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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01143402
First received: June 11, 2010
Last updated: October 2, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Ciliary Body and Choroid Melanoma, Medium/Large Size
Ciliary Body and Choroid Melanoma, Small Size
Iris Melanoma
Metastatic Intraocular Melanoma
Recurrent Intraocular Melanoma
Stage IV Intraocular Melanoma
Drug: selumetinib
Drug: temozolomide
Drug: dacarbazine
Other: laboratory biomarker analysis
Other: quality-of-life assessment
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Temozolomide Versus Hyd-Sulfate AZD6244 [NSC 748727] in Patients With Metastatic Uveal Melanoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival (PFS) (groups 1 and 2) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • PFS (group 3) [ Time Frame: 4 months ] [ Designated as safety issue: No ]
    Evaluated using a Simon mini-max design. Curves will be generated using Kaplan-Meier methodology.


Secondary Outcome Measures:
  • PFS [ 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 ] [ Designated as safety issue: No ]
    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.

  • Overall survival [ Time Frame: The time from randomization to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Toxicity according to the National Cancer Institute Common Toxicity Criteria [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Toxicity will be reported by type, frequency, and severity.

  • Response rate (complete and partial response) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Calculated along with a 95% confidence interval.


Other Outcome Measures:
  • Change in p-ERK [ Time Frame: Baseline up to 4 months ] [ Designated as safety issue: No ]
    Decrease in p-ERK will be correlated with disease status using Fishers exact test.

  • Change in p-AKT [ Time Frame: Baseline up to 4 months ] [ Designated as safety issue: No ]
    Correlated with disease status using Fishers exact test.

  • Change in PTEN [ Time Frame: Baseline up to 4 months ] [ Designated as safety issue: No ]
    Correlated with disease status using Fishers exact test.

  • Change in Ki67 [ Time Frame: Baseline up to 4 months ] [ Designated as safety issue: No ]
    Correlated with disease status using Fishers exact test.

  • Apoptosis in the paired samples, performed by caspase 3 cleavage [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Changes will be assessed by a Wilcoxon test.

  • FACT-M total score [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Changes in maximum standardized uptake value on FLT-PET scans [ Time Frame: Baseline up to 60 minutes post injection ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 159
Study Start Date: June 2010
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (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.
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Drug: dacarbazine
Given IV
Other Names:
  • DIC
  • DTIC
  • DTIC-Dome
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Experimental: Arm II (selumetinib)
Patients receive selumetinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: selumetinib
Given PO
Other Names:
  • ARRY-142886
  • AZD6244
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment

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.

After completion of study treatment, patients are followed up every 12 weeks.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01143402

  Show 34 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Richard Carvajal Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01143402     History of Changes
Other Study ID Numbers: NCI-2011-01411, NCI-2011-01411, CDR0000674866, 10-053, 8443, N01CM00100, U01CA132123, N01CM00099, N01CM62206, N01CM00070, N01CM00071, P30CA008748, N01CM62208
Study First Received: June 11, 2010
Last Updated: October 2, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Uveal Neoplasms
Eye Diseases
Eye Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Uveal Diseases
Dacarbazine
Temozolomide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014