Vorinostat in Treating Patients With Metastatic Melanoma of the Eye

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Uveal Melanoma; Stage IV Uveal Melanoma AJCC v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Vorinostat

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 Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (vorinostat); 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Vorinostat; Given PO; Other Names: SAHA; Suberoylanilide Hydroxamic Acid; MSK-390; Zolinza; L-001079038; Suberanilohydroxamic Acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate in patients with uveal melanoma	Defined as the rate of complete and partial responses. The response rate along with 90% confidence interval will be estimated.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival curves will be generated using Kaplan-Meier methodology.	From start of treatment to death or last follow-up will be estimated, assessed up to 3 years
Progression free survival	Progression-free survival curves will be generated using Kaplan-Meier methodology.	From start of treatment to date of progression, death or last follow-up will be estimated, assessed up to 3 years
Incidence of toxicities	Assessed by National Cancer Institute Common Toxicity Criteria 4.0. Toxicity will be reported by type, frequency and severity.	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gnaq mutation status	Associations of each unique mutation status with overall response will be assessed using Fisher's exact test.	Up to day 15
GNA11 mutation status	Associations of each unique mutation status with overall response will be assessed using Fisher's exact test.	Up to day 15
BAP1 mutation status	Associations of each unique mutation status with overall response will be assessed using Fisher's exact test.	Up to day 15

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Memorial Sloan Kettering Cancer Center; Institut Curie Paris; Moffitt Cancer Center P2C
• Investigators: Principal Investigator: Alexander N Shoushtari, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2012
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: April 26, 2012
• First Submitted That Met QC Criteria: April 26, 2012
• First Posted (Estimated): April 30, 2012

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Eye Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Uveal Diseases; Melanoma; Uveal Neoplasms; Uveal Melanoma; Organic Chemicals; Carboxylic Acids; Hydroxy Acids; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Vorinostat
• Other Study ID Numbers: NCI-2012-00860 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186689 (U.S. NIH Grant/Contract); U01CA069856 (U.S. NIH Grant/Contract); P30CA008748 (U.S. NIH Grant/Contract); N01CM62206 (U.S. NIH Grant/Contract); 12-027 (CaenUH); N01CM00100 (U.S. NIH Grant/Contract); CUMC-IRBAAAO5917; AAAO5917 (Memorial Sloan Kettering Cancer Center); MSKCC-12-027; 9111 (Other Identifier: CTEP)