Recurrent Melanoma, Stage III Skin Melanoma, Stage IV Skin Melanoma
Conditions
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGSelumetinib
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AZD6244 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. | 167 |
| Total | 167 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Not Treated | 151 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | AZD6244 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 60 Participants |
| Age, Categorical Between 18 and 65 years | 107 Participants |
| Region of Enrollment United States | 167 participants |
| Sex: Female, Male Female | 51 Participants |
| Sex: Female, Male Male | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 15 |
| serious Total, serious adverse events | 6 / 15 |
Outcome results
Primary
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
Time frame: Up to 4 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD6244 | Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST | Partial Response | 1 participants |
| AZD6244 | Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST | Stable Disease | 8 participants |
| AZD6244 | Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST | Progression of Disease | 6 participants |