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.

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.

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