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Report for Clinical Trial NCT00866177

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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
MeSH: Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the skin

2 Interventions

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Arm I

Name: Selumetinib

Description: Given orally

Type: Drug

Arm I


Primary Outcomes

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

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

Time: Up to 4 weeks

Purpose: Treatment

Single Group Assignment


There are 2 SNPs

SNPs


1 V600E

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

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

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


2 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 ---

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 ---



HPO Nodes


HPO:
Cutaneous melanoma
Genes 15
HRAS MITF CDKN2A BRAF NRAS NRAS WRN CDKN2A CXCR4 BAP1 POLH CDK4 ERCC3 XPC MC1R
Melanoma
Genes 98
MGMT NRAS POT1 NRAS XPA CTSC BRCA1 SDHC ERCC4 CXCR4 RAD51C CDKN2B ERCC3 XPC PALLD ERCC2 ERCC2 CHEK2 CDKN2A RAD51D GNAQ SDHD KRAS MBTPS2 BAP1 BAP1 CYSLTR2 RNF43 BAP1 CDKN2A PTPN11 CDK4 BRCA2 ERCC3 MITF TERF2IP ERCC4 CHEK2 BRCA1 TRPV3 POT1 OCA2 TERT CDKN2A AKT1 CDKN2A SF3B1 ERCC6 ERCC5 ERCC5 MDM2 BRCA2 BAP1 GNA11 ACD BRIP1 HRAS MRE11 BRAF TYR TP53 KLLN SEC23B PTEN PIK3CA XPA PERP MITF RAF1 BRAF POLH TP53 BARD1 NRAS SMAD4 RAD50 DDB2 ERCC2 NBN TERT MC1R SLC45A2 WRN PALB2 DDB2 PALB2 CDKN2A SDHB MC1R RAD51 TP53 XPC ERCC3 PTEN CDKN2A POLH CDK4 MC1R
Neoplasm of the skin
Genes 274
COL7A1 LZTS1 GTF2H5 SDHC NRAS KRAS ERCC2 KIT CTSC RASA1 RECQL4 SUFU ERCC2 TGFBR2 PORCN ERCC4 TARS1 ERCC3 XPC ERCC2 FH KRT17 NTHL1 PTEN MSH3 PIK3CA RASGRP1 IL7 ERCC4 TNFRSF1B SDHD PRKCD CYLD MBTPS2 CXCR4 KIT BMPR1A FAN1 NF1 KRT1 MSH3 CDKN2B KEAP1 DICER1 TNFRSF4 PTCH2 TERC CDKN2A KDSR CIB1 GJB4 PTCH2 CDKN2C RNF113A DCC COL7A1 ERCC3 ERCC4 SNAI2 CHEK2 IFNG TMC6 COL1A1 TRPV3 GJC2 TINF2 FLT4 PRKAR1A MSH2 MLH1 STAT1 KRT6B HPGD CASP10 TERT NLRP1 ERCC5 NUTM1 SLCO2A1 RSPO1 MDM2 PTEN FCN3 KRT16 DOCK8 HRAS BRAF NF2 TYR KRT17 NF1 PSENEN WRAP53 RNF6 MEN1 TSC1 MSH2 CYLD PTEN PERP IGHM TP53 PDGFB KRAS POLH BMPR1A BLM NOTCH3 TNFRSF1B KRT5 MLH3 SUFU KRT9 CTLA4 FLCN CD28 DDB2 NRAS ECM1 CTNNB1 MSH2 COL7A1 FLT4 TCF3 MEN1 FH KRT17 SMO NRAS MMP1 LMNA FGFR1 MVK PTCH1 GPR143 APC NF1 PMS1 CDK4 APC NF2 WNT10A GJB6 TSC2 KIT BLNK SPRED1 AKT1 NRAS SDHC NTHL1 SMARCB1 GJB2 MLH1 PMS2 LMNA MSH6 CXCR4 LAMB3 CD79B MPLKIP NF2 CDKN2A KIT MSH6 PIK3CA BAP1 PDGFRB VEGFC KLLN RMRP HRAS CTLA4 LRRC8A FAS KRAS BRD4 CARMIL2 SDHB MSH2 WNT10A PRKAR1A CYLD KRT14 IGLL1 PIK3CA HRAS TYR ERCC3 MITF GJB3 CD79A GNA14 MLH1 CDKN1A RPS20 GJB2 SLX4 PTCH1 OCA2 TP53 APC CDKN2A CIB1 AKT1 CDKN2A FDPS STK4 ERCC5 LAMA3 TMC8 PDGFB ING1 MSH6 KIT GJA1 LAMC2 PIK3R1 CDKN1B OCRL BLM FH NF1 GTF2E2 EPCAM KLLN SEC23B TGFBR2 SEMA4A PIK3CA XPA SLC17A9 TNFRSF10B FAS DKC1 APC RECQL4 CD28 NRAS PTEN MLH1 DDB2 TMC6 CTNNB1 ERCC2 SASH1 MC1R PMS2 SLC45A2 MVD SEC23B KIT WRN PTEN ALX3 SDHB FERMT1 FASLG PMVK MMP1 HRAS COL7A1 TP53 XPC ERCC3 WWOX CDKN1B PLCD1 GJB2 PTCH1 IKBKG POLH MC1R DCLRE1C