Randomized Phase II Trial of Temozolomide Versus Hyd-sulfate AZD6244 [NSC 748727] in Patients With Metastatic Uveal Melanoma
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
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
II. To correlate clinical outcome with changes in p-ERK, p-AKT, and PTEN expression by
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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression-free survival (PFS) (groups 1 and 2)
The primary analysis will be performed among the Gnaq/Gna11 mutant patients. A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Due to the potential for a large number of strata and small strata sizes, the standard asymptotic stratified logrank test will be verified for robustness utilizing a permutation reference distribution.
The time from randomization to the earlier date of objective disease progression per RECIST criteria or death due to any cause in the absence of progression, assessed up to 5 years
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
|Memorial Sloan Kettering Cancer Center||New York, New York 10021|
|Mayo Clinic||Rochester, Minnesota 55905|
|H. Lee Moffitt Cancer Center and Research Institute||Tampa, Florida 33612|
|University of Iowa Hospitals and Clinics||Iowa City, Iowa 52242|
|Washington University School of Medicine||Saint Louis, Missouri 63110|
|Fairview Ridges Hospital||Burnsville, Minnesota 55337|
|Hutchinson Area Health Care||Hutchinson, Minnesota 55350|
|United Hospital||St. Paul, Minnesota 55102|
|Ridgeview Medical Center||Waconia, Minnesota 55387|
|University of Wisconsin Hospital and Clinics||Madison, Wisconsin 53792-0001|
|Mercy Hospital||Coon Rapids, Minnesota 55433|
|Fairview-Southdale Hospital||Edina, Minnesota 55435|
|Abbott-Northwestern Hospital||Minneapolis, Minnesota 55407|
|Regions Hospital||Saint Paul, Minnesota 55101|
|Saint Francis Regional Medical Center||Shakopee, Minnesota 55379|
|Vanderbilt University||Nashville, Tennessee 37232-6305|
|Hennepin County Medical Center||Minneapolis, Minnesota|
|Emory University||Atlanta, Georgia 30322|
|Metro-Minnesota CCOP||St. Louis Park, Minnesota|
|Thomas Jefferson University Hospital||Philadelphia, Pennsylvania 19131|
|University of Chicago Comprehensive Cancer Center||Chicago, Illinois 60637-1470|
|Unity Hospital||Fridley, Minnesota 55432|
|Saint John's Hospital - Healtheast||Maplewood, Minnesota 55109|
|Minnesota Oncology Hematology PA-Maplewood||Maplewood, Minnesota 55109|
|North Memorial Medical Health Center||Robbinsdale, Minnesota 55422|
|Park Nicollet Clinic - Saint Louis Park||Saint Louis Park, Minnesota 55416|
|Minnesota Oncology and Hematology PA-Woodbury||Woodbury, Minnesota 55125|
|University of Colorado Cancer Center - Anschutz Cancer Pavilion||Aurora, Colorado 80045|
|Mount Sinai Medical Center CCOP||Miami Beach, Florida 33140|
|University of Michigan University Hospital||Ann Arbor, Michigan 48109|