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

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Brief Title

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

Official Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Progression-free Survival (PFS) (Evaluable Randomized Patients)

Secondary Outcome

 Median Overall Survival (Evaluable Randomized Patients)

Condition

Iris Melanoma

Intervention

Dacarbazine

Study Arms / Comparison Groups

 Arm I (temozolomide)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

120

Start Date

June 2010

Completion Date

May 2016

Primary Completion Date

May 2016

Eligibility 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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Paul Chapman, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT01143402

Organization ID

NCI-2011-01411

Secondary IDs

NCI-2011-01411

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Paul Chapman, Principal Investigator, Memorial Sloan Kettering Cancer Center


Verification Date

June 2017