Vorinostat in Treating Patients With Metastatic or Unresectable Melanoma

Phase 2

Completed

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

Interventions: Drug: vorinostat

Registration Number: NCT00121225

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	vorinostat	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.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate Assessed by Response Evaluation Criteria for Solid Tumors (RECIST)	Up to 5 years	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.

Secondary Outcome Measures

Name	Time	Method
Time to Progression Assessed by RECIST	Up to 5 years
Difference in HP1 and MacroH2A Nuclear Foci Expression Between Progressive Minus Stable Disease Outcomes	Baseline and day 15	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.
Number of Patients With p53 Allelic Variations (72R or 72P)	Baseline	Participants were assessed for p53 allelic variation at baseline
Comparison of VEGF Serum Levels to Response to Vorinostat	Baseline, Day 1, Day 8 and Day 15	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.

Trial Locations

Locations (4): Fox Chase Cancer Center
🇺🇸
Rockledge, Pennsylvania, United States
Juravinski Cancer Centre at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
Princess Margaret Hospital Phase 2 Consortium
🇨🇦
Toronto, Ontario, Canada
University Health Network-Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada