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Randomized Phase II Trial of Temozolomide Versus Hyd-sulfate AZD6244 [NSC 748727] in Patients With Metastatic Uveal Melanoma

Phase 2
18 Years
Open (Enrolling)
Ciliary Body and Choroid Melanoma, Medium/Large Size, Ciliary Body and Choroid Melanoma, Small Size, Iris Melanoma, Metastatic Intraocular Melanoma, Recurrent Intraocular Melanoma

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Trial Information

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.

Inclusion Criteria:

- 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

- 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

Exclusion Criteria:

- 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

- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS) (groups 1 and 2)

Outcome Description:

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.

Outcome Time Frame:

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

Safety Issue:


Principal Investigator

Richard Carvajal

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2010

Completion Date:

Related Keywords:

  • Ciliary Body and Choroid Melanoma, Medium/Large Size
  • Ciliary Body and Choroid Melanoma, Small Size
  • Iris Melanoma
  • Metastatic Intraocular Melanoma
  • Recurrent Intraocular Melanoma
  • Melanoma
  • Uveal Neoplasms



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