There are 47 clinical trials

Clinical Trials

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

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

NCT00866177 Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Other: Laboratory Biomarker Analysis Drug: Selumetinib

MeSH:Melanoma Skin Neoplasms

HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

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

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

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

2 An Open-Label, Multi-Center Study to Investigate the Objective Response Rate, Safety, and Pharmacokinetics of GSK1120212, a MEK Inhibitor, in BRAF Mutation-positive Melanoma Subjects Previously Treated With or Without a BRAF Inhibitor

MEK113583 is a Phase II open-label, multi-site study to investigate the objective response rate, safety, and pharmacokinetics of GSK1120212 in subjects with BRAF mutation-positive melanoma who were previously treated with or without a BRAF inhibitor. GSK1120212 is a potent and highly selective inhibitor of MEK activation and kinase activity.

NCT01037127 Cancer Drug: GSK1120212

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

The number of participants with best confirmed response was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. --- V600E --- --- V600E --- --- V600K ---

PFS was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. --- V600E --- --- V600E --- --- V600K ---

- Documented positive BRAF mutation (V600E, V600K, or V600D). --- V600E --- --- V600K ---

3 A Phase II (BRF113710) Single-arm, Open-label Study of GSK2118436 in BRAF Mutant Metastatic Melanoma

BRF113710 is a Phase II, single-arm, open-label study to assess the efficacy, safety, and tolerability of GSK2118436 administered twice daily as a single agent in subjects with BRAF mutant metastatic melanoma. Subjects will receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.

NCT01153763 Melanoma Drug: GSK2118436

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

The analysis was performed on Primary efficacy Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600E mutation.. Number of Participants With a Best Overall Response of CR or PR as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation. --- V600E --- --- V600K ---

The analysis was performed on Secondary efficacy analysis Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600K mutation.. Progression-free Survival (PFS) as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600E Mutation. --- V600K ---

For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.. Progression-free Survival (PFS) as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation. --- V600K ---

The analysis was performed on Primary efficacy Population and only those participants who had a CR or PR were analyzed.. Duration of Response as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation. --- V600K ---

Overall survival was estimated using kaplan-Meier model and median and 95 percent CI was presented.. Overall Survival for Participants Who Had a BRAF V600K Mutation. --- V600K ---

One participant out of the 92 participants (76 BRAF V600E patients + 16 BRAF V600K patients) did not have SBP and DBP collected after baseline.. Number of Participants With Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Levels. --- V600E --- --- V600K ---

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

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

NCT01245062 Melanoma Drug: GSK1120212 Drug: Chemotherapy

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.. Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator. --- V600K ---

5 BRF113929: An Open-Label, Two-Cohort, Multicentre Study of GSK2118436 as a Single Agent in Treatment Naïve and Previously Treated Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. Subjects in Cohort A will not have received any local brain therapy, and subjects in Cohort B will have received prior local therapy for brain metastases. Subjects will continue on treatment until disease progression, death, or unacceptable adverse event.

NCT01266967 Melanoma and Brain Metastases Drug: GSK2118436

MeSH:Melanoma Neoplasm Metastasis

HPO:Cutaneous melanoma Melanoma

A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. --- V600E --- --- V600K ---

Participants who had an overall response of not evaluable or a missing response were treated as non-responders.. Number of Participants With V600K Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator. --- V600K ---

Participants who had an overall response of not evaluable or a missing response were treated as non-responders.. Number of Participants With V600K Mutation-positive Melanoma With OIR, as Assessed by the Investigator. --- V600K ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Duration of Intracranial Response for the Subset of V600K Mutation-positive Participants. --- V600K ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Duration of Overall Response for the Subset of V600K Mutation-positive Participants. --- V600K ---

If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters [e.g., percent change from Baseline]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.. Progression-free Survival in V600K Mutation-positive Participants. --- V600K ---

OS was censored using the date of last known contact for those participants who were alive at the time of analysis.. Overall Survival in V600K Mutation-positive Participants. --- V600K ---

- Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation. --- V600E --- --- V600K ---

6 A Phase Ib/II Clinical Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies

This is an open label, single arm phase 1 dose escalation study and phase 2 study of BBI608 in combination with paclitaxel in patients with advanced malignancies. Currently the study is only enrolling patients with thymic carcinoma.

NCT01325441 Cancer Drug: BBI608 Drug: Paclitaxel

MeSH:Neoplasms

HPO:Neoplasm

If melanoma is positive for the V600E or V600K BRAF mutation, must have received at least one line of prior therapy with a BRAF-specific inhibitor; either alone or in combination. --- V600E --- --- V600K ---

7 A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma

This is a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to dabrafenib administered with a trametinib placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 340 subjects will be randomized 1:1 (combination therapy: dabrafenib monotherapy). Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). The primary endpoint is investigator-assessed, progression-free survival for subjects receiving the combination therapy compared with those receiving dabrafenib monotherapy. Subjects will be followed for overall survival; crossover will not be permitted.

NCT01584648 Melanoma Drug: dabrafenib Drug: dabrafenib plus trametinib placebo Drug: Trametinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). --- V600E --- --- V600K ---

8 Phase 1/2 Study of PI-3K Inhibition With PX-866 Combined With Vemurafenib (BRAF Inhibitor) in Patients With BRAF-mutant Cancer Including Advanced Melanoma

The purpose of the phase 1 portion of the study is to determine the maximally tolerated dose (MTD) or recommended dose (RD) and the safety/tolerability of PX-866 in combination vemurafenib in patients with any advanced BRAF-mutant cancer. The purpose of the phase 2 portion of the study is to compare progression free survival (PFS), antitumor activity (response rate), disease control rate (DCR), and the safety and tolerability of PX-866 in combination with vemurafenib vs. vemurafenib alone in patients with advanced BRAF-mutant melanoma at the doses recommended from Phase 1.

NCT01616199 Advanced BRAF-mutant Cancers Drug: PX-866 Drug: vemurafenib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Inclusion Criteria: - ≥ 18 years at time of consent - If a sexually active male or a sexually active female of child-bearing potential, agrees to use a highly effective form of contraception (including birth control pills, barrier device, or intrauterine device)from the time of consent 90 days following the last dose of study drug - If female of child-bearing potential, negative pregnancy test - For Phase 1: must have histologically or cytologically-confirmed advanced cancer that is BRAF mutation-positive (V600E or V600K) for which there is no remaining standard therapy with curative potential. --- V600E --- --- V600K ---

For Phase 2: must have histologically or cytologically-confirmed BRAF mutation-positive (V600E or V600K) advanced (defined as unresectable Stage IIIC or IV) melanoma that has not been treated with a selective BRAF inhibitor - For Phase 1: must have measurable or non-measurable disease. --- V600E --- --- V600K ---

These patients must have undergone appropriate imaging studies and currently be on a stable, lowest possible dose of steroids - History of allergic reactions attributed to compounds of similar chemical or biologic composition to PX-866 or vemurafenib - Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Uncorrectable electrolyte abnormalities or long QT syndrome - Poorly controlled diabetes mellitus - Pregnant, breastfeeding, or planning to become pregnant - Known to be human immunodeficiency virus (HIV)-positive - Inability to swallow pills - Previous treatment with a phosphatidylinositol-3-kinase (PI-3K) inhibitor - Any other significant medical or psychiatric condition that in the opinion of the investigator renders the patient inadequate for participation Inclusion Criteria: - ≥ 18 years at time of consent - If a sexually active male or a sexually active female of child-bearing potential, agrees to use a highly effective form of contraception (including birth control pills, barrier device, or intrauterine device)from the time of consent 90 days following the last dose of study drug - If female of child-bearing potential, negative pregnancy test - For Phase 1: must have histologically or cytologically-confirmed advanced cancer that is BRAF mutation-positive (V600E or V600K) for which there is no remaining standard therapy with curative potential. --- V600E --- --- V600K ---

9 An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor

The goal of this clinical research study is to learn if the combination of 2 drugs dabrafenib and trametinib can help to control melanoma that has or has not spread to the brain. The safety of this drug combination will also be studied. Dabrafenib is designed to block the mutated BRAF protein. This mutation is only found in moles of the skin and in melanoma cells. By blocking the protein, the drug may slow the growth of or kill cancer cells that have the protein. Trametinib is designed to block certain proteins that cause cancer cells to grow and multiply. This may cause the cancer cells to die.

NCT01619774 Melanoma Drug: GSK2118436 Drug: GSK1120212

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

3. BRAF mutation-positive melanoma (i.e., V600E, V600K or V600D) 4. For Cohort A, patients must have easily accessible tumor for a mandatory biopsy. --- V600E --- --- V600K ---

10 Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects With Advanced BRAF V600-Mutation Positive Solid Tumors

This is a 2-part, study to determine the safety, tolerability and pharmacokinetics of oral dabrafenib in children and adolescent subjects with advanced BRAF V600 mutation-positive solid tumors. Part 1 (dose escalation study) will identify the recommended Part 2 (tumor-specific expansion study) dose and regimen using a dose-escalation procedure. Approximately 6 to 18 subjects will participate in Part 1 and will receive a starting dose of 3 mg/kg and dose will deescalate or escalate between 1.5 milligram (mg)/kilogram (kg) and 6 mg/kg. Up to 6 subjects will be enrolled at one dose level dependent upon the number of subjects at the current dose level, the number of subjects who have experienced a dose limiting toxicity (DLT) at the current dose level, and the number of subjects enrolled but with data pending at the current dose level. Escalation may proceed until either a maximum tolerated dose (MTD) is established, or until the dose in which the median pharmacokinetic parameters consistent with exposure in adults are achieved. Cohorts may be added in order to evaluate additional dose levels. Part 2 consists of four disease-specific cohorts of subjects with tumors known to have BRAF V600 activation (pediatric low-grade gliomas, pediatric high-grade gliomas, Langerhans cell histiocytosis [LCH], and other tumors such as melanoma and papillary thyroid carcinoma [PTC]). Each cohort will enroll at least 10 subjects with a pre-dose and at least 1 post-dose disease assessment. In both the parts of the study, on Day 1, a single first dose will be administered, and repeat dosing will begin on Day 2. PK sampling will be performed on Day 1 and Day 15 for subjects >=25 kg in weight. For subjects <25 kg and >=10 kg in weight, blood samples for PK analysis will be collected on Day 1 and Day 15. For subjects <10kg in weight, blood samples for PK analysis will be collected after repeated administration on Day 15 only. Safety and tolerability will be assessed throughout the study. Treatment with dabrafenib will be continued until disease progression or until no clinical benefit or development of an unacceptable toxicity, or until they withdraw consent or begin a new therapy. At the end of treatment, a final study visit will occur.

NCT01677741 Neoplasms, Brain Drug: Dabrafenib

MeSH:Brain Neoplasms

HPO:Brain neoplasm

- BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing; centralized testing can confirm V600E and V600K mutations only). --- V600E --- --- V600K ---

11 LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations

This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression.If a subject is removed from the study for one of a variety of reasons including, but not limited to, an inability to tolerate the combination of dabrafenib and trametinib, a need to receive other therapy or completion of 3-years of study treatment without progression, and the subject later receives, as part of his/her standard of care, the combination of dabrafenib and trametinib and progresses on the standard of care regimen, then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

NCT01726738 Stage III Melanoma Stage IV Melanoma Unresectable Melanoma BRAF Mutant Melanoma Drug: BRAF inhibitor dabrafenib and MEK inhibitor trametinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Patients will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival.. Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: - Absolute neutrophil count >1.2 × 109/L - Hemoglobin >9 g/dL, platelets >75 × 109/L - PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) - Albumin >2.5 g/dL - Total bilirubin <1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) - AST and ALT < 2.5× ULN - CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. --- V600E --- --- V600K ---

Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: - Absolute neutrophil count >1.2 × 109/L - Hemoglobin >9 g/dL, platelets >75 × 109/L - PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) - Albumin >2.5 g/dL - Total bilirubin <1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) - AST and ALT < 2.5× ULN - CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. --- V600E --- --- V600K ---

12 Phase 1 Study of the BRAF Inhibitor Dabrafenib +/- MEK Inhibitor Trametinib in Combination With Ipilimumab for Unresectable or Metastatic Melanoma

This is an open-label, multi-center, dose-finding Phase 1 study that will enroll subjects at least 18 years old with unresectable or metastatic melanoma and BRAF V600 mutations. The primary objective of the study is to describe the safety for the doublet therapy (dabrafenib and ipilimumab) and the triplet therapy (dabrafenib/trametinib and ipilimumab). Preliminary efficacy data will also be collected. Subjects will be assigned to receive either the doublet combination (dabrafenib and ipilimumab) or the triplet combination (dabrafenib, trametinib, and ipilimumab). Subjects will be enrolled to dose-finding cohorts in the doublet combination (dabrafenib + ipilimumab) in a sequential 3+3 fashion. Following establishment of a dose for the doublet combination, an expansion cohort will be opened. At the same time, enrollment to dose finding cohorts for the triplet combination (dabrafenib + trametinib + ipilimumab) will begin in a sequential 6+6 fashion. Enrollment into triplet cohorts will take priority when both the doublet expansion arm and the triplet dose-finding arm are open for enrollment at the same time. Approximately 9-24 subjects will be enrolled to the dose finding portion of the study. Approximately 30 subjects will be enrolled to doublet expansion cohort and 30 subjects will be enrolled in the triplet expansion cohort. A two-week run-in period without ipilimumab will be followed by 4 intravenous doses of ipilimumab at the recommended dose and schedule. Oral daily dosing of dabrafenib or dabrafenib + trametinib will continue from the two-week run-in, through combination with ipilimumab, and post-ipilimumab until no longer of clinical benefit, in the opinion of the treating physician, or until unacceptable AE or death

NCT01767454 Solid Tumours Drug: Dabrafenib Drug: Trametinib Drug: Ipilimumab

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

PK samples have a +/-30 minute window for collection.. Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E --- --- V600K ---

Patients with active autoimmune disease or a history of autoimmune disease other than those mentioned above must be approved by the GSK medical monitor - Active pneumonitis or interstitial lung disease - Lactating female - History of another malignancy (Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible) - Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Any prohibited medication - Administration of an investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment(s) in this study - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Unwillingness or inability to follow the procedures outlined in the protocol Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E --- --- V600K ---

13 A Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases, Whose Tumors Harbor B-raf Mutations

The purpose of this trial is to study the activity of vemurafenib in untreated melanoma brain metastases harboring B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations that are not amenable to stereotactic radiosurgery based on size, number of lesions or location, to measure cerebrospinal fluid (CSF) levels of vemurafenib as an indicator of central nervous system penetrance and to measure levels of vemurafenib in normal brain tissue and brain metastases in those in whom surgical management is feasible.

NCT01781026 Melanoma Drug: Vemurafenib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.. Inclusion Criteria: - Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations. --- V600E --- --- V600K ---

Inclusion Criteria: - Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations. --- V600E --- --- V600K ---

14 Screening Protocol to Detect BRAF V600 Mutation-Positive Patients for Enrollment Into Clinical Research Studies of Vemurafenib

This is a screening study to detect BRAF V600 mutation-positive patients for enrollment into clinical research studies of Zelboraf (vemurafenib). Tumor samples will be collected and analyzed from eligible patients with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma. All institutions with identified patients as defined by this screening protocol will have potential access to the separate vemurafenib protocol MO28072.

NCT01804140 Multiple Myeloma, Neoplasms

MeSH:Multiple Myeloma

HPO:Multiple myeloma

V600E, V600K, V600D, and V600R are the different types of BRAF V600 mutations.. Inclusion Criteria: - Histologically confirmed solid tumors (excluding melanoma and papillary thyroid cancer) or multiple myeloma refractory to standard therapy or for which standard or curative therapy does not exist or is not considered appropriate by the investigator - Patients with multiple myeloma must have received at least one line of prior systemic therapy for the treatment of multiple myeloma Exclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status > 2 - Uncontrolled concurrent malignancy - Active or untreated CNS metastases - History of known carcinomatous meningitis - Prior treatment with a BRAF or MEK inhibitor (prior sorafenib is allowed) - Uncontrolled, severe medical illness or condition as defined in protocol MO28072 Inclusion Criteria: - Histologically confirmed solid tumors (excluding melanoma and papillary thyroid cancer) or multiple myeloma refractory to standard therapy or for which standard or curative therapy does not exist or is not considered appropriate by the investigator - Patients with multiple myeloma must have received at least one line of prior systemic therapy for the treatment of multiple myeloma Exclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status > 2 - Uncontrolled concurrent malignancy - Active or untreated CNS metastases - History of known carcinomatous meningitis - Prior treatment with a BRAF or MEK inhibitor (prior sorafenib is allowed) - Uncontrolled, severe medical illness or condition as defined in protocol MO28072 Multiple Myeloma, Neoplasms Multiple Myeloma null --- V600E --- --- V600K ---

15 A 2-part Phase III Randomized, Open Label, Multicenter Study of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. A total of approximately 900 patients will be randomized. Part 1: Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms: 1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm) 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or 3. vemurafenib 960 mg BID (denoted as vemurafenib arm) Part 2: Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms: 1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)

NCT01909453 Melanoma Drug: LGX818 Drug: MEK162 Drug: vemurafenib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Change from baseline in the EQ-5D.. Inclusion Criteria: - Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV) - Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization - Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. --- V600E --- --- V600K ---

IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), except the administration of BRAF or MEK inhibitors - Evidence of at least one measurable lesion as detected by radiological or photographic methods - ECOG performance status of 0 or 1 - Adequate bone marrow, organ function, cardiac and laboratory parameters - Normal functioning of daily living activities Exclusion Criteria: - Any untreated central nervous system (CNS) lesion - Uveal and mucosal melanoma - History of leptomeningeal metastases - History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease - Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients who have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at least 6 weeks prior to randomization - History of Gilbert's syndrome - Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor - Impaired cardiovascular function or clinically significant cardiovascular diseases - Uncontrolled arterial hypertension despite medical treatment - HIV positive or active Hepatitis B, and/or active Hepatitis C - Impairment of gastrointestinal function - Patients with neuromuscular disorders that are associated with elevated CK - Pregnant or nursing (lactating) women - Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: - Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV) - Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization - Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. --- V600E --- --- V600K ---

16 A Sequential Safety and Biomarker Study of BRAF-MEK Inhibition on the Immune Response in the Context of Combined CTLA-4 Blockade and PD-1 Blockade for BRAF Mutant Melanoma

This randomized phase I trial studies the side effects and best way to give ipilimumab with or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating melanoma.

NCT01940809 BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Drug: Dabrafenib Biological: Ipilimumab Other: Laboratory Biomarker Analysis Biological: Nivolumab Drug: Trametinib

MeSH:Melanoma Skin Neoplasms

HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.. Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma. --- V600E --- --- V600K ---

17 Dose-seeking and Efficacy Study of the Combination of the BRAF Inhibitor Vemurafenib and High-dose Interferon Alfa-2b for Therapy of Advanced Melanoma

This is a dose-seeking and efficacy study of combined BRAF Inhibitor Vemurafenib and High-dose Interferon alfa-2b for therapy of advanced melanoma.

NCT01943422 Melanoma Drug: High-dose Interferon alfa-2b Drug: Vemurafenib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

- BRAF V600E and V600K mutated - Cutaneous squamous cell carcinomas (SCC) lesions identified at baseline must be excised. --- V600E --- --- V600K ---

18 A Phase 1 Study of Dabrafenib in Combination With Lapatinib in BRAF Mutant Thyroid Cancer

This phase I trial studies the side effects and best dose of lapatinib when given together with dabrafenib in treating patients with thyroid cancer that cannot be removed by surgery and has not responded to previous treatment (refractory). Dabrafenib and lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01947023 Metastatic Thyroid Gland Carcinoma Unresectable Thyroid Gland Carcinoma Drug: Dabrafenib Drug: Dabrafenib Mesylate Drug: Lapatinib Drug: Lapatinib Ditosylate

MeSH:Carcinoma Thyroid Neoplasms Thyroid Diseases

HPO:Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Mean percentage change is calculated and compared with respect to each genotype.. Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E --- --- V600K ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - The effects of dabrafenib on the developing human fetus are unknown; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed due to drug-drug interactions which can render hormonal contraceptives ineffective) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be decreased - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8, since concentrations of dabrafenib may be increased - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dabrafenib, breastfeeding should be discontinued if the mother is treated with dabrafenib; these potential risks may also apply to other agents used in this study Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E --- --- V600K ---

19 An Open-Label, Multicentre, Corollary Study of Pre-Operative Therapy With Dabrafenib and the Combination of Dabrafenib With Trametinib in Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.

NCT01978236 Melanoma and Brain Metastases Drug: Dabrafenib 150 mg Drug: Trametinib 2.0 mg

MeSH:Melanoma Neoplasm Metastasis

HPO:Cutaneous melanoma Melanoma

Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. --- V600E --- --- V600K ---

It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. --- V600E --- --- V600K ---

Inclusion Criteria: - Signed written informed consent - Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. --- V600E --- --- V600K ---

multiple sclerosis) - A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection - Current acute infection requiring intravenous antibiotics - A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency - The history or evidence of following cardiac abnormalities: - Corrected QT (QTc) interval using Bazett's Formula; (QTcB) >= 480 msecs - A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - Coronary angioplasty or stenting within the past 12 weeks - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Abnormal cardiac valve morphology (>= Grade 2) documented by echocardiogram (ECHO) - History of or evidence of clinically significant uncontrolled cardiac arrhythmias - Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy - Subjects with intra-cardiac defibrillators or permanent pacemakers - Pregnant, lactating or breastfeeding females - Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2118436 or excipients that contraindicate their participation Inclusion Criteria: - Signed written informed consent - Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. --- V600E --- --- V600K ---

20 A Phase 1 Open-label Study of Safety and Tolerability of MEDI4736 in Subjects With Metastatic or Unresectable Melanoma in Combination With Dabrafenib and Trametinib or With Trametinib Alone

The purpose of this study is to determine the maximum tolerated dose and characterize the safety profile of durvalumab (MEDI4736) in combination with dabrafenib and trametinib or with trametinib alone in participants with metastatic or unresectable melanoma with BRAF-mutation positive or wild-type (WT) BRAF, respectively.

NCT02027961 Melanoma Biological: Durvalumab Drug: Dabrafenib Drug: Trametinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

The number of participants with positive serum antibodies to durvalumab post dosing are reported.. Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Melanoma Melanoma This is a multicenter, open-label study with a dose escalation phase followed by an expansion phase of durvalumab administered in combination with dabrafenib and trametinib or with trametinib alone in participants with BRAF V600 mutation-positive and WT unresectable or metastatic melanoma, respectively. --- V600E --- --- V600K ---

The number of participants with positive serum antibodies to durvalumab post dosing are reported.. Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Inclusion Criteria: - Adults >= 18 years old - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Measurable disease by radiographic or physical examination - Adequate organ and marrow function - Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: - Prior treatment with a BRAF inhibitor or MEK inhibitor - Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy - Active or prior documented autoimmune disease within the past 2 years - History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) - History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension - Active, untreated central nervous system (CNS) metastases - Women who are pregnant or lactating Melanoma Melanoma This is a multicenter, open-label study with a dose escalation phase followed by an expansion phase of durvalumab administered in combination with dabrafenib and trametinib or with trametinib alone in participants with BRAF V600 mutation-positive and WT unresectable or metastatic melanoma, respectively. --- V600E --- --- V600K --- --- V600E --- --- V600K ---

21 Phase I Study of AT13387 in Combination With Dabrafenib and Trametinib in Patients With BRAF-Mutant Melanoma and Other Solid Tumors

This phase I trial studies the side effects and best dose of onalespib when given together with dabrafenib and trametinib in treating patients with BRAF-mutant melanoma or solid tumors that have spread to another place in the body (metastatic) or cannot be removed by surgery. Onalespib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02097225 BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Malignant Solid Neoplasm Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Solid Neoplasm Drug: Dabrafenib Other: Laboratory Biomarker Analysis Drug: Onalespib Other: Pharmacological Study Drug: Trametinib

MeSH:Melanoma Skin Neoplasms Neoplasms

HPO:Cutaneous melanoma Melanoma Neoplasm Neoplasm of the skin

m^2 - Potassium > 3 and < 5.5 mEq/L - Magnesium > 1.2 and < 2.5 mEq - Left ventricular >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) ejection fraction - Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) from 14 days prior to randomization, throughout the treatment period, and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Ability to understand and the willingness to sign a written informed consent document - Able to swallow and retain oral medication, and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Exclusion Criteria: - Patients who received prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to day 1 of cycle 1; patients are permitted to be on dabrafenib and trametinib standard of care at start of therapy without wash-out period prior to day 1 of cycle 1; dosing will change to protocol determined dose levels on day 1 of cycle 1 - Patients must not have received prior HSP90 inhibitor therapy - Patients who are receiving any other investigational agents; patients who have taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization - Patients with history of activating RAS mutation positive tumors regardless of interval from current study; however, patients may have concurrent BRAFV600 and RAS mutations in the tumor to be treated with protocol therapy - Patients must have no clinical evidence of leptomeningeal or brain metastasis causing spinal cord compression that are symptomatic or untreated or not stable for >= 4 weeks (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History of known immediate or delayed hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to AT13387, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO) - Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the mother being treated with the study drugs - Patients known to be human immunodeficiency virus (HIV)-positive patients and on combination antiretroviral therapy are ineligible - History of another malignancy other than the study indication under this trial within 5 years of study enrollment; does not apply to subjects who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, in situ breast cancer, or other in situ cancers - Exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History of interstitial lung disease or pneumonitis - History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): - History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm mercury (Hg) - History or evidence of cardiovascular risk including any of the following: - An average of the three most recent QT intervals corrected for heart rate using the Bazett's formula QTcB >= 460 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - Prior placement of an implantable defibrillator - History of or identification on screening imaging of intracardiac metastases - No known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV); patients with chronic or cleared HBV infection and HCV infection are eligible - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Malignant Solid Neoplasm Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Solid Neoplasm Melanoma Skin Neoplasms Neoplasms PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of onalespib (AT13387) given weekly in combination with dabrafenib and trametinib in patients with BRAF-mutant metastatic or unresectable solid tumors. --- V600E --- --- V600K ---

22 A Phase 1 Expansion Cohort Evaluating the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Unresectable Melanoma

This phase I clinical trial studies the side effects of selinexor in treating patients with melanoma that cannot be removed by surgery. Drugs used in chemotherapy, such as selinexor, may stop the growth of tumor cells, by stopping them from dividing.

NCT02120222 Recurrent Melanoma Drug: selinexor Other: Correlative studies

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

interleukin 2) and a BRAF and/or MEK inhibitor (if tumor contains the V600E or V600K mutation) for 628 metastatic disease. --- V600E --- --- V600K ---

23 A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma

This randomized phase II trial studies how well dabrafenib and trametinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery and contains a B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02196181 Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma Drug: Dabrafenib Drug: Dabrafenib Mesylate Drug: Trametinib Drug: Trametinib Dimethyl Sulfoxide

MeSH:Melanoma Skin Neoplasms

HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E --- --- V600K ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E --- --- V600K ---

24 Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)

This is a single arm phase II trial focused on how dabrafenib and trametinib before and after surgery works in treating patients with stage IIIB-C melanoma that has a specific mutation in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib and trametinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving dabrafenib and trametinib after surgery may kill any remaining tumor cells.

NCT02231775 BRAF V600E Mutation Present BRAF V600K Mutation Present Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Drug: Dabrafenib Other: Laboratory Biomarker Analysis Procedure: Therapeutic Conventional Surgery Drug: Trametinib

MeSH:Melanoma Skin Neoplasms

HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.. Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E --- --- V600K ---

uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E --- --- V600K ---

uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency BRAF V600E Mutation Present BRAF V600K Mutation Present Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Study enrollment was stopped in April 2016 due to a substantial improvement in RFS in Arm B vs Arm A treated patients. --- V600E --- --- V600K ---

25 BRAF, Autophagy and MEK Inhibition in Metastatic Melanoma: A Phase I/II Open-Label Trial of Dabrafenib, Trametinib and Hydroxychloroquine in Patients With Advanced BRAF Mutant Melanoma

The primary purpose of this study is to determine the maximum tolerated dose (MTD) and preliminary safety of hydroxychloroquine (HCQ) when administered in conjunction with oral dabrafenib and trametinib (D+T) in patients with advanced BRAF mutant melanoma.

NCT02257424 Advanced BRAF Mutant Melanoma Drug: Trametinib 2 mg daily Drug: hydroxychloroquine (HCQ) Drug: dabrafenib 150 mg orally twice a day

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

- Patients must have histologically confirmed melanoma unresectable Stage III or Stage IV positive for BRAF V600E, V600K, V600R or V600D by a CLIA approved assay. --- V600E --- --- V600K ---

26 A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease

Erdheim-Chester Diseases (ECD) is a very rare non-Langerhans cell histiocytosis of unknown origin and pathogenesis. It has been reported mainly in adult males over the age of 40 years, although cases have been reported in females as well. Children are rarely affected. Mutation of the BRAF gene, specifically BRAFV600E, has been recently identified in 50% of Erdheim Chester lesions in a French cohort. This somatic mutation is believed to be the driver mutation in positive cases. The clinical characteristics of ECD range from asymptomatic to multisystemic involvement; longitudinal progression and natural history are becoming better understood. ECD commonly affects the bones, kidneys, retroperitoneal space, skin and brain. If untreated, the disease progresses rapidly, causing fatal outcomes due to severe lung disease, chronic renal failure, cardiomyopathy and other complications. The diagnosis of ECD relies upon imaging studies and specific pathologic findings in biopsies of affected organs, i.e., fibrosis and infiltration of tissues with foamy histiocytes, lymphocytes, and plasma cells. Immunohistochemistry reveals cells positive for CD68 and CD163 and negative for CD1a, with 20% positivity to S-100. There is no standard treatment for ECD, although chemotherapy, radiation, stem cell transplantion, alpha-interferon, anakinra, imatinib and sirolimus have been proposed. The recent discovery of the BRAFV600E mutation in several ECD patients has opened a new area for treatment options. Vemurafenib, an FDA approved BRAF inhibitor for the treatment of patients with metastatic or unresectable melanoma with the V600E mutation, binds to this form of mutated BRAF causing protein inactivation. The use of vemurafenib in patients with ECD has been reported in 3 patients who experienced remission of the disease, and is currently being studied in the U.S. and Europe as monotherapy. Tumor/disease resistance to vemurafenib has occurred in melanoma and other cancers, although it has not been reported in patients with ECD. In this protocol, we propose to clinically evaluate ECD patients with the BRAFV600E mutation and administer combination therapy with dabrafenib, a BRAFV600E inhibitor, and trametinib, an inhibitor of MEK, downstream of BRAF. Screening for possible contraindications will be made prior to the administration of the first dose. With this trial, we will determine the safety, tolerability, and efficacy of dabrafenib and trametinib in patients with ECD who harbor the BRAFV600E mutation. Dabrafenib 150mg will be given twice daily p.o.; trametinib 2mg will be given once daily p.o. Patients will be seen 1 week, 1 month, 2 months, 4 months, and 6 months, 8 months, 10 months and 12 months to complete a oneyear trial.

NCT02281760 BRAF V600E Mutation Drug: Dabrafenib Mesylate Drug: Trametinib Dimethyl Sulfoxide

MeSH:Erdheim-Chester Disease

Affected tissue must harbor the BRAF V600E or V600K mutation. --- V600E --- --- V600K ---

27 A Phase 1, Open-Label, Multicenter, Multi-Dose Escalation Study of CM-24 (MK-6018) as Monotherapy and In Combination With Pembrolizumab (MK-3475) in Subjects With Selected Advanced or Recurrent Malignancies

The purpose of this study is to evaluate the safety and tolerability of humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 (CM-24 [MK-6018]), administered intravenously as monotherapy and in combination with Pembrolizumab (MK-3475), in participants with selected advanced or recurrent malignancies. Escalating multiple doses will be evaluated to determine the recommended dose for Phase 2 clinical studies.

NCT02346955 Non-small Cell Lung Carcinoma (NSCLC) Melanoma Bladder Cancer Colorectal Cancer Gastric Cancer Ovarian Cancer Biological: CM-24 (MK-6018) Biological: Pembrolizumab (MK-3475)

MeSH:Carcinoma, Non-Small-Cell Lung

HPO:Non-small cell lung carcinoma

- Participants in the Monotherapy Expansion Cohort must have one of the following advanced or recurrent malignancies: cutaneous melanoma showing primary progression following treatment with an anti-programmed cell death (PD) or anti-PDL1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Participants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Melanoma with BRAF V600E or V600K mutation-positive melanoma must have progressed on, or were intolerant to, prior BRAF- or MEK-inhibitor therapy - Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with progressing or new tumors since last antitumor therapy - Must have adequate hematologic, renal, and liver function - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Females must not be pregnant (negative human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) or breastfeeding - Women of childbearing potential and male participants must agree to use adequate contraception throughout the study and for up to 180 days after study treatment - An estimated life expectancy of at least 3 months - Must consent to provide an archival tumor biopsy sample at any time point from screening to study exit - Must consent to allow the acquisition of new tissue biopsy samples during the study Exclusion Criteria: - History of severe hypersensitivity reactions or immune related adverse events to other monoclonal antibodies - History of other active malignancy within the prior 2 years - History of insulin-dependent or uncontrolled Diabetes Mellitus - History of inflammatory bowel disease - Autoimmune disorders - Known HIV and/or Hepatitis B or C infections - Known systemic bleeding or platelet disorder - Receipt of live vaccines with 4 weeks (28 days) of study - History or evidence of non-infectious pneumonitis that required steroids or current pneumonitis Inclusion Criteria: - Males and females ≥18 years of age - Participants in the Dose Escalation portion must have one of the following advanced or recurrent malignancies: gastrointestinal (colorectal or gastric); ovarian; melanoma; non-small cell lung adenocarcinoma; or bladder. --- V600E --- --- V600K ---

- Participants in the Monotherapy Expansion Cohort must have one of the following advanced or recurrent malignancies: cutaneous melanoma showing primary progression following treatment with an anti-programmed cell death (PD) or anti-PDL1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Participants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Melanoma with BRAF V600E or V600K mutation-positive melanoma must have progressed on, or were intolerant to, prior BRAF- or MEK-inhibitor therapy - Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with progressing or new tumors since last antitumor therapy - Must have adequate hematologic, renal, and liver function - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Females must not be pregnant (negative human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) or breastfeeding - Women of childbearing potential and male participants must agree to use adequate contraception throughout the study and for up to 180 days after study treatment - An estimated life expectancy of at least 3 months - Must consent to provide an archival tumor biopsy sample at any time point from screening to study exit - Must consent to allow the acquisition of new tissue biopsy samples during the study Exclusion Criteria: - History of severe hypersensitivity reactions or immune related adverse events to other monoclonal antibodies - History of other active malignancy within the prior 2 years - History of insulin-dependent or uncontrolled Diabetes Mellitus - History of inflammatory bowel disease - Autoimmune disorders - Known HIV and/or Hepatitis B or C infections - Known systemic bleeding or platelet disorder - Receipt of live vaccines with 4 weeks (28 days) of study - History or evidence of non-infectious pneumonitis that required steroids or current pneumonitis Non-small Cell Lung Carcinoma (NSCLC) Melanoma Bladder Cancer Colorectal Cancer Gastric Cancer Ovarian Cancer Carcinoma, Non-Small-Cell Lung null --- V600E --- --- V600K ---

28 A Three Arms Prospective, Randomized Phase II Study to Evaluate the Best Sequential Approach With Combo Immunotherapy (Ipilimumab/Nivolumab) and Combo Target Therapy (LGX818/MEK162) in Patients With Metastatic Melanoma and BRAF Mutation

To evaluate the best sequencing approach with the combination of target agents (LGX818 plus MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in patients with metastatic melanoma and BRAF V600 mutation.

NCT02631447 Metastatic Melanoma Drug: LGX818 Drug: MEK162 Drug: Nivolumab Drug: Ipilimumab

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

4. Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria; 5. Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment; 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; 7. Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E --- --- V600K ---

29 Dose-seeking Study of Pembrolizumab Plus Vemurafenib and Cobimetinib for Therapy of Advanced Melanoma

The study plans to treat patients with pembrolizumab and thus blocking the PD-1/PD-L1 axis would render tumor-infiltrating lymphocytes (TILs) in the tumor parenchyma more functional as a consequence of BRAF inhibition, such that T cell activation by BRAFi would not be dampened by the PD-1/PD-L1 interaction. This combination would reverse dysfunction among T cells in the tumor parenchyma, maximizing T cell mediated immune anti-tumor efficacy. Progression free survival (PFS) with pembrolizumab in KEYNOTE-001 was 57% at 6 months, and 46.4% in the more recently reported phase III trial. PFS with vemurafenib treatment in BRIM-3 was ~50% at 6 months. Combined treatment with pembrolizumab, cobimetinib and vemurafenib for BRAF mutant melanoma is hypothesized to be safe and to improve the PFS compared to these recent historical controls. Because this combination has not yet been tested, and because the primary objective is to assess safety, the investigators are staging accrual in the first phase of the trial. The study aims to accrue up to 30 patients to the mTPI design of this study with the expectation that there will be at least 30 patients treated at RP2D. In case there are less than 30 patients on the RP2D, additional patients will be accrued. Patients will continue to receive treatment with pembrolizumab, vemurafenib and cobimetinib until disease progression or dose limiting toxicity. Patients with treatment response and no dose limiting toxicity may receive treatment with pembrolizumab for up to 24 months.

NCT02818023 Melanoma Drug: Pembrolizumab Drug: Vemurafenib Drug: Cobimetinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Only patients with BRAF V600E or V600K mutated tumors will be enrolled. --- V600E --- --- V600K ---

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

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

NCT02858921 Melanoma Drug: Dabrafenib Drug: Trametinib Drug: Pembrolizumab

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

V600D, V600K, V600R, V600M). --- V600D --- --- V600K ---

31 A Phase 1b Trial of Talimogene Laherparepvec in Combination With Dabrafenib and Trametinib in Advanced Melanoma With an Activating BRAF Mutation

The purpose of the study is to determine safety and tolerability of the combination of talimogene laherparepvec in combination with dabrafenib and trametinib in BRAF mutated advanced melanoma.

NCT03088176 Melanoma BRAF Gene Mutation Drug: Talimogene Laherparepvec 1 Million Pfu/Ml Inj,Susp,1Ml,Vil Drug: Talimogene Laherparep 100 Mil Pfu/Ml 1Ml Drug: Dabrafenib Drug: Trametinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Primary or recurrent Stage IIIB to IVM1c melanoma for whom surgery is not recommended 3. Activating BRAF mutation (limited to V600E or V600K mutations if being treated first-line, but can include any well-defined BRAF mutation after failure of prior immunotherapy) 4. Measurable disease defined as follows: At least one melanoma lesion that can be accurately and serially measured in one dimension and for which the longest diameter is ≥10 mm as measured by calipers, CT scan, or MRI. --- V600E --- --- V600K ---

32 A Phase I/II Study of LY3022855 With BRAF/MEK Inhibition in Patients With Melanoma

This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation The interventions involved in this study are: - LY3022855 - Vemurafenib - Cobimetinib

NCT03101254 Melanoma Drug: LY3022855 Drug: Vemurafenib Drug: Cobimetinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

LY3022855 With BRAF/MEK Inhibition in Patients With Melanoma This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation The interventions involved in this study are: - LY3022855 - Vemurafenib - Cobimetinib Progression Free Survival. --- V600E --- --- V600K ---

Disappearance of all target lesions.. Inclusion Criteria: - For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. --- V600E --- --- V600K ---

- For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and cannot have received prior BRAF or MEK inhibitor therapy. --- V600E --- --- V600K ---

Inclusion Criteria: - For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. --- V600E --- --- V600K ---

33 Low-dose Interleukin-2 and Pembrolizumab Among Patients With Metastatic Melanoma and Renal Cell Carcinoma

This study will evaluate the safety and disease control rate of the combination of pembrolizumab plus low-dose interleukin-2 in patients who have either advanced melanoma or renal cell cancer.

NCT03111901 Carcinoma, Renal Cell Melanoma Drug: Pembrolizumab Drug: Interleukin-2

MeSH:Carcinoma Melanoma Carcinoma, Renal Cell

HPO:Carcinoma Clear cell renal cell carcinoma Cutaneous melanoma Melanoma Papillary renal cell carcinoma Renal cell carcinoma

If the melanoma expresses a BRAF mutation of V600E, V600K, or V600R patient must have received and progressed through a BRAF inhibitor or have failed that therapy due to toxicity. --- V600E --- --- V600K ---

34 A Phase I Open-Label Dose Escalation of GD3 ADC (Pfizer PF-06688992) in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma (B802WI209568)

The purpose of this research study is to learn about the safety and effectiveness of the study drug, PF-06688992. Before this study, PF-06688992 has never been given to people. PF-06688992 is a targeted therapy for people with cancer. The investigators linked a chemotherapy drug to an antibody (protein found in the blood). The antibody will connect to GD3 which is found on most melanomas but on very few other cells in the body. The investigators hope that in this way, it will deliver this chemotherapy directly to the melanoma and not to normal tissues.

NCT03159117 Melanoma Drug: PF-06688992

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

- Patients whose melanomas harbor a BRAF V600E or V600K mutation must have progressed on a RAF inhibitor. --- V600E --- --- V600K ---

35 Combination of Targeted Therapy (Encorafenib and Binimetinib) Followed by Combination of Immunotherapy (Ipilimumab and Nivolumab) vs Immediate Combination of Immunotherapy in Patients With Unresectable or Metastatic Melanoma With BRAF V600 Mutation : an EORTC Randomized Phase II Study (EBIN)

This is a multicenter, 2-arm open-label, randomized comparative phase II study. The objective of this trial is to prospectively evaluate whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves progression free survival compared to combination immunotherapy nivolumab + ipilimumab alone in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

NCT03235245 Unresectable Stage III Melanoma Stage IV Melanoma Drug: Nivolumab + Ipilimumab Drug: Encorafenib + Binimetinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Inclusion Criteria: - Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma - Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment - Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E --- --- V600K ---

Note: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on binimetinib treatment - Impaired cardiovascular function or clinically significant cardiovascular diseases - Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100mmHg, despite current therapy - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to starting study treatment - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including stroke, transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis Inclusion Criteria: - Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma - Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment - Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E --- --- V600K ---

36 Phase Ib Study to Test the Safety and Potential Synergy of Pembrolizumab (Anti-PD-1) and AMG386 (Angiopoietin-2 (Ang-2) in Patients With Advanced Solid Tumor

This research study is studying an investigational combination of drugs as a possible treatment for advanced solid tumors: melanoma, ovarian, renal, or colorectal cancer. The drugs involved in this study are: - Pembrolizumab - AMG386

NCT03239145 Advanced Solid Tumor Drug: Pembrolizumab Drug: Trebananib

MeSH:Neoplasms

HPO:Neoplasm

Melanoma patients with BRAF V600E or V600K mutation-positive melanoma who have previously received a BRAF inhibitor with or without a MEK inhibitor) are eligible. --- V600E --- --- V600K ---

37 Phase II Study of Durvalumab (MEDI4736) (Anti-PD-L1) and Trametinib (MEKi) in MSS Metastatic Colon Cancer

The goal of this clinical research study is to learn if durvalumab and trametinib can help to control microsatellite stable (MSS) colorectal cancer. The safety of these drugs will also be studied. This is an investigational study. Durvalumab is FDA approved and commercially available for the treatment of previously treated advanced bladder cancer. Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K. It is investigational to use durvalumab and trametinib to treat MSS colorectal cancer. Up to 56 participants will be enrolled in this study. All will take part at MD Anderson.

NCT03428126 Malignant Neoplasms of Digestive Organs Colorectal Cancer Colon Cancer Drug: Durvalumab Drug: Trametinib

MeSH:Colorectal Neoplasms Colonic Neoplasms Neoplasms

HPO:Colon cancer Neoplasm Neoplasm of the colon Neoplasm of the large intestine

Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K. --- V600E --- --- V600K ---

38 A Phase I/II Study of MCS110 With BRAF/MEK Inhibition in Patients With Melanoma After Progression on BRAF/MEK Inhibition

This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation. The interventions involved in this study are: - MCS110 - Dabrafenib - Trametinib

NCT03455764 Melanoma Drug: MCS110 Drug: Dabrafenib Drug: Trametinib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

MCS110 With BRAF/MEK Inhibition in Patients With Melanoma This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation. --- V600E --- --- V600K ---

Inclusion Criteria: - For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. --- V600E --- --- V600K ---

- For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and have had progression of disease on prior BRAF and MEK inhibitor therapy. --- V600E --- --- V600K ---

39 A Biospecimen Collection Study to Evaluate the Pharmacokinetic, Pharmacodynamic, and Resistance Profile to Trametinib and Dabrafenib in BRAF-V600E Mutated Recurrent Gliomas

This is a surgical biospecimen collection study. The purpose of this study is to understand how much of two drugs (dabrafenib and trametinib) are able to penetrate brain tumors and turn off the RAF signaling pathway. This is important because these drugs are currently FDA approved for other tumors and may have efficacy in brain tumors with the BRAF V600E mutation.

NCT03593993 Glioma BRAF V600E Pleomorphic Xantho-Astrocytoma Glioblastoma Procedure: Surgical Cohort

MeSH:Glioblastoma Glioma Astrocytoma

HPO:Astrocytoma Glioblastoma multiforme Glioma Subependymal giant-cell astrocytoma

Allowable mutations include V600E, V600K, V600R, and V600D. --- V600E --- --- V600K ---

40 Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations

This is a single-centre, open-label Phase II study of the investigational drugs binimetinib and encorafenib that will be taken my mouth (orally) daily in adult patient with advanced and/or metastatic solid tumors for which no other standard therapy is available. The main purpose is to evaluate the objective response rate (ORR) of the study drugs in the growth of the cancer in patients with class 2 and 3 BRAF mutations.

NCT03839342 Solid Tumor Drug: Binimetinib Drug: Encorafenib

MeSH:Neoplasms

HPO:Neoplasm

6. Malignancy must express one of the following BRAF alterations: BRAF mutation affecting codon: 241, 257, 367, 462, 463, 464, 466, 467, 469, 485, 581, 586, 594, 595, 596, 597 598, 599, 601; V600 BRAF mutations: V600K (for any malignancy except melanoma), V600D, V600M, V600R; BRAF deletions ie. --- V600K ---

Any patient with a tumor expressing a BRAF V600E mutation 2. Any patient with melanoma whose tumor expresses a BRAF V600K mutation 3. Prior therapy with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or any MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib). --- V600E --- --- V600K ---

41 An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of Agents Co-Administered With Encorafenib and Binimetinib in Patients With BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors

This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.

NCT03864042 Advanced Solid Tumors Metastatic Melanoma Drug: losartan Drug: dextromethorphan Drug: caffeine Drug: omeprazole Drug: midazolam Drug: rosuvastatin Drug: bupropion immediate release (IR) Drug: encorafenib Drug: binimetinib Drug: modafinil

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K ---

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K --- --- V600E --- --- V600K ---

- Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; - ARM 1 ONLY: Positive urine cotinine test at screening - ARM 3 ONLY: - History of psychosis, depression or mania; - History of angioedema; - History of mitral valve prolapse; - History of left ventricular hypertrophy; Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K ---

- Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; - ARM 1 ONLY: Positive urine cotinine test at screening - ARM 3 ONLY: - History of psychosis, depression or mania; - History of angioedema; - History of mitral valve prolapse; - History of left ventricular hypertrophy; Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K --- --- V600E --- --- V600K ---

42 A Multicenter, Open-label Phase 1b Study of the Combination of Binimetinib and Encorafenib in Adolescent Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma

This is a multicenter Phase 1b, open-label study to evaluate the pharmacokinetic, safety and efficacy of binimetinib and encorafenib co-administered to adolescent patients with BRAF V600-mutant advanced/metastatic melanoma. The study consists of a Safety Run-in Phase to determine the RDE (recommended dose in expansion), followed by an Expansion Phase.

NCT03878719 Melanoma Drug: binimetinib Drug: encorafenib

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

- Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer Stage IIIB, IIIC, or IV. - Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or central laboratory - Adequate cardiac function: - Left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO or multi-gated acquisition (MUGA) scan and above the institutional lower limit of normal (LLN); - Triplicate average baseline QTcF value ≤ 450 ms. - Adequate bone marrow, organ function, and laboratory parameters: - Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; - Hemoglobin ≥ 9 g/dL with or without transfusions; - Platelets ≥ 75 × 10⁹/L without transfusions; - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN); in patients with liver metastases ≤ 5 × ULN; - Total bilirubin ≤ 1.5 × ULN; - Creatinine ≤ 1.5 × institutional ULN for age, or calculated creatinine clearance ≥ 70 mL/min/1.73 --- V600E --- --- V600K ---

43 Phase II, Multicentre Clinical Trial to Evaluate the Activity of Encorafenib and Binimetinib Administered Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain

Phase II clinical trial, with two cohorts of patients included in parallel, all with melanoma BRAF mutated and brain metastases without previous local treatment in the brain. Cohort 1 will include patients with asymptomatic brain metastases and cohort 2 will include patients with symptomatic brain metastasis.

NCT03898908 Metastatic Melanoma Brain Metastases Drug: encorafenib Drug: binimetinib Radiation: Whole brain radiation therapy Radiation: Radiosurgery/stereotactic radiosurgery

MeSH:Melanoma Neoplasm Metastasis

HPO:Cutaneous melanoma Melanoma

- Histologically confirmed diagnosis of unresectable metastatic cutaneous melanoma, or unknown primary melanoma with one or more brain metastasis with a diameter of 10 to 50 mm, measured by contrast enhanced MRI. - Presence of a BRAF V600E or V600K mutation, or both, in their tumour tissue. --- V600E --- --- V600K ---

44 A Phase II Study of Binimetinib in Combination With Encorafenib in Adults With Recurrent BRAF V600-Mutated High-Grade Astrocytoma or Other Primary Brain Tumor

The goal of this study is to estimate the efficacy of encorafenib and binimetinib as measured by radiographic response in recurrent high-grade primary brain tumors.

NCT03973918 High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Drug: Encorafenib Drug: Binimetinib Biological: Research Bloods Biological: Tumor Tissue

MeSH:Glioblastoma Astrocytoma Gliosarcoma

HPO:Astrocytoma Glioblastoma multiforme Subependymal giant-cell astrocytoma

High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Glioblastoma Astrocytoma Gliosarcoma Primary Objective Estimate the efficacy of combination treatment with encorafenib and binimetinib, as measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs). --- V600E --- --- V600K ---

45 A Phase I Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic Thyroid Cancer

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

NCT03975231 BRAF NP_004324.2:p.V600E BRAF V600K Mutation Present Thyroid Gland Anaplastic Carcinoma Drug: Dabrafenib Radiation: Intensity-Modulated Radiation Therapy Drug: Trametinib

MeSH:Thyroid Neoplasms Thyroid Carcinoma, Anaplastic Carcinoma Thyroid Diseases

HPO:Abnormality of the thyroid gland Anaplastic thyroid carcinoma Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

- Presence of BRAF mutation (V600E or V600K) in tumor tissue. --- V600E --- --- V600K ---

BRAF NP_004324.2:p.V600E BRAF V600K Mutation Present Thyroid Gland Anaplastic Carcinoma Thyroid Neoplasms Thyroid Carcinoma, Anaplastic Carcinoma Thyroid Diseases PRIMARY OBJECTIVES: I. To assess the safety and tolerability (maximum tolerated dose [MTD]) of concurrent intensity modulated radiation therapy (IMRT) and BRAF-MEK inhibitors dabrafenib and trametinib in patients with BRAF-mutated anaplastic thyroid cancer. --- V600K ---

46 Immune Monitoring During Systemic Therapy of Metastatic Malignant Melanoma

The mean survival time in the advanced tumor stage in the presence of distant metastases in malignant melanoma was less than 9 months until a few years ago. Intensive research efforts have led to the development of promising new therapeutic strategies and their clinical application. These include on the one hand mutation-specific inhibitors of important for cell division serine-threonine kinase BRAF such as vemurafenib, dabrafenib and encorafenib and inhibitors of the downstream target protein, the mitogen-activated protein kinase kinase (MEK), such as trametinib, binimetinib and cobimetinib. The group of immunotherapeutics is a second new class of drugs, in which great hope for the treatment of metastatic melanoma is placed. Antibody-mediated blockage of surface molecules expressed on immune cells, referred to as immune checkpoints, results in activation of the immune system. As a result, an anti-tumor immune response is triggered, which has led to considerable therapeutic success in metastatic melanoma. To date, three checkpoint inhibitors have been approved for the treatment of metastatic melanoma. Ipilimumab is an antibody that binds cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); Pembrolizumab and nivolumab cause immune stimulation by binding the Programmed Death Receptor (PD1). However, the impact of the therapy on the immune system as a whole is largely unknown. A comprehensive understanding of these effects is crucial to be able to further develop the therapy and to evaluate useful combination therapies with other immunomodulatory agents. Within the framework of this project changes of the immune response under a systemic therapy of the malignant melanoma are to be characterized. The material for the analysis comes from blood samples collected during routine patient check-ups. The aim of the analyzes is to precisely characterize the effects of the different therapeutics on the function of the immune system. In particular, the study will investigate whether certain therapeutic agents can weaken or activate the immune system and thus, in addition to the direct effect on the tumor cells, mediate indirect therapeutic effects via immune modulation. In the long term, the investigators want to use the knowledge gained to further improve the already existing therapeutic strategies of malignant melanoma by additional modulation of the immune system.

NCT04158544 Metastatic Melanoma

MeSH:Melanoma

HPO:Cutaneous melanoma Melanoma

The two most common BRAF mutations (V600E and V600K) constitutively activate the MAP kinase signaling pathway that drives the proliferation and survival of cancer cells. --- V600E --- --- V600K ---

47 Altering Adjuvant Therapy Based on Pathologic Response to Neoadjuvant Dabrafenib and Trametinib (ALTER-PATH NeoDT)

This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. Patients who achieve a pathologic complete response after 8 weeks of neoadjuvant dabrafenib and trametinib will receive adjuvant dabrafenib and trametinib. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as spartalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving dabrafenib, trametinib, and spartalizumab may help to control melanoma.

NCT04310397 Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 Pathologic Stage IIID Cutaneous Melanoma AJCC v8 Drug: Dabrafenib Biological: Spartalizumab Procedure: Therapeutic Conventional Surgery Drug: Trametinib

MeSH:Melanoma Skin Neoplasms

HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

Dabrafenib, Trametinib, and Spartalizumab for the Treatment of BRAF V600E or V600K Mutation Positive Stage IIIB/C/D Melanoma This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. --- V600E --- --- V600K ---

Dabrafenib, Trametinib, and Spartalizumab for the Treatment of BRAF V600E or V600K Mutation Positive Stage IIIB/C/D Melanoma This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. --- V600E --- --- V600K --- --- V600E --- --- V600K ---

Only cases where a complete surgical resection with tumor- free margins can safely be achieved are defined as resectable - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Act (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Patients who have been previously treated in the adjuvant setting with ipilimumab or interferon alpha or investigational vaccines for melanoma will be eligible for treatment after a 28 day wash-out period - Patients who have previously received anti PD-1 in the adjuvant setting will be allowed if it has been six months or longer since previous drug exposure - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Women of childbearing potential, defined as all women physiologically capable of becoming pregnant will be required to use highly effective methods of contraception during dosing and for 150-days after stopping treatment with spartalizumab. --- V600E --- --- V600K ---

HPO Nodes