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

Phase 2

Completed

Conditions: Stage III Skin Melanoma
Recurrent Melanoma
Stage IV Skin Melanoma

Interventions: Other: Laboratory Biomarker Analysis
Drug: Selumetinib

Registration Number: NCT00866177

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 167

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	Laboratory Biomarker Analysis	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.
Arm I	Selumetinib	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.

Primary Outcome Measures

Name	Time	Method
Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST	Up to 4 weeks	Anti-tumor response defined as either a Complete Response, Partial Response, or Stable Disease as defined by RECIST

Secondary Outcome Measures