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

Iris Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01143402
• Other study ID #: NCI-2011-01411
• Secondary ID: NCI-2011-01411CD
• Status: Active, not recruiting
• Phase: Phase 2
• First received: June 11, 2010
• Last updated: June 5, 2016
• Start date: June 2010

Study information

• Verified date: June 2016
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 159
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Dacarbazine
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Quality-of-Life Assessment
Ancillary studies

Drug:
• Selumetinib
Given PO
• Temozolomide
Given PO

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Apoptosis in the paired samples, performed by caspase 3 cleavage	Changes will be assessed by a Wilcoxon test.	Up to 5 years	No
Other	Change in Ki67	Correlated with disease status using Fishers exact test.	Baseline up to 4 months	No
Other	Change in p-AKT	Correlated with disease status using Fishers exact test.	Baseline up to 4 months	No
Other	Change in p-ERK	Decrease in p-ERK will be correlated with disease status using Fishers exact test.	Baseline up to 4 months	No
Other	Change in PTEN	Correlated with disease status using Fishers exact test.	Baseline up to 4 months	No
Other	Changes in maximum standardized uptake value on FLT-PET scans	A paired student's t-test will be performed. Analysis of variance will also be performed to obtain the significance of FLT-PET uptake on each lesion between patients.	Baseline up to 60 minutes post injection	No
Other	FACT-M total score	Summarized using descriptive statistics for each assessment time and by treatment group. The scores will be compared between treatment groups using a mixed effect model for repeated measures analysis method. Treatment difference will be estimated from the model for each assessment time.	Up to 5 years	No
Primary	PFS (group 3)	Evaluated using a Simon mini-max design. Curves will be generated using Kaplan-Meier methodology.	4 months	No
Primary	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 Response Evaluation Criteria In Solid Tumors (RECIST) criteria or death due to any cause in the absence of progression, assessed up to 5 years	No
Secondary	Overall survival	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 death due to any cause, assessed up to 5 years	No
Secondary	PFS	A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Curves will be generated using Kaplan-Meier methodology.	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	No
Secondary	Response rate (complete and partial response)	Calculated along with a 95% confidence interval.	Up to 5 years	No
Secondary	Toxicity according to the National Cancer Institute Common Toxicity Criteria	Toxicity will be reported by type, frequency, and severity.	Up to 5 years	Yes