Vorinostat in Treating Patients With Metastatic or Unresectable Melanoma

Study Overview
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Brief Summary
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This phase II trial is studying how well vorinostat works in treating patients with metastatic or unresectable melanoma. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine the objective response rate in patients with metastatic or unresectable melanoma treated with vorinostat. SECONDARY OBJECTIVES: I. Determine time to progression in patients treated with this drug. II. Determine the utility of HP1 and/or macro H2A nuclear foci as biomarkers of response in patients treated with this drug. III. Correlate the presence of 72R or 72P variant p53 polymorphisms with response and time to progression in patients treated with this drug. IV. Determine gene expression profiles that may predict response to this drug and gene expression changes that occur after treatment with this drug in these patients. OUTLINE: This is a multicenter study. Patients receive oral vorinostat once daily 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 for 4 weeks and then every 3 months thereafter.

Official Title
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A Phase II Study of Vorinostat in Patients With Advanced Melanoma

Conditions
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Recurrent Melanoma, Ciliary Body and Choroid Melanoma, Medium/Large Size, Extraocular Extension Melanoma, Iris Melanoma, Uveal Melanoma, Recurrent Intraocular Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Drug: vorinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically/cytologically confirmed melanoma that is metastatic/unresectable Residual, recurrent, or metastatic disease by radiographic examination. Measurable disease (at least 1 lesion in at least 1 dimension (longest diameter) as >20mm with conventional techniques or >10mm with spiral CT scan, within 4 weeks prior to registration No prior therapy or 1 prior treatment (cytokine/chemotherapy/combination) for metastatic disease allowed. Patients should not take valproic acid, another histone deacetylase inhibitor, for at least 2 weeks prior to enrollment. At least 4 weeks from prior therapy to be eligible or 6 weeks if last regimen included BCNU or mitomycin C Age>=18 years Life expectancy >=3 months. ECOG<2 (Karnofsky ≥60%) Leukocytes >3,000/mcL Absolute neutrophil count >1,500/mcL Platelets >100,000/mcL Total bilirubin within institutional limits AST/ALT≤2.5Xinstitutional ULN Creatinine within institutional limits OR creatinine clearance >60mL/min/1.73 m2 if creatinine levels above institutional limits Eligibility of patients taking medications with potential to affect activity/PK of Vorinostat will be determined by PI Must not use concomitant steroids except topical/inhaled use Vorinostat effects on developing human fetus are unknown. Women of childbearing potential (WOCBP) and sexually active males must agree to use accepted/effective contraception method prior to study entry and for duration of the study Ability to understand/willingness to sign written informed consent Must have paraffin block of tumor tissue available for future studies Exclusion Criteria: Chemotherapy/radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering study May not be receiving any other investigational agents Known brain metastases History of allergic reactions attributed to compounds of similar chemical/biologic composition to Vorinostat Uncontrolled intercurrent illness including but not limited to ongoing/active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women excluded because Vorinostat is a HDAC inhibitor agent with potential for teratogenic or abortifacient effects HIV-positive patients receiving combination antiretroviral therapy are ineligible because of potential for PK interactions with Vorinostat

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients will receive vorinostat by mouth once a day for 4 weeks. Treatment may repeat every 4 weeks for as long as benefit is shown. Patients will be evaluated for 4 weeks and every 3 months thereafter. | Drug: vorinostat<br>* Patients will receive vorinostat by mouth once a day for 4 weeks. Treatment may repeat every 4 weeks for as long as benefit is shown. Patients will be evaluated for 4 weeks and every 3 months thereafter.<br>* Other names: Zolinza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) | Per Response Evaluation Criteria in Solid Tumours Criteria (RECIST v1.0) for target lesions and are assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in sum of longest diameter of target lesions; Objective Response (OR) = CR+ PR. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression Assessed by RECIST |  | Up to 5 years | 
| Difference in HP1 and MacroH2A Nuclear Foci Expression Between Progressive Minus Stable Disease Outcomes | Macro H2A and HP1 expression levels were compared through analysis of log fold changes in antibody expression in a multivariate general linear model between progressive disease and stable disease outcomes. | Baseline and day 15 | 
| Number of Patients With p53 Allelic Variations (72R or 72P) | Participants were assessed for p53 allelic variation at baseline | Baseline | 
| Comparison of VEGF Serum Levels to Response to Vorinostat | Blood specimens were collected from participants on Day 1 Cycle 1 prior to treatment (baseline), Day 1 3-4 hours following Vorinostat ingestion, Day 8 and Day 15. VEGF serum concentrations were detected using the Luminex multiplexed assay, where the median fluorescence intensity results were analyzed by a weighted five-parameter logistic method. The values were averaged across all time points per participant. | Baseline, Day 1, Day 8 and Day 15 |