I. To assess the progression-free survival (PFS) in three separate patient populations with metastatic uveal melanoma: Patients on COHORT 1 (Gnaq/Gna11 mutant uveal melanoma; temozolomide [TMZ]/dacarbazine [DTIC] naive) treated with AZD6244 (selumetinib) or TMZ (or DTIC); patients on both COHORT 1 and COHORT 2 (Gnaq/Gna11 mutant and Gnaq/Gna11 wild-type uveal melanoma; TMZ/DTIC naive) treated with AZD6244 or TMZ (or DTIC); and patients on COHORT 3 (Gnaq/Gna11 mutant or wild-type uveal melanoma; previously treated with TMZ/DTIC) treated with AZD6244.
I. To assess overall survival (OS). II. To assess the overall response rate (RR). III. To determine the tolerability of MEK inhibitor AZD6244 in patients with advanced uveal melanoma.
IV. To correlate PFS, OS, and overall RR with Gnaq and Gna11 mutational status.
I. To correlate clinical outcome with baseline p-ERK, p-AKT, and PTEN expression by immunohistochemistry.
II. To correlate clinical outcome with changes in p-ERK, p-AKT, and PTEN expression by immunohistochemistry.
III. To correlate clinical outcome with changes in Ki67 and cleaved caspase 3. IV. To explore the overall quality of life (QoL) of the treatment groups as measured by the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire.
V. To explore the radiographic effects of treatment with AZD6244 as assessed by 18F fluorothymidine (18F-FLT)-PET imaging.
OUTLINE: Patients in groups 1 and 2 are randomized to 1 of 2 treatment arms. Patients in group 3 are assigned to arm II.
ARM I: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may crossover to arm II.
ARM II: Patients receive selumetinib PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks.
- Patients must have metastatic histologically or cytologically confirmed uveal melanoma; if histologic or cytologic confirmation of the primary is not available, confirmation of the primary diagnosis of uveal melanoma by the treating investigator can be clinically obtained, as per standard practice for uveal melanoma
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
- Life expectancy > 3 months
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Leukocytes >= 3,000/mm^3
- Absolute neutrophil count (ANC) >= 1,500/mm^3
- Platelets >= 100,000/mm^3
- Hemoglobin >= 9.0 g/dL (not requiring transfusions within the past 2 weeks)
- Total bilirubin =< 1.5 times upper limit of normal (ULN); note: patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times ULN (=< 5 X institutional ULN for patients with concurrent liver metastases)
- Creatinine =< 1.5 mg/dL
- Tumor Gnaq and Gna11 status must be determined on all patients using a Clinical Laboratory Improvement Act (CLIA) approved assay; if initial CLIA testing is performed locally, patients must consent to provide a tumor block or unstained slides to Memorial Sloan-Kettering Cancer Center (MSKCC) for central review of Gnaq and Gna11 status
- Patients must agree to provide all imaging studies for central radiology review
- Ability to understand and the willingness to sign a written informed consent document
- Patients may not be receiving any other investigational agents
- Eligibility for enrollment in each cohort is dependent upon tumor Gnaq/Gna11 status and prior therapy as follows:
- Cohort 1: no prior TMZ or DTIC; mutant Gnaq/Gna11 status
- Cohort 2: no prior TMZ or DTIC; wild-type Gnaq/Gna11 status
- Cohort 3: received prior TMZ or DTIC; mutant or wild-type Gnaq/Gna11 status
- Patients may have had any number of prior therapies, but cannot have previously been treated with a MEK inhibitor at least 3 weeks must have elapsed since the last dose of systemic therapy; at least 6 weeks must have elapsed if the last regimen included carmustine (BCNU), mitomycin C or an anti-CTLA4 antibody; patients must have experienced disease progression on their prior therapy in the opinion of the treating investigator
- Patients with active or untreated brain metastases; treated brain metastases must have been stable for at least 2 months
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to TMZ or DTIC or selumetinib (AZD6244)
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or bleeding, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study; breast-feeding should be discontinued if the mother is treated with AZD6244
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
- Note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle
- Women of child-bearing potential must have a negative pregnancy test prior to entry
- Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
- Patients with compensated HIV, with adequate CD4+ T-cell counts, and not requiring antiretroviral medication will be allowed
- Patients taking vitamin E supplements while on study
- No concomitant anti-cancer chemotherapy or other systemic drugs; palliative radiation therapy will be allowed as long as the patient meets all other eligibility criteria
- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
- Patients with QTc interval > 450 msecs or other factors that increase the risk of QTc prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excluded
- Required use of a concomitant medication that can prolong the QTc interval while receiving AZD6244; patients who can discontinue medications that prolong the QTc interval while receiving AZD6244 are eligible
Last updated: 05/06/2013