Vorinostat for the Treatment of Class 2 High Risk Uveal Melanoma
This early phase I trial studies how well vorinostat works in treating patients with high risk uveal (eye) melanoma. Researchers are finding that the cells in uveal melanomas are mostly divided into two types: class 1 and class 2. The class 2 cells tend to have a higher chance of moving to other organs in the body, while the class 1 cells mostly stay in the eye. Vorinostat may be able to change class 2 cells into the less aggressive class 1-type cells by "turning on" the genes in the cell that suppresses tumors.
Inclusion Criteria
- Uveal melanoma tumor determined by ophthalmic ultrasound or clinical assessment
- High-risk (class 2) uveal melanoma as determined by gene expression profiling (GEP; DecisionDx-UM Castle Biosciences Inc, Friendswood, TX)
- No evidence of metastatic disease
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Life expectancy of greater than 3 months
- Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
- Absolute neutrophil count (ANC) > 1,500 cells/mm^3
- Platelet count > 100,000/mm^3
- Hemoglobin > 10.0 g/dL
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
- Total bilirubin < 2 x ULN
- Glycosylated hemoglobin measurement (hemoglobin A1C) =< 5.7%
- Alkaline phosphatase < 3 x ULN
- Serum creatinine < 2 x ULN or a creatinine clearance > 60 mL/min
- Note: Patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation until 4 months after completion of study drug administration. Women of child-bearing potential must have a negative serum or urine test at time of enrollment. 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 therapy, and 4 months after completion of study drug administration
- Willingness to comply with all the visits and procedures (including providing all biological specimens) as required by the protocol and the informed consent form (ICF)
- Ability to understand the investigational nature, potential risks and benefits of the research study and to provide valid written informed consent
Exclusion Criteria
- Definitive therapy of the primary uveal melanoma by either surgery or radiotherapy
- History of another malignancy except for those who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies not requiring active therapy, are eligible. Consult the study principal investigator if unsure whether second malignancies meet the requirements specified above
- Any major surgery or extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to initiation of study therapy
- History of prior vorinostat use
- Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study therapy and during the study
- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to vorinostat (i.e. histone deacetylase [HDAC] inhibitor hydroxamates such as panobinostat and belinostat)
- A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec
- Concurrent administration of vorinostat and agents that can cause corrected QT (QTc) prolongation is not permitted
- Concurrent administration of vorinostat and other HDAC inhibitors is not permitted due to the increased risk of thrombocytopenia and gastrointestinal bleeding
- Patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with vorinostat
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infections, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements
- History of pulmonary embolism (PT) or deep-vein thrombosis (DVT) (catheter associated thrombosis excluded)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03022565.
PRIMARY OBJECTIVES:
I. To determine the degree of re-differentiation from a class 2 to a class 1–like phenotype in uveal melanoma tumors.
II. To determine the proportion of patients whose tumors re-differentiated from a class 2 to a class 1-like phenotype based on a pre-specified threshold of re-differentiation.
SECONDARY OBJECTIVES:
I. Toxicity during vorinostat therapy and up to one month after vorinostat treatment completion.
II. Tumor size before and after vorinostat therapy.
III. Recurrence-free survival (RFS).
IV. Overall survival (OS) and disease specific survival (DSS).
EXPLORATORY OBJECTIVE:
I. Global histone acetylation levels in peripheral blood mononuclear cells (PBMCs) before and after vorinostat therapy.
OUTLINE:
Patients receive vorinostat orally (PO) once daily (QD) on days 1-15 in the absence of disease progression or unacceptable toxicity. Patients also undergo fine-needle aspiration (FNA) biopsy at baseline and day 15.
After completion of study treatment, patients are followed up at 2 and 4 weeks and then every 3 months for 2 years, every 4 months for 2 years, and every 6 months for 1 year.
Trial PhasePhase O
Trial Typetreatment
Lead OrganizationUniversity of Miami Miller School of Medicine-Sylvester Cancer Center
Principal InvestigatorJames William Harbour
- Primary ID20160653
- Secondary IDsNCI-2019-06918
- ClinicalTrials.gov IDNCT03022565