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

Phase 2
18 Years
Open (Enrolling)
Metastatic Intraocular Melanoma, Recurrent Intraocular Melanoma

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Trial Information

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


I. To determine the overall objective response rate (RR) to vorinostat in patients with
metastatic uveal melanoma harboring a GNAQ or GNA11 mutation.


I. To determine the overall survival (OS) of these patients. II. To determine the
progression-free survival (PFS) of these patients. III. To determine the tolerability of
vorinostat in patients with metastatic uveal melanoma.


I. To correlate overall objective RR with guanine nucleotide binding protein (G protein), q
polypeptide (GNAQ), guanine nucleotide binding protein (G protein), alpha 11 (Gq class)
(GNA11), and BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) (BAP1)
mutational status.

II. To correlate clinical outcome with changes in histone acetylation status by

III. To correlate clinical outcome with changes in known proliferation and apoptosis markers
including proliferation-related Ki-67 antigen (Ki67) by immunohistochemistry and BCL2-like
11 (apoptosis facilitator) (BIM), survivin, v-myc myelocytomatosis viral oncogene homolog
(avian) (c-myc), Mcl-1, cleaved poly (ADP-ribose) polymerase 1 (PARP), γ-H2A histone family,
member X (H2AX), and RAD51 homolog (S. cerevisiae) (RAD51) by western blot.

IV. To assess for changes in pathways, such as the mitogen-activated protein kinase (MAPK)
pathway, with treatment.


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)

- Patients must have measurable disease as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) version 1.1

- Patients must have experienced disease progression on their prior therapy, in the
opinion of the treating investigator

- Tumor GANQ, GNA11, and BAP1 mutational status must be determined on all patients; if
initial testing is performed locally or not available, Memorial Sloan-Kettering
Cancer Center (MSKCC) patients must consent to provide a tumor block or unstained
slide to MSKCC 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 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

- No patients with active or untreated brain metastases; treated brain metastases must
have been stable for at least 2 months

- 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 times institutional upper limit of normal (ULN) (=< 3 times
institutional ULN if the patient has Gilbert syndrome)

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase [SGPT])
=< 2.5 times institutional ULN if no liver metastasis present (=< 5 times
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 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

- Pregnant women are excluded from this trial; breastfeeding should be discontinued if
the mother is treated with vorinostat

- 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

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to vorinostat

- Human immunodeficiency virus (HIV)-positive patients on combination chemotherapy will
be eligible unless the CD4 count is < 200 cells/mm^3 within one month of study

- No second malignancy requiring active therapy

- No refractory nausea and vomiting, chronic gastrointestinal diseases (e.g.,
inflammatory bowel disease), or significant bowel resection that would preclude
adequate absorption

- QTc < 475 milliseconds

- No patients who cannot swallow capsules

- 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 carmustine
(BCNU) or mitomycin C

- At least 6 weeks must have elapsed if the last regimen included an anti-CTLA4

- No patients who are receiving any other investigational agents

- 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])

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response (complete and partial response) in patients with GNAQ/GNA11 mutant uveal melanoma

Outcome Description:

For this study a two-stage design will be used to evaluate objective response. At the final analysis, response will be classified by type and duration and 95% confidence intervals, adjusted for the interim looks, will be calculated.

Outcome Time Frame:

Up to 1 year

Safety Issue:


Principal Investigator

Richard Carvajal

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2012

Completion Date:

Related Keywords:

  • Metastatic Intraocular Melanoma
  • Recurrent Intraocular Melanoma
  • Melanoma
  • Uveal Neoplasms



Memorial Sloan-Kettering Cancer CenterNew York, New York  10021