung carcinoma Subependymal giant-cell astrocytoma

Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R --- --- G719A --- --- L861Q ---

Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R --- --- G719A --- --- L861Q --- --- L858R --- --- G719A --- --- L861Q ---

History of hypersensitivity to active or inactive excipients of WSD0922-FU or drugs with a similar chemical structure or class to WSD0922-FU - Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of WSD0922-FU - Inadequate bone marrow reserve or organ function - Patients with NSCLC LM who are unable to undergo collection of CSF Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R --- --- G719A --- --- L861Q ---

History of hypersensitivity to active or inactive excipients of WSD0922-FU or drugs with a similar chemical structure or class to WSD0922-FU - Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of WSD0922-FU - Inadequate bone marrow reserve or organ function - Patients with NSCLC LM who are unable to undergo collection of CSF Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R --- --- G719A --- --- L861Q --- --- L858R --- --- G719A --- --- L861Q ---

Primary Outcomes

Description: The RP2D is either the maximum tolerated dose (MTD) or the highest dose tested (in the case that none of the doses are deemed higher than the MTD), whichever is higher.

Measure: Recommended phase 2 dose

Time: Up to 28 days

Secondary Outcomes

Measure: Incidence of adverse events

Time: Up to 4-6 weeks after study completion

Description: The overall response rate will be defined as the number of patients with a partial response (PR) or better that is confirmed in consecutive evaluations (at least 8 weeks apart) divided by the total number of evaluable patients. A 95% confidence interval will also be constructed using the properties of the binomial distribution.

Measure: Overall response rate

Time: Up to 5 years

Description: Duration of response is defined as the number of days between a patient's first occurrence of a PR (or better) and progression. If a patient goes off study prior to progression (for another reason) then they will be censored at that time. A time to event analysis will be performed utilizing the Kaplan-Meier method which will yield a median DOR.

Measure: Duration of response (DOR)

Time: From the first occurrence of a PR (or better) and progression, assessed up to 5 years

Description: A patient's progression free survival time is the number of days between study entry and disease progression. These data will be analyzed utilizing the Kaplan-Meier method which will yield a median PFS time.

Measure: Progression Free Survival (PFS)

Time: From study entry to disease progression, assessed up to 5 years

Other Outcomes

Measure: Maximum plasma Concentration [Cmax] of WSD0922-FU after a single dose of WSD0922-FU

Time: Cycle 1 Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours

Measure: Area under the plasma concentration versus time curve (AUC) of WSD022-FU after a single dose of WSD0922-FU

Time: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours of day 1 of cycles 1 and 2; and pre-dose day 1 of cycles 3 and 4

Measure: Maximum plasma Concentration [Cmax] of WSD0922-FU after multiple doses of WSD0922-FU

Time: Cycle 1 Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours

Measure: Area under the plasma concentration versus time curve (AUC) of WSD022-FU after multiple doses of WSD0922-FU

Time: Cycle 1 Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours

Measure: CSF concentration of WSD0922-FU after multiple doses of WSD0922-FU (Dose Expansion - NSCLC leptomeningeal metastases (NSCLC LM) cohort only).

Time: Cycle 2 Day 1

Measure: Brain tumor concentration of WSD0922-FU after a single dose of WSD0922-FU (Dose Expansion - Brain tumor penetration (BTP) cohort only).

Time: Cycle 0 Day 1

Measure: Tumor EGFR inhibition after a single dose of WSD0922-FU (Dose Expansion - Brain tumor penetration (BTP) cohort only).

Time: Cycle 0 Day 1

Measure: Effect of food on Maximum plasma Concentration [Cmax] of WSD0922-FU after a single dose of WSD0922-FU (Dose Expansion - NSCLC LM cohort only).

Time: Cycle 0 Day 1 and Cycle 0 Day 4

Measure: Effect of food on Area under the plasma concentration versus time curve (AUC) of WSD022-FU after a single dose of WSD0922-FU (Dose Expansion - NSCLC LM cohort only).

Time: Cycle 0 Day 1 and Cycle 0 Day 4

84 A Phase II, Multi-centre Study, to Evaluate the Efficacy and Safety of Osimertinib Treatment for Patients With EGFR-mutated Non-small Cell Lung Cancer (NSCLC) With Brain or Leptomeningeal Metastases

Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of Progression-Free Survival (PFS) when used as 1st line treatment. In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. In case of local progression, treatment of the site in progression by radiotherapy and/or surgery is considered. As these local treatments can cause long-term adverse effects, systemic treatments are increasingly being considered in this indication. Brain and leptomeningeal metastases are the most frequent isolated site of progression in EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. However, its efficacy in patients with cerebral or leptomeningeal metastases is still poorly understood.

NCT04233021
Conditions
  1. Non Small Cell Lung Cancer Metastatic
  2. Leptomeningeal Metastasis
  3. Brain Metastases
  4. EGFR Activating Mutation
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Meningeal Carcinomatosis
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The following mutations are considered to be activating: L858R, exon 19 deletions, exon 19 insertions, L861Q, G719X. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Objective Response Rate at 6 months using EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)

Measure: Objective Response Rate

Time: 6 months

Secondary Outcomes

Description: Time from enrollment until death due to any cause

Measure: Overall Survival

Time: About 24 months

Description: Time from enrollment to first observation of progression (EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)) or date of death (from any cause)

Measure: Progression-free 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 event

Time: From time of informed consent through treatment period and up to 30 days post last dose of study treatment (about 24 months)

Description: EORTC QLQ-C30-LC13 (Qualify of Life Questionnaire C30 and Lung Cancer 13) questionnaire

Measure: Evaluate the Quality of life

Time: From time of randomisation through treatment period (about 24 months)

Description: QLQ BN20 (Brain Neoplasm N20) questionnaire

Measure: Evaluate the Quality of life

Time: From time of randomisation through treatment period (about 24 months)

85 A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC

This phase II trial compares cabozantinib alone and the combination of cabozantinib and nivolumab to standard chemotherapy in the treatment of patients with non-squamous non-small cell lung cancer (NSCLC). Cabozantinib 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. Ramucirumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as docetaxel, gemcitabine hydrochloride, paclitaxel, and nab-paclitaxel, 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 cabozantinib alone or in combination with nivolumab may be more effective than standard chemotherapy in treating patients with non-small cell lung cancer.

NCT04310007
Conditions
  1. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  3. Stage III Lung Cancer AJCC v8
  4. Stage IIIA Lung Cancer AJCC v8
  5. Stage IIIB Lung Cancer AJCC v8
  6. Stage IIIC Lung Cancer AJCC v8
  7. Stage IVA Lung Cancer AJCC v8
  8. Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
Interventions
  1. Drug: Cabozantinib S-malate
  2. Drug: Docetaxel
  3. Drug: Gemcitabine Hydrochloride
  4. Drug: Nab-paclitaxel
  5. Biological: Nivolumab
  6. Drug: Paclitaxel
  7. Biological: Ramucirumab
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

If small cell elements are present the patient is ineligible - ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient's tumor(s) must be tested and known negative for EGFR tyrosinase kinase inhibitor (TKI) sensitizing mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by fluorescence in situ hybridization [FISH], next generation sequencing [NGS], or immunohistochemistry [IHC]) by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods. --- L858R --- --- L861Q ---

Primary Outcomes

Description: The final analysis of PFS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). The two primary comparisons of PFS will each use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of PFS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. At the final analyses, in the event that both primary PFS comparisons of the combination of nivolumab with cabozantinib and cabozantinib alone versus the standard chemotherapy are statistically significant, PFS will be compared between the two experimental arms (combination of nivolumab with cabozantinib versus [vs.] cabozantinib alone), using a stratified log rank test with a one-sided type I error rate of 10%.

Measure: Progression-free survival (PFS) for patient population with non-squamous no-small cell lung cancer (NSCLC)

Time: After 58 events (From time of randomization to documented disease progression [site review of imaging] or death from any cause, whichever occurs first)

Secondary Outcomes

Description: The final analysis of OS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). OS will be tested in a hierarchical fashion if the primary comparison of PFS between treatment arms is statistically significant, using a log rank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of OS, including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. OS will be further tested in a hierarchical fashion if the comparison of PFS between the two experimental arms is statistically significant. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. Subset analyses of PFS and OS by treatment arm will be estimated and compared within subsets.

Measure: Overall survival (OS) for each arm

Time: From time of randomization to documented disease progression (site review of imaging) or death from any cause, whichever occurs first, assessed up to 3 years

Description: Will be evaluated via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response [CR] + partial response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.

Measure: Best objective response for each arm

Time: Every 6 weeks for the first year on study, and then every 12 weeks after year one

Description: Will be determined using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Response rates (complete response [CR] + pathologic response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.

Measure: Toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib

Time: Up to 3 years after completion of study treatment

Other Outcomes

Description: The measurement of each time point will be performed using the revised CHOI criteria will be only applied to arms A, B, and T, which will include anti-angiogenic therapy. Both the RECIST1.1 and revised CHOI criteria will assess the overall best response as CR, partial PR, stable disease (SD), or progressive disease (PD). Their concordance will be assessed using the weighted Cohen's kappa coefficient (k) with quadratic weights. As a rule of thumb, the level of concordance between the two criteria will be considered poor (k <0), slight (k 0-0.20), fair (k 0.21-0.40), moderate (k 0.41-0.60), substantial (k 0.61-0.80), and almost perfect (k 0.81 - 1).

Measure: The RECIST1.1 response at each time point

Time: Every 6 weeks for the first year on study, and then every 12 weeks after year one

Description: The progression status and the progression time will be assessed in agreement. The progression status is a binary measurement and the agreement will be assessed using the Cohen's kappa coefficient. For progression time, will assess the temporal agreement using the method developed by Zeng et al.

Measure: Agreement between central view and site review in terms of progression-free survival

Time: After the completion of study treatment

Description: Correlative biomarker research will be performed on tissue and blood specimens collected within this trial.

Measure: Correlative biomarker research

Time: After the completion of study treatment

86 A Phase III, Randomised, Controlled, Multi-center, 3-Arm Study of Neoadjuvant Osimertinib as Monotherapy or in Combination With Chemotherapy Versus Standard of Care Chemotherapy Alone for the Treatment of Patients With Epidermal Growth Factor Receptor Mutation Positive, Resectable Non-small Cell Lung Cancer

This is a Phase III, randomised, controlled, 3-arm, multi-centre study of neoadjuvant osimertinib as monotherapy or in combination with chemotherapy, versus SoC chemotherapy alone, for the treatment of patients with resectable EGFRm Non-Small Cell Lung Cancer

NCT04351555
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Cisplatin
  3. Drug: Carboplatin
  4. Drug: Placebo
  5. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing - A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (ie, T790M, G719X, Exon20 insertions, S7681 and L861Q). --- L858R --- --- T790M --- --- L861Q ---

Primary Outcomes

Description: Defined as ≤10% residual cancer cells in the main tumour, as assessed per central pathology laboratory post-surgery

Measure: Major Pathological Response (MPR)

Time: From date of randomization to an average of 12 weeks after the first dose

Secondary Outcomes

Description: Defined as absence of any residual cancer cells in the dissected tumour samples, including the main tumour and lymph nodes, assessed post-surgery

Measure: Pathological complete response (pCR)

Time: From date of randomization to an average of 12 weeks after the first dose

Description: An event is defined as documented disease progression that precludes surgery or requires non-protocol therapy; recurrence or a new lesion, local or distant (a new primary malignancy confirmed by pathology is not considered to be an EFS event.); death due to any cause

Measure: Event-free survival (EFS)

Time: Up to approximately 42 months after the last patient is randomized

Description: Patients will be followed up to approximately 5.5 years after they are randomized.

Measure: Overall Survival (OS)

Time: Up to approximately 5.5 years after the last patient is randomized

Description: DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first.

Measure: Disease free survival (DFS)

Time: From date of randomization up to approximately 42 months after date of resection

Description: Measured using pathologic mediastinal lymph node evaluation

Measure: Downstaging

Time: From date of randomization to an average of 12 weeks after the first dose

Description: Assess disease-related symptoms, functioning, and global health status/quality-of-life in patients

Measure: Difference between treatment arms in change from baseline in EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items)

Time: From randomization to 264 weeks post-surgery

Measure: Concordance of EGFRm status between tumour tissue DNA and patient-matched plasma-derived ctDNA

Time: Baseline

Measure: Corcordance of EGFR mutation status between the local and central cobas EGFR mutation test results from baseline tumour samples

Time: Baseline

Measure: PK plasma concentrations of osimertinib

Time: From the pre-dose of Cycle 2 to post-dose of Cycle 3 (each cycle is 21 days)

Description: Assess lung cancer-associated symptoms and side effects from conventional chemotherapy and radiotherapy

Measure: Difference between treatment arms in change from baseline in EORTC QLQ-LC13 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items)

Time: From randomization to 264 weeks post-surgery

Other Outcomes

Description: The cure rate is defined as the percentage of people in this study who are still alive and disease free for a certain period of time after they finished the surgery. Here 5-year landmark cure rate will be calculated in the same time as OS analysis.

Measure: Cure rate

Time: From the surgery until 5 years after surgery

Description: Other clinical variables include deaths, laboratory data, vital signs (pulse and BP), ECG, LVEF, ECOG performance status, and ophthalmologic assessment

Measure: Number of adverse events as assessed by CTCAE 5.0 and other clinical variables for safety and tolerability profile of neoadjuvant osimertinib as monotherapy or in combination with chemotherapy prior to surgery compared with chemotherapy alone

Time: From the time of enrollment to either 28-days after the last dose of last study treatment for patients who do not undergo surgery, or 90-days post-surgery

Measure: MPR using plasma-derived circulating-free tumour DNA (ctDNA)

Time: From randomization to 5 years post-surgery

87 A Phase II, Open-Label, Multicenter, Single-Arm, Prospective Clinical Study to Investigate the Efficacy and Safety of Tislelizumab Combined With Chemotherapy in Non-squamous NSCLC With EGFR Sensitizing Mutation Who Failed EGFR TKI Therapy

A phase II, open-label, multicenter, single-arm, prospective clinical study to investigate the efficacy and safety of tislelizumab (anti-pd1 antibody) combined with chemotherapy in non-squamous non-small cell lung cancer patients with EGFR sensitizing mutation who failed EGFR TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) therapy.

NCT04405674
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Tislelizumab
  2. Drug: Carboplatin and Nab-paclitaxel
  3. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

2. Documentation of tumor EGFR sensitizing mutation before EGFR TKI treatment, including 19del, L858R, G719X, S786I and L861Q. --- L858R --- --- S786I --- --- L861Q ---

Primary Outcomes

Description: Progression-free survival (per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first. Subjects who do not have disease progression will be censored at their last valid tumor assessment. PFS rate at 1 year as estimated by Kaplan-Meier method.

Measure: 1-Year Progression-Free Survival Rate (1-Year PFS Rate)

Time: up to 24 months after enrollment or study close

Secondary Outcomes

Description: Progression-free survival (PFS per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.

Measure: Progression-Free Survival (PFS)

Time: up to 24 months after enrollment or study close

Description: ORR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).

Measure: Objective Respond Rate (ORR)

Time: up to 24 months after enrollment or study close

Description: DCR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR), or stable disease (SD).

Measure: Disease Control Rate (DCR)

Time: up to 24 months after enrollment or study close

Description: OS is defined as the time from the starting date of study drug to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: up to 24 months after enrollment or study close

Description: DoR (per RECIST 1.1) is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first.

Measure: Duration of Response (DoR)

Time: up to 24 months after enrollment or study close

88 A Phase II Trial of Durvalumab (MEDI4736) in Combination With Chemotherapy in Virus-infected Patients With Non-small Cell Lung Cancer

This is a phase II trial of durvalumab in combination of platinum-based chemotherapy. Patients with stage IV Non-Small-Cell-Lung Cancer (NSCLC) with human immunodeficiency virus (HIV) infection (cohort 1) or hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (cohort 2) will be eligible. Patients will receive standard platinum-based chemotherapy plus durvalumab for 4 cycles (every 3 weeks), followed by durvalumab (with or without pemetrexed for non-squamous NSCLC) maintenance therapy. We hypothesized that Durvalumab in combination with standard chemotherapy is safe and effective for the treatment of stage IV NSCLC in patients with HIV, HBV, or HCV infection.

NCT04499053
Conditions
  1. Carcinoma, Non-Small Cell Lung
Interventions
  1. Drug: Durvalumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: 1. Sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q) and/or ALK translocations by locally approved laboratory testing including blood-based liquid biopsy. --- L858R --- --- L861Q ---

Primary Outcomes

Description: Incidence of treatment-emergent Adverse Events according to NCI CTCAE v5.0.

Measure: Adverse Events

Time: At the end of Cycle 4 (each cycle is 3 weeks)

Description: Radiological response will be evaluted using Recist Version 1.1 Criteria

Measure: Radiological Response

Time: At the end of Cycle 4 (each cycle is 3 weeks)

Secondary Outcomes

Description: Evaluate changes in viral load with study treatment

Measure: Changes in Viral Load

Time: At the end of Cycle 4 (each cycle is 3 weeks)

Description: Cytokine secretion assays will be performed on blood samples before, during, and after treatment.

Measure: Change in Cytokine Secretion Assays

Time: 36 months

Description: Baseline immune biomarkers (e.g. PD-L1 expression, composition of T cells in tumor microenvironment) using multiplex IHC will be compared between responders and non-responders to find predictive biomarkers associated with response to treatment.

Measure: Correlation of Multiplex IHC to response

Time: 36 months

Description: The blood tumor mutational burden (bTMB) between responders and non-responders will be compared.

Measure: Correlation of bTMB and treatment outcome

Time: 36 months

89 Dacomitinib in Advanced Non-small Cell Lung Cancer Patients With Uncommon EGFR Mutations: A Single Center and Exploratory Study

This is a single center and exploratory study, aiming to analyze the efficacy and safety of dacomitinib-a pan-HER and irreversible TKI in subjects with diagnosed stage IIIB/IV or recurrent NSCLC. All subjects will have tumors that test positive for at least one uncommon EGFR activating mutation (do not have drug-resistant pattern, e.g. 20 insertion or 20T790M). All patients will be of histo- and/or cytopathology confirmed. Determination of the EGFR mutation type will be performed in the pathological department of Shanghai Chest Hospital. Both ARMS method or targeted sequencing are acceptable. It is not acceptable for subjects with the presence of the exon 20T790M mutation or insertion together with either EGFR activating mutations (exon 19 deletion or the L858R mutation in exon 21) or uncommon EGFR mutations. 10ml peripheral blood must be available for concomitant study. All eligible subjects must have adequate renal, hepatic, and hematologic function, as defined in "inclusion criteria". Patients will receive continuous oral therapy with the study drugs (dacomitinib 45 mg) until progressive disease as defined by RECIST version 1.1 or judged by investigator that the patient no longer derives clinical benefit from study treatment. At the time of progression and removal from study treatment, the subject may receive any regulatory approved therapy at the judgment of the investigator. Timely and complete disease assessments in this study are important. Every effort should be made to ensure disease assessments performed as scheduled to prevent the introduction of bias into the assessment of efficacy. Failure to perform any of the required disease assessments will result in the inability to determine disease status for that time point. Frequent off schedule or incomplete disease assessments have the potential to weaken the study conclusion. Subjects who have progressive disease per RECIST version 1.1 confirmed by the investigator believes it is in their best interest to continue on their study therapy, will be allowed to continue on their therapy with or without local therapy (e.g. surgical removal and/or radiation of a single lesion), at the discretion of the investigator until any alternate or additional systemic anti-cancer therapy regimen is implemented. The subsequent new cancer therapy (including, for systemic therapy, drugs administered, date of initiation and discontinuation of each drug) and OS will be recorded. Each subject will be followed for survival status and subsequent cancer therapies up to 48 months from the date of first dosing. This data may be collected from subjects by telephone, and if collected should be entered into the CRF.

NCT04504071
Conditions
  1. Non-small Cell Lung Cancer Metastatic
  2. EGF-R Positive Non-Small Cell Lung Cancer
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Mutation in exon 20: Including S768I, V765A, T783A, V774A, S784P, R776C, R776H, V765M, G779C, G779F, G779S, T783A, T783I, L798F, L798H, K806E, Q812R, L814P Mutation in exon 21: L861Q, R831H, V834I, L838P, L861R. --- S768I --- --- V765A --- --- T783A --- --- V774A --- --- S784P --- --- R776C --- --- R776H --- --- V765M --- --- G779C --- --- G779F --- --- G779S --- --- T783A --- --- T783I --- --- L798F --- --- L798H --- --- K806E --- --- Q812R --- --- L814P --- --- L861Q ---

Primary Outcomes

Description: ORR was defined as the proportion of patients with a complete response (CR) or partial response (PR) per the investigator's assessment using RECIST 1.1 criteria

Measure: Objective response rate (ORR)

Time: 6-12 weeks

Secondary Outcomes

Description: The disease control rate (DCR) was defined as the sum of the proportions of patients who had CR, PR, and stable disease (SD) using RECIST 1.1 criteria

Measure: Disease control rate

Time: 6-12 weeks

Description: PFS was defined as the time from study treatment initiation to the first occurrence of documented disease progression or death from any cause during the study, whichever occurred first.

Measure: PFS

Time: 13-15months

Description: OS was defined as the time from the first dose of study treatment to the time of death from any cause during the study.

Measure: Overall survival

Time: 22-25months

90 A Single-arm, Open-label, Phase 1b Study Evaluating the Efficacy and Safety of Olmutinib 600 mg QD in Patients With T790M-positive NSCLC After Treatment With an EGFR-TKI

The purpose of this study is to evaluate the efficacy and safety of olmutinib 600 mg QD in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT04510415
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Olmutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Defined as a best overall confirmed response of either CR or PR according to the RECIST version 1.1

Measure: Objective response rate (ORR)

Time: 24 months

Secondary Outcomes

Description: Defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Measure: Disease control rate (DCR)

Time: 24 months

Description: Defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Measure: Duration of overall tumor response (DR)

Time: 24 months

Description: Defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Measure: Progression-free survival (PFS)

Time: 24 months

Description: Defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Measure: Time to progression (TTP)

Time: 24 months

91 A Phase II Trial of Osimertinib and Abemaciclib With a Focus on Non-Small Cell Lung Cancer Patients With EGFR Activating Mutations With Osimertinib Resistance

Lung cancer is the leading cause of cancer deaths. Advances in the systemic treatment of non-small cell lung cancer (NSCLC) have increased survival in metastatic EGFR-mutated NSCLC. However resistance to therapy can develop. NSCLC tumors with EGFR-activating mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors with overall response rates approximating 80%. The third generation EGFR compound osimertinib is a standard first line option. Resistance to the third generation EGFR-TKI osimertinib can develop with a median PFS of 18.9 months. Current research examining acquired resistance to EGFR-TKIs has focused on overcoming these main mechanisms of EGFR-TKI resistance and understanding the impact of co-occurring alterations. Frequently altered pathways concomitantly affected with EGFR in lung cancer are cell cycle genes. This study will explore a strategy to inhibit EGFR and CD4/6 in resistant EGFR mutated lung cancer patients post progression on osimertinib.

NCT04545710
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Abemaciclib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- Tumor must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q). --- L858R --- --- L861Q ---

Primary Outcomes

Description: Rate of Progression Free Survival at 6 months on the combination.

Measure: Progression Free Survival at 6 months

Time: 6 months

92 Phase 2 Study of PD-1 Inhibitor JTX-4014 Alone and in Combination With Vopratelimab, an ICOS Agonist, in Biomarker-selected Subjects With Metastatic NSCLC After One Prior Platinum-containing Regimen

This is a Phase 2, open-label study to evaluate PD-1 inhibitor JTX-4014 alone and in combination with vopratelimab, an ICOS agonist, in biomarker-selected adult subjects with metastatic NSCLC who are PD-1/PD-L1 inhibitor naïve and have progressed on a platinum based chemotherapy regimen.

NCT04549025
Conditions
  1. NSCLC
Interventions
  1. Drug: JTX-4014
  2. Drug: Vopratelimab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Current or past participation in a study of an investigational agent or using an investigational device in the metastatic setting - Chemotherapy < 28 days prior to planned C1D1 - Prior immunotherapy including, but not limited to PD-1 or PD-L1 inhibitor mAb at any time, including JTX-4014; therapy with any mAb that specifically binds to ICOS, including vopratelimab; or chimeric antigen receptor T cell therapy - Use of anticancer therapies listed below in the metastatic setting (allowed as prior treatment for localized disease): 1. Biologic therapy 2. Targeted small molecule therapy 3. Organ transplantation, including allogeneic or autologous stem cell transplantation - Positive test for any of the following epidermal growth factor receptor gene mutations in blood or tumor: Exon 18 G719A; Exon 18 G719C; Exon 18 G719S; Exon 19 Del; Exon 20 S768I; Exon 20 T790M; Exon 20 Ins; Exon 21 L858R; Exon 21 L861Q - Prior whole brain radiation Inclusion Criteria: - Able and willing to participate and comply with all study requirements - Histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) with evaluable or measurable disease according to RECIST v1.1 with at least 1 measurable lesion - Confirmed tumor RNA signature score - Experienced progression of locally advanced or metastatic NSCLC after 1 prior systemic antineoplastic platinum-containing regimen (adjuvant therapy will count as a regimen if administered within 1 year before the relapse) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Predicted life expectancy of ≥ 3 months - Adequate organ function - WOCBP must agree to use highly effective birth control Exclusion Criteria: - Concurrent anticancer treatment or subject is expected to require any other form of antineoplastic therapy while on study, either approved or investigational. --- G719A --- --- G719C --- --- G719S --- --- S768I --- --- T790M --- --- L858R --- --- L861Q ---

- Current or past participation in a study of an investigational agent or using an investigational device in the metastatic setting - Chemotherapy < 28 days prior to planned C1D1 - Prior immunotherapy including, but not limited to PD-1 or PD-L1 inhibitor mAb at any time, including JTX-4014; therapy with any mAb that specifically binds to ICOS, including vopratelimab; or chimeric antigen receptor T cell therapy - Use of anticancer therapies listed below in the metastatic setting (allowed as prior treatment for localized disease): 1. Biologic therapy 2. Targeted small molecule therapy 3. Organ transplantation, including allogeneic or autologous stem cell transplantation - Positive test for any of the following epidermal growth factor receptor gene mutations in blood or tumor: Exon 18 G719A; Exon 18 G719C; Exon 18 G719S; Exon 19 Del; Exon 20 S768I; Exon 20 T790M; Exon 20 Ins; Exon 21 L858R; Exon 21 L861Q - Prior whole brain radiation NSCLC Carcinoma, Non-Small-Cell Lung JTX-4014 is a fully human IgG4 monoclonal antibody designed to specifically bind to PD-1 and block its interaction with its ligands, PD-L1 and PD-L2, to augment anti-tumor T cell activity. --- G719A --- --- G719C --- --- G719S --- --- S768I --- --- T790M --- --- L858R --- --- L861Q ---

Primary Outcomes

Description: Mean percent change from baseline in all measurable lesions

Measure: Change in measurable lesion size

Time: averaged over 9 and 18 weeks

Secondary Outcomes

Description: ORR according to RECIST v1.1

Measure: ORR

Time: up to 24 months

Description: PFS according to RECIST v1.1

Measure: PFS

Time: up to 24 months

Description: Landmark progression free survival (PFS)

Measure: Landmark progression free survival (PFS)

Time: 9months

Description: Disease control rate (DCR) according to RECIST v1.1

Measure: Disease control rate (DCR)

Time: up to 24 months

Description: Median duration of response (DOR) according to RECIST v1.1

Measure: Median duration of response (DOR)

Time: up to 24 months

Description: Median overall survival (OS)

Measure: Median overall survival (OS)

Time: up to 24 months


HPO Nodes


HP:0002088: Abnormal lung morphology
Genes 1393
CDC45 SMARCA4 TBC1D24 ELN SNX10 SLC1A4 GRHL3 CFAP298 RSPH4A EDNRB TMEM94 CARD11 LPIN2 CD3E COG4 PGM3 ECM1 GNPTAB LIMK1 HLA-DRB1 CFTR CD247 PDGFRA LMNA FBN1 NTRK1 SOS2 PSAT1 ZBTB24 GP1BB MANBA CLEC7A IL2RG TARS1 DNAAF2 NSD2 SEC24C DNAJB13 DNAAF3 EXOSC9 DYNC2LI1 NELFA EDARADD NPHP3 STING1 GDF1 COL2A1 MAP3K20 CTRC HLA-DPB1 OFD1 SMARCD2 ABCA12 ERCC6 FGF20 LZTR1 SCNN1G SLC25A24 BLNK NKX2-5 TRIP13 SOX10 GAS2L2 TYK2 HELLS TTC21B FOXH1 DNAAF6 INPPL1 ITGA8 PERP EIF2AK4 OCRL GPR35 GTF2E2 NEB FOXC2 MASP2 STAT5B COL11A2 FBXW11 MYO5A CTLA4 LBR FCGR2A PRKCD RANBP2 HYLS1 IL21R DGCR8 BMPER GATA4 NSD1 TSC2 FLCN LTBP3 CYBA SPINK5 ATP5F1A CTLA4 FLT4 TERC KCNJ6 FOXH1 TCF4 NAGLU GUSB SHROOM4 EVC LIPN RNU4ATAC TPM3 PTPN11 CDT1 MUSK HERC2 NEK1 FLNB EPG5 GAS1 FBLN5 NRAS ACP5 MCIDAS MAN2B1 TIMM8A COL13A1 BCOR MYLK PTPN22 SLC35A1 SLC46A1 HGSNAT RASGRP1 LYST ZNF341 XIAP LRRC56 FGFR1 IGH NODAL WDR19 LETM1 TRIP4 EFEMP2 NCF1 MCM4 SFTPC SOS1 STRA6 RSPH4A IL2RB RAG2 RAC1 DISP1 PHGDH WRAP53 PSMC3IP RBM10 PANK2 PEX1 TNFRSF13C GLI3 WNT3 ARID2 SBDS NPAP1 ACTA1 BLM CD40LG BRAF ICOS FASLG PRKN CCDC103 SNORD116-1 FOXP3 MEFV PTEN TDGF1 IL6R CIITA SLC2A10 CYTB ENG GLI2 FGF8 DNAJB13 CCDC39 STAT6 INVS IDUA GATA4 RPS15A NOP10 IFNG HLA-DRB1 FLNA JAG1 HABP2 VANGL1 GNPTAB MYBPC3 TBX6 MKRN3 SNORD115-1 LACC1 ELANE SMN1 DYNC2H1 KIF20A RPL10 ARHGAP31 PGM3 PEX13 CDON IL7R RAF1 SCNN1A STAG2 PLEC FLI1 CITED2 SIX3 TCIRG1 ETFA MITF MST1 ZNHIT3 LAMA2 IFT81 PDGFRB CYP4F22 DNAAF4 HLA-B FAT4 ZIC2 CALCRL KMT2E HFE CSF2RB CD55 IGH TTC37 DICER1 NFKB2 PEPD GPC6 TNFRSF13B FGF8 RAF1 ABCA3 STK36 RFX5 DPP9 RYR1 SFTPA1 SHH SKIV2L IRF1 LAT DCLRE1C SON SLC25A22 TLL1 AP3D1 TGFBR1 NODAL AGT ZMYND10 SOX18 NOS1 TPM2 BUB1B TRIP11 ERAP1 TNFRSF1B REST ZIC2 CTCF RAC2 CTLA4 PLP1 GAS1 EFL1 FMO3 TRIP4 RYR1 CIITA DLL3 AP3B1 PRTN3 PIGN TBX1 ABCA3 EFEMP2 AGA CHRND PCNT PKHD1 RSPH1 ZAP70 PAX3 NDN CHRNG NHLRC1 ACE DNAH1 KRAS IL12A KEAP1 ALDH18A1 SCNN1G ACADVL DCTN4 IRF5 TRAPPC4 CCN2 PTCH1 DKC1 GMNN TNFRSF13B GLI2 MCIDAS SCN11A ROR2 IVNS1ABP TRPV4 TSC1 FANCB ZEB2 RPL10 ODAD1 MESP2 CHST14 IL23R SLC12A6 MGP CFAP300 SMAD3 RSPH9 UMPS DHCR7 KRAS SFTPC COL13A1 SNRPN BUB3 FAM13A GAS8 WDR35 MFAP5 CACNA1B ZCCHC8 NTNG1 FLCN AK2 INPPL1 CHAT CCDC40 IL2RG CDC42 DYNC2H1 CD3G TASP1 SLC18A3 DGCR6 HOXD13 SCNN1G WT1 KAT6B WT1 MAP3K8 STAT1 ACTA1 TGFB3 MUC5B PRKAG2 SMN1 TAP1 SMAD4 ABL1 MED25 CHD7 TERT COG4 LMNA SULT2B1 GBA SPEF2 RREB1 SDR9C7 CEP57 CFI IDUA FUCA1 FLCN TBX1 HPS4 PIGT SAMD9L FLNC ESS2 NCF4 LRBA DRC1 DYNC2I2 RFXAP KIAA0586 DNAH5 DOCK8 PTEN MAN2B1 ZMPSTE24 TP53 ATM LAMC2 ACTL6A TRAF3IP2 POLR3H RELA TBX5 PARN CR2 IRF5 MED13 NUP88 GALNS TAP2 AFF4 UNG DNAAF4 RFC2 BCL11B NCF1 HPS1 CD3D RELB PTPN11 ODAD4 TDGF1 KAT6B PMM2 CYP2A6 RUNX2 POLA1 SGSH RIPPLY2 SERPINA1 WAS NDUFAF6 MMP21 SPP1 GLDN NSDHL ZFPM2 IL17F IL6ST IRAK4 KAT6B ACTL6B LRRC8A TAPBP CCNO GLI3 PLCG2 HK1 BMP15 TMEM260 MYL2 LEP ERCC3 TRPV3 IGLL1 EPM2A CCDC65 PRKCD SLC18A3 TAPT1 BMPR2 CD79B SLC7A7 FLNA FAM20C HLA-DRB1 SLCO2A1 CD46 XIAP DKC1 CYBB MYT1L CD3E AFF4 MESP2 VHL POLE BCOR FOXH1 BMP2 HYDIN TNNI3 RARA MAT2A EOGT NFIX MEFV DVL3 PTH1R BCL10 RNF168 CBL ITGA8 NEU1 KRAS CEP55 MYD88 NPM1 IGLL1 TP53 RSPO2 RRAS TRIP11 TGIF1 WAC ADA PKD1L1 UNC119 ACTA2 PSMD12 ACTA1 STRA6 PIGN GAA CD8A BCOR NEK9 TERT DHCR7 IKZF1 TSC2 LEPR SLC35A1 MUSK ARSB COG6 VPS51 COLQ WDR1 RASA2 TTC7A LTBP4 BTK GPC3 STAT3 GAS1 RUNX1 TTC12 WASHC5 INTU CD3D WT1 STAT3 BPTF CRTAP SLC2A10 COL2A1 COMT CCDC40 ASAH1 LIFR MEFV ACVRL1 MYH3 FAT4 DNAI2 LAMB3 PIEZO2 FOXE3 GRIP1 NFKB2 PIGL PTCH1 TGFBR2 ATP6V1E1 COL6A3 IL1RN PAFAH1B1 FOXH1 TP53 CRELD1 MBTPS2 RYR1 TNFRSF13B GRIP1 TGIF1 CLCN7 SP110 CC2D2A COL6A1 STN1 APC2 ITPR1 TCTN3 SMARCC2 PNP SLC11A1 GLUL PKHD1 ALPL BLM ACP5 WDR19 ASCC1 TDGF1 TFRC MGP DLL1 WNT4 IFT140 CCN2 SHH SMAD3 TGIF1 PRKAR1A EHMT1 EP300 CASP8 TGFBR1 ITGA7 AARS2 ERF DNMT3B FGFR1 IRF2BP2 CHRNG HLA-DQB1 SPAG1 SRP54 UBE2A CCNQ TINF2 BUB1 LFNG CARD11 DHCR24 ARID1B SELENON RMRP WAS NEK10 MAPK1 GATA6 SCNN1B TRIM28 DHCR24 SYT2 DOCK6 USB1 B3GLCT DLL1 CCR1 POLR3A PRPS1 HIRA RSPH1 SLC26A2 TNFSF12 PIK3R1 IER3IP1 GSN TINF2 NME8 SVBP LIG4 IL7R ALB COL11A2 COL3A1 NHLRC2 KIAA0319L TGFB1 DLL1 IFNGR1 LAMTOR2 DNAAF5 NXN CTLA4 CEP57 HLA-DRB1 MINPP1 CASP10 PTPN22 TBX20 RAB3GAP2 ALOXE3 ZIC2 NUP107 HES7 LRRC56 HLA-DQA1 KIF1A GAS8 TERT PSAP DNAI2 NOTCH2 DPM2 CD81 NODAL DNAH9 NABP1 PRKAR1A NUMA1 TBC1D23 NFKB2 DLL4 ORC6 FANCB SMARCB1 FCGR2B SIX3 GBA GATA4 MDM2 LAMA3 DSP KIF11 MLXIPL HLA-DRB1 NOTCH2 ADGRG6 DNAH5 SLC26A2 DYNC2I1 ATP6V0A2 EGFR ZBTB24 LYST ODAD4 CACNA1C CYBB RNF125 DPF2 RIT1 CITED2 RLIM WDR35 DYNC2I2 GATA6 RTEL1 IRF8 DISP1 GAS1 ABCA12 TRIP13 GPC3 ODAD3 DNAAF2 MECP2 BIRC3 SFTPB ELN CFTR NOTCH3 SCNN1A KMT2D DIS3L2 MDM4 IL17RA EPHB4 CCDC39 FBLN5 SPIDR TCF20 KLHL41 WNT3 IL17RA FCGR3A JMJD1C VPS33A UFD1 ODAD1 IKBKB CHEK2 FADD RSPH3 ZMIZ1 CREBBP TNFSF11 SCNN1B FREM2 CCR6 AGA SCNN1A ADA RAG1 RAG1 LMNA BRCA2 TGM1 TSC1 DLL1 SIX3 CARMIL2 GTF2I AKT1 CCDC65 ARID1A FGF20 RIPK4 ALG9 CFB RAG2 SCNN1G APOE SOX4 RAB27A MUC5B EWSR1 NECTIN1 ZMYND10 SGCG DNAAF6 CDON TAF1 IGHM LMNA LAMB2 LEP CSF2RA CD79A CFTR HPS6 DOK7 RCBTB1 CCBE1 FIP1L1 COQ7 SERPINF2 PWAR1 RPGR VPS33A ELN SPECC1L TET2 BTK SCNN1A RLIM IL7R EPG5 HLA-DRB1 TGFB2 PIK3CD GLA NBN HYDIN PSMB8 VAMP1 SDCCAG8 TINF2 FCGR2A SHH ARHGAP31 RAC2 CD19 DSE DDX6 HLA-B SERPINH1 GLI2 FLNA MARS1 ALMS1 SCNN1B ITCH SPAG1 DISP1 DNAAF5 IDUA TGFB2 FGF8 MSN SMARCE1 CHST14 WRN BCR FGFR3 SERPINA1 WDFY3 RAG1 PRPS1 FASLG DNASE1 NIPBL KLHL40 RAG2 MRAS RHOH ZAP70 TK2 FGFR1 CREBBP MYRF ALOX12B NOD2 RFXANK MYH11 EVC2 DYNC2LI1 ZEB2 IFIH1 RARB GBA USP9X IKBKB ABCA3 MYOD1 GATA6 CCNO CSPP1 TBCE GBA RARB NAA10 TSC1 FAS WNT4 PLCG2 ETFDH G6PC3 MS4A1 SPINK1 CD19 UBAC2 FLCN EXTL3 GUSB DYNC2I2 ATP11A NGLY1 SAMD9 NME8 TRAIP RRAS2 PYROXD1 SIK1 SLC26A2 RAG1 MYOD1 ALMS1 NKX2-5 IL21 FOXP1 PUF60 LAMTOR2 BCL2 SMAD4 TBL1XR1 ACTC1 FOXJ1 ARID1B HELLPAR SCNN1B DGCR2 DOCK3 FSHR MIF CYBC1 SNAI2 CSPP1 CCBE1 SMARCD1 IRAK1 JAK3 STAG2 PCGF2 CXCR4 LEPR DDR2 BCL6 POLA1 TRMT1 PTCH1 RPGR GATA6 CSF2RB CHRNA1 ASAH1 ASAH1 RAG2 NAB2 TERT MYSM1 BTK FRAS1 DCLRE1C BTNL2 CFTR NOP10 KNSTRN FOXJ1 PEPD TERT NR5A1 CDON MARS1 BRAF TCF3 NKX2-1 ICOS ZMPSTE24 DNAH11 OSTM1 ALG12 KATNIP AGTR1 PPP1CB BMPR2 CAV1 TGFB1 KPTN ADA TPP2 MKRN3-AS1 SLC25A1 FARSB GPC4 FUZ MYH6 HLA-DPA1 FBLN5 SRP54 TNFSF12 IGHM NEK10 RSPH3 TTC12 CRKL RASGRP1 SELENON PTPN22 DLL3 CLPB DOCK8 GLI3 HPGD THOC2 LOX RBPJ PIGN SMC1A DCLRE1C DNAL1 RIPK1 ZBTB16 CFH BTNL2 GLE1 SFTPC FOXF1 KLRC4 CCND1 CD79A EGFR TNNT2 DNAJC21 IL12A-AS1 IFT80 TSC1 CTSC USP9X MKKS SFTPA2 PIK3R1 CHRNG CITED2 TNFRSF13C ELN ADAMTS2 NR2F2 RSPO2 CFTR SCARB2 NKX2-5 SOX18 ADNP DNMT3B CCR6 TCIRG1 PAX6 STAT4 SETD2 DRC1 CFAP221 C11ORF95 TSC2 IFT172 TNFRSF13C FBN1 ARVCF RNF168 NFKBIA NFKB1 BAP1 NEPRO SLC52A3 PRSS1 SLC26A2 CLIP2 MKS1 GLI1 CRELD1 FGFR3 SFTPC FCN3 NCF2 SIM1 CD28 BAZ1B P4HTM DNAAF3 GAS2L2 CCDC103 UGP2 CEP120 GATA2 ETFB DICER1 IL6 ICOS CDCA7 CDKN2A SIX3 JAGN1 SFTPB DNASE1L3 PPP2R1B MBTPS2 CLCA4 STX1A KIAA0586 AGGF1 BNC1 POU6F2 MYH3 PHGDH STAT3 HRAS SFTPA2 DNAH11 LRRC6 SLC35C1 CDON IL17RC ASXL1 TRIM28 COL3A1 CD79B KDM6A UBB NHP2 NAA10 NCF4 CCDC22 MAGEL2 TBC1D24 PARN NRAS MTHFD1 MYH7 MIR140 BLNK LCK NFE2L2 CSF2RA MYSM1 DNAI1 MYT1L RAG2 CAV1 ZIC2 PRKG1 HACD1 MPLKIP TLL1 PIK3CA NSMCE3 IL10 PRSS2 SMPD1 IFT80 NLRC4 COL6A2 FLNB OFD1 PARN RB1 SCN9A MCTP2 FGF8 MAGEL2 FANCF CORO1A PIK3R1 PRKDC CR2 GBA EP300 TGFBR2 PIK3CD CASP8 CRLF1 PLVAP RAPSN NOTCH1 H19 PTCH1 NCF2 SH3KBP1 CR2 ERBB2 DNAAF1 AGRN RFXANK TDGF1 LGI4 GLE1 IL2RA SOX11 IL2RG MEFV ATM STAT3 ODAD3 SERPINF2 CYBC1 SNAP25 SMPD1 TRPS1 REN SHH ELP1 GLI2 CHRM3 IL2RG PNP GREB1L BACH2 SRSF2 NPHP3 CREBBP RIT1 BGN SH2D1A WIPF1 GATA6 DDR2 CTC1 FAS DYNC2I1 KITLG TBX1 TGIF1 RFX5 DCLRE1C CFAP410 GTF2IRD1 GPKOW FAS DONSON CCNQ ELN FADD SLC5A7 GDF1 ERCC2 TERC CBL ADAMTS3 TBX20 ODAD2 STAT4 SLC29A3 FOXE1 CBL FBN1 DVL3 MALT1 IFT43 DSG1 TECPR2 RTEL1 IPW NGLY1 CYBA PIEZO1 NHP2 EP300 TNFRSF11A DZIP1L CCND1 TLR4 CD81 FAM111B LRRC6 RTEL1 BCORL1 PORCN RAG1 SLC34A2 COPA DICER1 FRAS1 DNAI1 TERC MYPN NFKB1 ODAD2 ITCH TBCD ELANE NPM1 CXCR4 PWRN1 TNFRSF1A FOXP1 MYO9A DNAAF1 TGFB1 RFXAP C4A PML RAG1 TREX1 SMPD1 CREBBP SLC22A18 ELN TSC2 A2ML1 FSHR SETBP1 USB1 NADK2 MS4A1 CHAMP1 TERT NKX2-1 PTPRC SCN10A NEK8 CEP120 SMO CFI LMOD3 ELP1 NAA10 POLR2A NODAL GFI1 PLG RNF113A HSPG2 TBL2 EMG1 SFTPB STK11 SLC7A7 RSPH9 MRPS22 TERC CFAP298 WT1 CD19 RET JAK3 AICDA GLB1 GTF2H5 NIPAL4 PLOD1 MESP2 DYNC2I1 RNU4ATAC ZEB2 TANC2 ITGA3 NBN GNS FOXN1 STAT1 DISP1 B2M
HP:0002664: Neoplasm
Genes 1537
H19 RPS19 WT1 GPR101 CHEK2 MYD88 VEGFC PGM3 CTNNB1 PDGFRA IRF1 RHBDF2 PICALM FANCC GDNF RET PRKAR1A NELFA BCL10 KRT10 BLK TINF2 SMARCD2 NSD2 BRCA1 KRAS TRIP13 KCNH1 PERP CDH23 IKBKG MCC JAK2 MET GTF2E2 FOXC2 NF1 RAD51 TP53 ERCC4 WNT10A ASXL1 CTLA4 FLT4 DVL3 BRCA1 MLH3 NSD1 ERCC2 TSC2 FANCL RPS14 CDC73 TNFRSF4 STAG3 MSTO1 AIP EVC RET PLCD1 SDHB NEK1 POLH ASXL1 BRAF IL7 MAP2K1 ARSA BRAF COL4A5 CYLD KRT14 MLLT10 RASGRP1 H19 XIAP NTHL1 FGFR2 IGH DNAJC21 LETM1 MCM4 MYF6 CD70 FAM149B1 FGFR3 TERF2IP TNFRSF13C GLI3 DDX41 RPL26 PRLR SBDS LIG4 MGMT RERE KLLN FANCM WT1 PHB AXIN2 KIT PTEN TGFBR2 GJA1 PDGFRL STAT6 TYR CPLANE1 IFNG SIX6 JAG1 PALB2 SSX1 FANCG KIT MYO1H ELANE RPS19 H19-ICR KRT6B IDH2 PLCB4 FGFR1 BAP1 MINPP1 MST1 SMARCB1 PDGFRB RB1 FAT4 NF1 HFE SDHD WT1 TET2 BMPR1A RAF1 POLR1D CBFB SKIV2L IRF1 COL18A1 HMBS RET MMEL1 IGF2R JAK2 SEC23A BUB1B XPC ING1 AXIN2 KIT PALB2 MAGT1 STAC3 ALK SLC25A13 TMEM231 SHOX TDGF1 REST SMO SMARCA4 DNM2 TSR2 LIN28B GNAS WT1 CDKN1A DNAJC21 DKC1 BAP1 SRGAP1 ALX1 PTPN11 CBL APC SCN11A MAP3K1 RPL10 KLF6 PAX7 APC C1S NRTN BUB3 KRT5 LIG4 CARD14 GNAS MLH1 CDKN2A GNA11 TMEM127 ESR1 IL2RG KRT1 MET NF2 SDHAF2 SDHD WT1 MAP3K8 STAT1 PHOX2B PTPRJ PTCH2 CHD7 TERT LMNA ERCC6 EDNRB XPA PDGFRA OFD1 VHL SAMD9L SF3B1 FERMT1 BRCA1 GDF2 CASP8 TP53 LAMC2 GFI1B FANCD2 PYGL CR2 AR REST APPL1 APC CYP2A6 SEMA3C WT1 CDKN2A CTSA LRRC8A PHOX2B SMARCB1 NAGS FLI1 SOX2 RAD21 TMEM127 APC FGF3 BAP1 BUB1 RAD51 DKC1 RAD54B VHL EPCAM ASXL1 SRC HRAS BMP2 SLC25A11 PTH1R KRAS MYD88 NPM1 PTEN SH3GL1 PHOX2B TP53 SMAD4 XPA GATA4 MLH1 PMS2 STK11 FANCC DHCR7 PTCH1 CDC73 CYLD MEN1 CLCNKB CHEK2 RNF139 HABP2 POLE H19-ICR MMP1 RPL27 CC2D2A PIK3CA GPC3 ABL1 PALLD WASHC5 INTU ERCC5 DYNC2LI1 SLC22A18 TP53 CDH1 SHH MPL AKT1 NFKB2 NRAS PIGL CASP8 MYC KCNE3 DLST TAF15 TNFRSF13B GDNF EYA1 APC2 TNFRSF1B TCTN3 PPOX PNP PKHD1 BLM ODC1 IL12A TERT STK11 KRT17 IDH1 CIB1 RPL18 DVL1 ARHGAP26 PHOX2B CASP8 RPGRIP1L KRT6A SDHB FGFR2 VAMP7 JAK2 SRY DNMT3A EPAS1 KCNQ1OT1 MSH6 KRAS SDHB WNT5A DNMT3A RUNX1 TRIM28 DHCR24 USB1 VANGL2 GCM2 LIG4 KRAS SDHB ENG SEMA3D TRNS2 MINPP1 CASP10 NTHL1 LMOD1 SUFU FOXH1 CD81 ALX4 F13B BMPR1B RB1 CACNA1S CHIC2 VHL HRAS KIF11 KCNJ11 WRN SLC37A4 GNAQ LZTR1 CCND1 CPLX1 NR4A3 RYR1 NBEAL2 GATA2 TP63 APC KRAS HNF1B SUFU GNB1 MSX2 GPC3 CEL TCTN3 OCA2 MDM4 RB1 TMC6 ASCL1 AR BRIP1 CHEK2 AAGAB TSC1 TXNRD2 POLD1 CARMIL2 APC PIK3CA AKT1 POLE FAN1 RAD21 G6PC BRD4 PTCH2 MSH2 DHH EWSR1 SPRTN SDHC PTCH1 ALX3 CD79A TMEM67 INPP5E CCBE1 KRT6B BRCA2 ITK GINS1 HLA-DRB1 SNAI2 NBN PHOX2B BRAF CDH1 FANCE TYR GPC4 NF1 CD19 MVD AIP AR NBN TMEM107 BRIP1 ATRX BCHE MITF WRN BCR BCR NF2 SERPINA1 SDHB RABL3 PARN ANTXR2 TERT DPM1 IFIH1 GDF5 ZAP70 MEN1 TP53 GNAS BRCA2 TMC8 NODAL LETM1 VANGL1 TBXT BRCA1 FIBP FLT4 IL1B CCL2 FGFR3 SUFU MTAP ELANE CD19 HNF4A SAMD9 BUB1B KLHDC8B SLC26A2 FGFR3 FOXP1 PUF60 RUNX1 PTCH2 TRNK FLT4 TYROBP MPL KRAS RAD54L PIK3CA FAH CHEK2 CPLANE1 FAM20C CXCR4 DDR2 POU6F2 TMC6 SEC23B RET TRNP TFE3 TP53 NAB2 ANTXR1 MYSM1 SDHAF2 BTK TNFRSF10B DCLRE1C L2HGDH CDKN2A CYP11B2 BRCA2 SDHD TET2 TMEM216 BRAF PTCH2 TCF3 RPL11 NNT FLT3 BAX HAX1 IGF2 AKT1 FGFR3 MLH3 PLA2G2A TCF4 MLH3 NOTCH1 ERCC4 RRAS2 GPC4 DICER1 LZTS1 DOCK8 CASP10 GREM1 HPGD COL1A1 DCLRE1C IDH1 XRCC3 SUFU DNAJC21 PDGFRB TP53 NLRP1 WWOX TSC1 CTSC USP9X PDCD10 MEN1 ASCL1 RNF43 TNFRSF13C ESCO2 ZFPM2 AP2S1 PRCC HMBS ADA2 GANAB WT1 RNF43 HRAS KRAS SETD2 ATP6V1B2 FLT3 TJP2 BMPR1A PDGFB KIAA0753 PTEN STK4 NFKB1 BAP1 PMS1 MSR1 SLC26A2 RECQL4 MSH2 JAK2 ATRX FH RECQL4 FCN3 CD28 ASPSCR1 ADAR WHCR NOTCH3 GATA2 SMARCE1 CDKN2A RET ESCO2 EXT1 ERCC5 TET2 MBTPS2 NF1 OFD1 AGGF1 MVK KIT MUTYH HRAS KRIT1 FGFR1 TRIM28 CHEK2 CD79B GNAS BRCA2 KDSR BAX HACE1 MAP2K2 EDN3 ERCC2 CTNNB1 IL6 IGH PIK3CA MSH3 FZD2 SMPD1 SNAI2 PHOX2B SLC26A2 OFD1 PAX4 RB1 TRIP13 EWSR1 SCN9A PIK3R1 GBA EP300 PIK3CA HMMR KIT PDE6D ZSWIM6 SH3KBP1 SRP54 FUZ USP8 WT1 TERT MAFA FOXO1 GJB3 RAD51D POT1 SDHC PRKAR1A CREB1 SH2D1A WIPF1 WWOX PIK3CA NF2 HNF4A FAS RNASEH2A CD27 ATRX SPRED1 RPS14 FDPS RNR1 PALB2 NF1 MN1 TET2 GPC4 KDR SOX9 RAD51 MAX MYLK EP300 SHOX FOXE1 TCOF1 ESCO2 MYH11 HSPA9 MAD2L2 KRT9 CYP2D6 RFWD3 FANCE KRAS CCND1 LMO1 PTCH1 PORCN EDN3 PDGFRA DICER1 FANCA TERC CTBP1 SDHD ANTXR1 CXCR4 RAD50 BRCA2 MC1R MPL SLC22A18 MMP1 KRT16 F13A1 TSC2 ENG SETBP1 WT1 TET2 SDHC SMAD4 ZFHX3 GFI1 RNF113A STK11 KARS1 FOXE1 CDKN2B WT1 ERBB3 SMARCAD1 PDGFRL DMPK GTF2H5 NF2 CEBPA RPS28 PMS1 AKT1 PRDM16 NBN GCK SPINK1 ERBB2 JAK2 KIT DKC1 EXT1 JAK2 COL7A1 AXIN1 SLC22A18 NRAS ECM1 GNPTAB ABCA5 CDH1 NRAS ERCC6 VANGL1 RAD51C MYCN HBB TP53 SRY FANCI AKT1 MITF LEMD3 TARS1 TET2 NSD2 DAXX DYNC2LI1 OGG1 EXT1 TNFSF15 TERT ERCC6 DMRT3 SLC25A11 CTNNB1 VHL KLLN MLH3 EIF2AK4 GJB6 BARD1 OCRL GPR35 MYC DLST KRAS MSH3 RMRP PRKCD KLF6 NEUROD1 FANCG SLC17A9 BMPER FLCN SDHC SF3B1 STS GNA14 TERC MNX1 CAT TCF4 TUBB TRNQ BRCA2 IL12RB1 PDX1 CDKN2A SLC26A4 SDHC PPM1D NRAS PRKAR1A NRAS TAL1 KIF1B DNMT3A PDGFB MRAP ERCC3 CDC73 PRF1 RFWD3 PMVK RPL15 FGFR1 TP53 BICC1 HNF1A GATA1 RTEL1 RPS15A ERCC4 WRAP53 NR0B1 BCR FGFR2 SEC23A KRT17 NR5A1 VHL BLM BRAF ICOS POLD1 RPS27 FASLG CYSLTR2 PTEN PRKN THPO KIF7 NRAS TAL2 BRAF WDPCP DCC MSH6 NOP10 WNT10A PSAP ERCC2 CALR ACD SLX4 ACAN HABP2 GJB4 TET2 PHF21A ERCC3 MDH2 APC PALB2 RPL10 KRT17 PGM3 IL7R ARL6IP6 APC TCIRG1 NF1 SMAD4 PTPN3 PIK3CA ABCA5 FGFR2 TGFBR2 BRCA2 HNF1A RNASEH2C PAX6 IGH TTC37 DICER1 SRY GPC6 TOP2A KIT OFD1 PALB2 NRAS MC1R SDHD TFAP2A FGFR3 TNFRSF1B REST PTEN MST1R SCN4A BRCA2 CDKN2A FGFR2 ZIC2 EFL1 ECE1 NUP214 DDB2 GPC3 KCNQ1 PTEN HNF1B FN1 ASCC1 SPIB SRP72 PTEN FANCB KCNJ10 AKT1 KRAS KEAP1 INS DISP1 PTEN SASH1 CDKN1C ACTB TNFRSF13B MYH8 EDN1 IVNS1ABP NSUN2 TSC1 RAD51C MSH3 ATP7B RET PTPN12 STIM1 DHCR7 KRAS SFTPC BMPR1A XPC TMC8 KCNJ10 KDM6B STK11 KRAS GNAQ KRAS HFE HOXD13 B3GALT6 RPL5 KAT6B GATA2 MUC5B PIK3CA USP8 GDNF SMAD4 MVK RHBDF2 SSX2 CEP57 RAD51C NEK9 JAK2 PDGFB NRAS KRT1 PIK3CA MFN2 DOCK8 PTEN IL7 SDHC ATM AKT1 BRCA1 RELA GCDH PIK3CA IDH2 HRAS CTLA4 GPR143 ERCC2 GATA2 PTPN11 IGF2 SMAD4 NDUFAF6 CDH23 RPS7 RAD54B TP53 MUTYH GLI3 PTPN11 BRIP1 CDKN1B SF3B1 PTCH1 CIB1 ERCC3 PTPN11 TRPV3 GDNF IGLL1 PRKCD CTNNB1 PIK3CA PTPN11 SLCO2A1 FAH BRCA1 ETV6 BRCA2 EPCAM TP53 EXT1 BCL10 TRPS1 BMPR1A ATM MPL KRT17 MAX SLC12A3 ADA TERT UBE2T TSC2 TCTN3 MSH2 BDNF BTK SKI RPS20 NRAS RUNX1 DCC MSH2 RPS24 WT1 TRNF TFAP2A RPL35 RPS17 SDHA RARA CDC73 SBDS POLH BRAF LAMB3 RNF6 PIEZO2 KCNQ1OT1 CCM2 PHKA2 POU2AF1 TP53 TREM2 ABCC8 EXT2 ALK PHKG2 NUTM1 SLC26A4 PTCH1 MUTYH PALLD NBN FANCA SQSTM1 ELMO2 ACP5 TWIST1 TRIM37 RPL31 HFE RET DLC1 SDHB EP300 TREX1 HSPG2 ATP7A MSH6 C2CD3 CHRNG SRP54 TINF2 BUB1 PSENEN SMAD4 NF1 ERCC3 ARID1B RMRP WAS GATA2 MAPK1 BIN1 COL7A1 EDN3 PIK3CA IGF2 H19-ICR TUBB FH MLH1 TNFSF12 PIK3R1 RASA1 F5 SH2B3 CTNNB1 FOXI1 SUFU TLR2 SRSF2 CDKN1B GJC2 OPCML LEMD3 FIBP TRNS1 HNF1A VHL PTEN PRKAR1A MSH2 CYLD CTHRC1 COL7A1 DDB2 SDHC GJB2 LIG4 MDM2 LAMA3 CHEK2 MTOR CDON SMARCE1 TAF1 GNAQ TP53 RAD54L WWOX BMPR1A CCND1 GFI1 BCL10 PTEN CTNNB1 DHX37 SLX4 FGF8 XRCC4 TRIP13 CDC73 BIRC3 NOTCH3 DIS3L2 PKD2 KIF1B GNA11 ARMC5 CREBBP DIS3L2 HRAS LMX1B BAP1 BRCA2 POT1 ABCB11 AURKA RASA1 SMARCB1 ALX4 GPC3 MGAT2 PAX3 IGHM LMNA TCF4 GATA1 TRNK IDH1 LRP5 CALR FH RET SEC23B APC TET2 SETBP1 WT1 PMS2 POLR1C SIX3 EPHB2 RPL35A RET TINF2 CD28 CYP26C1 MNX1 ALX3 KIT CPOX GJB2 DLL1 MSTO1 RSPO1 TEK EXT2 ABCC6 COL2A1 GNAS FH FASLG BAP1 COL14A1 YY1 RAG2 RB1CC1 MAP2K1 RHOH STAR CREBBP RECQL4 EVC2 HBB ERBB2 ABL1 NDP SUFU NF2 MSH6 ATP7A TSC1 FAS SLC6A17 MS4A1 NQO2 FLCN EXTL3 SOS1 RNASEL NPM1 KIT GNAI3 TRNH RAG1 HRAS BUB1B IGF2 PLAG1 FANCD2 BCL2 NEK1 KIT ATP7A PIK3CA SMARCB1 PCGF2 LIG4 BCL6 NUP214 FLNA IRF5 ACVR1 GAS1 DYNC2H1 RSPRY1 TRAF7 RNASEH2B REST RPS29 TGIF1 TERT PIGA TP53 CDK4 GPR101 ACVRL1 SAMHD1 MSL3 MAPRE2 SLC45A2 CTNNB1 ADA KLF11 NKX2-1 GLI2 PKD1 MAP3K1 SRP54 TNFSF12 ND5 CRKL RASGRP1 BCL10 RPS26 GLI3 TRNL1 AR SDHA RB1 MLH1 MC2R TGFBR1 KIT CYP11B1 AXIN2 EGFR PIK3CA RECQL4 EXOC6B SMO SFTPA2 NRAS CDKN1B TP53 PIK3CA MSH6 ACTG2 POT1 SDHB RNF6 CALR KCNN3 C11ORF95 TSC2 CD96 SOS1 COL2A1 SMAD7 GLI1 FANCF MPL CDH1 BRCA2 BRAF ATR SDHA FLCN DICER1 IL1RN ICOS AIP RSPO1 DICER1 GCM2 XRCC2 DNASE1L3 PPP2R1B TGFBR2 MTM1 CDKN2C SIX1 MEN1 POU6F2 SRD5A3 STAT3 ERCC3 TG ASXL1 CDKN2B CYLD NHP2 CCDC22 TBC1D24 BLNK DIS3L2 SH2B3 MPLKIP AHCY PCNA EXT2 EXT2 MEN1 PARN WRAP53 TP53 HBB GABRD NUMA1 APC ZSWIM6 BRCA1 GJB2 KCNAB2 AIP USF3 RUNX1 H19 HDAC4 SDHD UROD PDGFRB CR2 HRAS CDH1 ERBB2 TNPO3 LPP SDHD IL2RG ATM BARD1 TREX1 POLE C2CD3 ERCC4 SLC25A13 PNP KRAS SRSF2 SDHB FGFR3 CASR CASP10 TET2 CTC1 ENPP1 SOX6 PIK3CA BMPR1A ERCC2 TERC CBL ADAMTS3 PIGL BCR SAMD9L NOD2 CBL TGFBR2 MALT1 SEMA4A ANTXR2 SLC37A4 TBX2 DHH STS SDHB TERT KRT16 DZIP1L RTEL1 SDHD CCND1 AKT1 FOXI1 CDK4 NSD1 MLH1 FLCN DLEC1 FGFRL1 MTMR14 GCGR TBX18 CREBBP MXI1 APC BCL10 COL11A2 TERT MC1R SCN10A RPS10 SMO BRCA2 KIT ATM PRKN MRE11 KIF1B KCNH1 VHL GPR101 GNAS PMS2 ACD WDPCP MAD1L1