Temozolomide or Selumetinib in Treating Patients With Metastatic Melanoma of the Eye

Phase 2

Completed

Conditions: Iris Melanoma
Recurrent Uveal Melanoma
Stage IV Uveal Melanoma
Medium/Large Size Posterior Uveal Melanoma
Ocular Melanoma With Extraocular Extension
Small Size Posterior Uveal Melanoma

Interventions: Drug: Dacarbazine
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Drug: Selumetinib
Drug: Temozolomide

Registration Number: NCT01143402

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II trial studies temozolomide to see how well it works compared to selumetinib in treating patients with melanoma of the eye that has spread to other places in the body. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether temozolomide is more effective than selumetinib in treating melanoma of the eye.

Detailed Description: PRIMARY OBJECTIVES:

I. To assess the progression-free survival (PFS) in three separate patient populations with uveal melanoma: Patients on COHORT 1 (guanine nucleotide binding protein \[G protein\], q polypeptide \[Gnaq\]/G protein, alpha 11 \[Gna11\] 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.

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Overall response rate (RR). III. To determine the tolerability of AZD6244 in patients with advanced uveal melanoma.

IV. To correlate PFS, OS, and overall RR with Gnaq and Gna11 mutational status.

TERTIARY OBJECTIVES:

I. To correlate clinical outcome with baseline phosphorylated (p)-extracellular signal-regulated kinases (ERK), p-v-akt murine thymoma viral oncogene homolog 1 (AKT), and phosphatase and tensin homolog (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 (FLT)-positron emission tomography (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 are unable to be treated with temozolomide may be treated with dacarbazine intravenously (IV) every 3 weeks (with approval from the Principal Investigator). 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 120

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; pathologic confirmation of diagnosis will be performed at Memorial Sloan-Kettering Cancer Center (MSKCC) or at a participating site
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 of greater than 3 months
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Leukocytes >= 3,000/mcL
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 9.0 g/dL (not requiring transfusions within the past 2 weeks)
Total bilirubin =< 1.5 times upper limit of normal; 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 upper limit of normal for patients with no concurrent liver metastases
AST(SGOT)/ALT(SGPT) =< 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 MSKCC for central review of Gnaq and Gna11 status; this central review may be performed retrospectively and will not delay patient treatment on study
Patients must agree to provide all imaging studies for central radiology review; this central radiology review may be performed retrospectively and will not be utilized for decision making for patients on study
Ability to understand and the willingness to sign a written informed consent document
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
Every effort must be made to avoid administration of drugs that are inhibitors or inducers of cytochrome P450 1A2 (CYP1A2) and CYP3A4

Exclusion Criteria

Patients may have had any number of prior therapies, but cannot have previously been treated with a mitogen-activated protein kinase kinase (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 may not be receiving any other investigational agents
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 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; women of child-bearing potential must have a negative pregnancy test prior to entry; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; please 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
Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; patients with compensated HIV, with adequate cluster of differentiation (CD)4+ 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 corrected QT (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
Every effort must be made to avoid the use of a concomitant medication that can prolong the QTc interval while receiving AZD6244; if the patient cannot discontinue medications that prolong the QTc interval while receiving AZD6244, close cardiac monitoring should be performed

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (temozolomide)	Dacarbazine	Patients receive temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who are unable to be treated with temozolomide may be treated with dacarbazine IV every 3 weeks (with approval from the Principal Investigator). Patients who experience disease progression may crossover to arm II.
Arm I (temozolomide)	Laboratory Biomarker Analysis	Patients receive temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who are unable to be treated with temozolomide may be treated with dacarbazine IV every 3 weeks (with approval from the Principal Investigator). Patients who experience disease progression may crossover to arm II.
Arm I (temozolomide)	Quality-of-Life Assessment	Patients receive temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who are unable to be treated with temozolomide may be treated with dacarbazine IV every 3 weeks (with approval from the Principal Investigator). Patients who experience disease progression may crossover to arm II.
Arm II (selumetinib)	Laboratory Biomarker Analysis	Patients receive selumetinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm II (selumetinib)	Quality-of-Life Assessment	Patients receive selumetinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm I (temozolomide)	Temozolomide	Patients receive temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who are unable to be treated with temozolomide may be treated with dacarbazine IV every 3 weeks (with approval from the Principal Investigator). Patients who experience disease progression may crossover to arm II.
Arm II (selumetinib)	Selumetinib	Patients receive selumetinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) (Evaluable Randomized Patients)	The time from randomization to the earlier date of objective disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) criteria or death due to any cause in the absence of progression, assessed up to 5 years	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.

Secondary Outcome Measures

Name	Time	Method
Median Overall Survival (Evaluable Randomized Patients)	The time from randomization to death due to any cause, assessed up to 5 years	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.

Trial Locations

Locations (33): University Health Network-Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Mount Sinai Medical Center
🇺🇸
Miami Beach, Florida, United States
Emory University/Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
University of Iowa/Holden Comprehensive Cancer Center
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Iowa City, Iowa, United States
Fairview-Southdale Hospital
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Edina, Minnesota, United States
Fairview Ridges Hospital
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Burnsville, Minnesota, United States
Unity Hospital
🇺🇸
Fridley, Minnesota, United States
Hutchinson Area Health Care
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Hutchinson, Minnesota, United States
Saint John's Hospital - Healtheast
🇺🇸
Maplewood, Minnesota, United States
Metro Minnesota Community Oncology Research Consortium
🇺🇸
Saint Louis Park, Minnesota, United States
Park Nicollet Clinic - Saint Louis Park
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Saint Louis Park, Minnesota, United States
Regions Hospital
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Saint Paul, Minnesota, United States
Saint Francis Regional Medical Center
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Shakopee, Minnesota, United States
United Hospital
🇺🇸
Saint Paul, Minnesota, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Minnesota Oncology and Hematology PA-Woodbury
🇺🇸
Woodbury, Minnesota, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
University of Colorado Cancer Center - Anschutz Cancer Pavilion
🇺🇸
Aurora, Colorado, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
University of Chicago Comprehensive Cancer Center
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Chicago, Illinois, United States
University of Michigan Comprehensive Cancer Center
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Ann Arbor, Michigan, United States
Abbott-Northwestern Hospital
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Minneapolis, Minnesota, United States
Hennepin County Medical Center
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Minneapolis, Minnesota, United States
Mayo Clinic
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Rochester, Minnesota, United States
Vanderbilt University/Ingram Cancer Center
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Nashville, Tennessee, United States
Wisconsin Clinical Cancer Center
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Milwaukee, Wisconsin, United States
North Memorial Medical Health Center
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Robbinsdale, Minnesota, United States
Mercy Hospital
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Coon Rapids, Minnesota, United States
Ridgeview Medical Center
🇺🇸
Waconia, Minnesota, United States
Minnesota Oncology Hematology PA-Maplewood
🇺🇸
Maplewood, Minnesota, United States
Thomas Jefferson University Hospital
🇺🇸
Philadelphia, Pennsylvania, United States