Vorinostat in Treating Patients With Metastatic Melanoma of the Eye

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Brief Title

Vorinostat in Treating Patients With Metastatic Melanoma of the Eye

Official Title

A Phase 2 Study of Vorinostat (NSC 701852) in Metastatic Uveal Melanoma

Brief Summary

      This phase II trial studies how well vorinostat works in treating patients with melanoma of
      the eye that has spread to other parts of the body (metastatic). Vorinostat may stop the
      growth of tumor cells by blocking some of the enzymes needed for cell growth.
    

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the overall objective response rate (RR) to vorinostat in patients with
      metastatic uveal melanoma.

      SECONDARY OBJECTIVES:

      I. Overall survival (OS). II. Progression free survival (PFS). III. To determine the
      tolerability of vorinostat in patients with metastatic uveal melanoma.

      EXPLORATORY OBJECTIVES:

      I. To correlate clinical outcome with changes in histone acetylation status by
      immunohistochemistry.

      II. To correlate clinical outcome with changes in known proliferation and apoptotic markers
      including Ki67 by immunohistochemistry and BIM, survivin, c-myc, Mcl-1, cleaved PARP,
      gamma-H2AX and RAD51 by western blot.

      III. To assess for changes in pathways such as the MAPK pathway with treatment. IV. To
      describe the evolution of circulating cell-free, tumor-derived deoxyribonucleic acid (DNA)
      levels measured by pyrophosphorolysis activated polymerization (PAP) in plasma of patients
      under treatment for metastatic uveal melanoma.

      V. To correlate overall objective RR with GNAQ, GNA11, SF3B1 and BAP1 mutational status.

      OUTLINE:

      Patients receive vorinostat orally (PO) twice daily (BID) for 3 days weekly for 4 weeks.
      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall response rate in patients with uveal melanoma

Secondary Outcome

 Overall survival

Condition

Metastatic Uveal Melanoma

Intervention

Laboratory Biomarker Analysis

Study Arms / Comparison Groups

 Treatment (vorinostat)
Description:  Patients receive vorinostat PO BID for 3 days weekly for 4 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Other

Estimated Enrollment

40

Start Date

April 20, 2012


Primary Completion Date

June 30, 2022

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 Columbia University, Memorial
             Sloan-Kettering Cancer Center (MSKCC) or Vanderbilt University Medical Center

          -  Patients must have measurable disease as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) version 1.1

          -  Age >= 18 years. Because limited dosing or adverse event data are currently available
             on the use of vorinostat in patients < 18 years of age, children are excluded from
             this study, but will be eligible for future pediatric single-agent trials, if
             applicable

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy of greater than 3 months

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9.0 g/dL not requiring transfusions within the past 2 weeks

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); =< 3 x
             institutional ULN if the patient has Gilbert's syndrome

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN if no liver metastasis present; =< 5 x institutional ULN if
             liver metastases are present

          -  Creatinine =< 1.5 mg/dL

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Vorinostat is toxic to the developing human fetus. For this reason and because Class D
             agents are known to be teratogenic, women of child-bearing potential and men must
             agree to use effective contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry and for the duration of study participation. Should a
             woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately. Men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and 4 months after
             completion of vorinostat administration

        Exclusion Criteria:

          -  Patients may have had any number of prior therapies. 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 BCNU or mitomycin C. At least 6 weeks must have elapsed if
             the last regimen included an anti-CTLA4 antibody. Patients must have experienced
             disease progression on their prior therapy in the opinion of the treating investigator

          -  Patients who are 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 vorinostat

          -  Patients receiving HDAC inhibitors or compounds with HDAC inhibitor like activity,
             such as valproic acid, are ineligible. Patients who have received such agents may
             enroll on this study after a 14-day washout period

          -  Patients on warfarin will be excluded from the trial if they cannot be switched to an
             acceptable alternative medication (i.e. low molecular weight heparin [LMWH]).
             Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were
             observed in patients receiving vorinostat concomitantly with coumarin-derivative
             anticoagulants

          -  Pregnant women are excluded from this study because vorinostat is a Class D agent with
             the potential for teratogenic or abortifacient effects. Because there is an unknown
             but potential risk for adverse events in nursing infants secondary to treatment of the
             mother with vorinostat, breastfeeding should be discontinued if the mother is treated
             with vorinostat

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy will be eligible unless the CD4 count is < 200 cells/mm^3 within one month of
             study enrollment (as requested by Cancer Therapy Evaluation Program [CTEP]). These
             patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy

          -  A second malignancy requiring active therapy

          -  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

          -  Corrected QT interval (QTc) > 475 milliseconds

          -  Patients who cannot swallow capsules
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alexander N Shoushtari, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01587352

Organization ID

NCI-2012-00860

Secondary IDs

NCI-2012-00860

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)

Collaborators

 Institut Curie Paris

Study Sponsor

Alexander N Shoushtari, Principal Investigator, Memorial Sloan Kettering Cancer Center


Verification Date

September 2021