Vorinostat in Treating Patients With Metastatic Melanoma of the Eye

PRIMARY OBJECTIVES:

I. To determine the overall objective response rate (RR) to vorinostat in patients with
metastatic uveal melanoma harboring a guanine nucleotide binding protein (G protein), q
polypeptide (GNAQ) or guanine nucleotide binding protein (G protein), alpha 11 (Gq class)
(GNA11) mutation.

SECONDARY OBJECTIVES:

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

IV. To correlate overall objective RR with GNAQ, GNA11 and breast cancer 1 (BRCA1) associated
protein-1 (ubiquitin carboxy-terminal hydrolase) (BAP1) mutational status.

TERTIARY 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 BCL2-like 11 (apoptosis facilitator) (BIM),
baculoviral IAP repeat containing 5 (survivin), v-myc avian myelocytomatosis viral oncogene
homolog (c-myc), myeloid cell leukemia 1 (Mcl-1), cleaved poly (ADP-ribose) polymerase 1
(PARP), gamma-H2A histone family, member X (gamma-H2AX) and RAD51 recombinase (RAD51) by
western blot.

III. To assess for changes in pathways such as the mitogen-activated protein kinase (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.

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.

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

- 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

- 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

- Tumor GANQ, GNA11, and BAP1 mutational status must be determined on all patients; if
initial testing is performed locally or not available, MSKCC or Columbia University
Medical Center (CUMC) patients must consent to provide a tumor block or unstained
slides to MSKCC or CUMC for central review of mutational status; if tissue is not
available, a pre-treatment biopsy will be necessary for eligibility

- Patients enrolled at Vanderbilt University Medical Center may have GNAQ and GNA11
mutational status determined on a Clinical Laboratory Improvement Act
(CLIA)-approved assay at Vanderbilt University Medical Center, CUMC, or MSKCC;
tissue must be sent to MSKCC for BAP1 mutational status determination

- The determination of mutational status may be performed retrospectively and will
not delay patient treatment on study as long as tissue is available for molecular
analysis

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-cytotoxic T-lymphocyte-associated protein 4 (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 histone deacetylase (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, 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 cluster of differentiation (CD)4 count is < 200
cells/mm^3 within one month of study enrollment

- 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