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

National Cancer Institute (NCI)

Status and phase: Completed; Phase 2

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

Treatments: Drug: Selumetinib; Other: Laboratory Biomarker Analysis

Study type: Interventional

Funder types: NIH

Identifiers

NCT00866177

N01CM62206 (U.S. NIH Grant/Contract)

P30CA008748 (U.S. NIH Grant/Contract)

09-003

CDR0000637669

MSKCC-09003

8252 (Other Identifier)

NCI-2009-01164 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 167 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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167 participants in 1 patient group

Arm I

Experimental group

Description:

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.

Treatment:

Drug: Selumetinib

Other: Laboratory Biomarker Analysis