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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
Group Labels: 1

Arm I

Name: Selumetinib

Description: Given orally
Type: Drug
Group Labels: 1

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

Allocation: N/A

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:
HP:0008069: Neoplasm of the skin
Genes 277
TGFBR2 DOCK8 KRT17 PORCN ERCC4 OCA2 PTEN SDHC SUFU RNF6 KRT6B PIK3CA TNFRSF1B DDB2 KRT14 SDHD FASLG COL1A1 CARMIL2 LRRC8A BAP1 NF1 FLT4 NRAS LAMC2 RSPO1 OCRL TP53 NTHL1 PTEN NF1 FH LAMB3 COL7A1 PERP FH NRAS TINF2 SLC17A9 RECQL4 PTCH2 RPS20 CD79B KRT17 BMPR1A MLH1 NF1 GJB3 LZTS1 MSH3 SUFU GNA14 IKBKG PTCH1 KIT HRAS BRAF APC PRKAR1A MMP1 KRT17 TP53 KEAP1 SMO PTCH1 ERCC5 MVD TERC PTEN SEMA4A CD79A SMARCB1 GJB2 KIT FLT4 KRT9 MC1R SEC23B VEGFC ERCC3 FGFR1 BLNK TNFRSF1B MSH6 TCF3 PLCD1 MEN1 FAS KRAS CTSC RECQL4 CD28 CDKN2B WWOX CTLA4 COL7A1 HRAS CDKN2A TP53 WNT10A NLRP1 ERCC2 IFNG MBTPS2 MDM2 KRAS GTF2E2 MLH1 STAT1 TMC8 SNAI2 BMPR1A CDKN1A KDSR CD28 CYLD ERCC2 ERCC4 NRAS DCLRE1C SLC45A2 PMS1 MITF MSH3 NUTM1 IL7 PIK3CA ERCC3 SDHC PTCH2 MLH1 CIB1 MSH6 CDKN2A NF1 CIB1 TNFRSF10B NF2 APC SLCO2A1 BLM GJA1 GTF2H5 PIK3CA TARS1 CXCR4 CDK4 PIK3R1 CYLD GJC2 GPR143 DDB2 LAMA3 SDHB MVK PMVK PIK3CA EPCAM GJB2 NF2 MSH2 WRAP53 MEN1 RASA1 KRAS LMNA CTNNB1 CDKN1B POLH GJB6 MPLKIP IL6 CXCR4 NOTCH3 TSC2 AKT1 PSENEN PMS2 RASGRP1 CASP10 ERCC3 MC1R SDHB KIT RMRP PTEN TGFBR2 PDGFRB CYLD RNF113A ALX3 BLM CTNNB1 FH KIT STIM1 TYR TMC6 HRAS CHEK2 KRT1 DICER1 DKC1 MSH2 COL7A1 NRAS PTEN FDPS PRKCD NRAS CDKN2A XPC WNT10A SEC23B XPA CDKN1B ERCC2 HPGD ERCC5 SLX4 TNFRSF4 FCN3 MMP1 ECM1 USF3 LMNA XPC NTHL1 KRT16 KIT PDGFB FAN1 ERCC4 SPRED1 PDGFB ING1 FERMT1 MLH1 KLLN ERCC2 GJB4 MSH6 APC TERT POLH BRD4 WRN SASH1 TMC6 MSH2 HRAS APC PMS2 ERCC3 KIT CTLA4 KLLN IGHM STK4 FAS GJB2 MLH3 TRPV3 CDKN2C IGLL1 TYR MSH2 NF2 COL7A1 AKT1 DCC FLCN PTCH1 TSC1 CDKN2A KRT5 PRKAR1A
Protein Mutations 4
D299G P13K V600E V600K
SNP 0