Vorinostat in Treating Patients With Metastatic Melanoma of the Eye

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01587352
First received: April 26, 2012
Last updated: July 28, 2014
Last verified: June 2014
  Purpose

This phase II trial studies how well vorinostat works in treating patients with melanoma of the eye that has spread to other parts of the body. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Metastatic Intraocular Melanoma
Recurrent Intraocular Melanoma
Drug: vorinostat
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Vorinostat (NSC 701852) in Metastatic Uveal Melanoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Overall response rate in patients with GNAQ/GNA11 mutant uveal melanoma, defined as the rate of complete and partial responses [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The response rate along with 90% confidence interval will be estimated.


Secondary Outcome Measures:
  • Overall survival [ Time Frame: From start of treatment to death or last follow-up will be estimated, assessed up to 3 years ] [ Designated as safety issue: No ]
    Overall survival curves will be generated using Kaplan-Meier methodology.

  • Progression free survival [ Time Frame: From start of treatment to date of progression, death or last follow-up will be estimated, assessed up to 3 years ] [ Designated as safety issue: No ]
    Progression-free survival curves will be generated using Kaplan-Meier methodology.

  • Incidence of toxicities assessed by National Cancer Institute Common Toxicity Criteria 4.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    Toxicity will be reported by type, frequency and severity.

  • Gnaq mutation status [ Time Frame: Up to day 15 ] [ Designated as safety issue: No ]
    Associations of each unique mutation status with overall response will be assessed using Fisher's exact test.

  • GNA11 mutation status [ Time Frame: Up to day 15 ] [ Designated as safety issue: No ]
    Associations of each unique mutation status with overall response will be assessed using Fisher's exact test.

  • BAP1 mutation status [ Time Frame: Up to day 15 ] [ Designated as safety issue: No ]
    Associations of each unique mutation status with overall response will be assessed using Fisher's exact test.


Estimated Enrollment: 40
Study Start Date: April 2012
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat)
Patients receive vorinostat PO BID for 3 days weekly for 4 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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
  • Tumor GANQ, GNA11, and BAP1 mutational status must be determined on all patients; if initial testing is performed locally or not available, MSKCC patients must consent to provide a tumor block or unstained slides 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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01587352

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Richard D. Carvajal    646-888-4161    carvajar@mskcc.org   
Principal Investigator: Richard D. Carvajal         
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Jeffrey A. Sosman    615-343-6653    jeff.sosman@vanderbilt.edu   
Principal Investigator: Jeffrey A. Sosman         
Sponsors and Collaborators
Investigators
Principal Investigator: Richard Carvajal Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01587352     History of Changes
Other Study ID Numbers: NCI-2012-00860, NCI-2012-00860, MSKCC-12-027, CDR0000732297, 12-027, 9111, N01CM62206, U01CA069856, P30CA008748
Study First Received: April 26, 2012
Last Updated: July 28, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Uveal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Eye Neoplasms
Neoplasms by Site
Eye Diseases
Uveal Diseases
Vorinostat
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 28, 2014