MEK Inhibitor AZD6244 in Treating Patients With Stage III or Stage IV Melanoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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. SECONDARY OBJECTIVES: I. Identify other genetic predictors of sensitivity to MEK inhibition. OUTLINE: Patients are stratified according to pAKT expression (low vs high). Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Tumor tissue samples are collected for correlative laboratory studies. Samples are assessed for expression of pAKT, pPRAS40, and PTEN by IHC and mutations in BRAF, NRAS, KIT, and PIK3CAP by MALDI-TOF. PTEN is sequenced in tumors using whole genome amplification followed by high-throughput bidirectional dideoxynucleotide sequencing of PCR-amplified gene products. After completion of study treatment, patients are followed for 4 weeks.

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

Conditions
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Recurrent Melanoma, Stage III Skin Melanoma, Stage IV Skin Melanoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Selumetinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Selumetinib<br>* Given orally<br>* Other names: MEK Inhibitor AZD6244;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST | Anti-tumor response defined as either a Complete Response, Partial Response, or Stable Disease as defined by RECIST | Up to 4 weeks |