This randomized phase II trial studies how well sunitinib malate or valproic acid works in preventing high-risk uveal (eye) melanoma from spreading to other parts of the body. Sunitinib malate may stop the transmission of growth signals into tumor cells and prevents these cells from growing. Valproic acid may change the expression of some genes in uveal melanoma and suppress tumor growth.
PRIMARY OBJECTIVES: I. To assess the efficacy of adjuvant sunitinib malatate (sunitinib) and adjuvant valproic acid used for 6 months to improve overall survival (OS) at 2 years in patients with high risk uveal melanoma. (Cohort 1) II. To assess the efficacy of adjuvant sunitinib used for 12 months to improve 1.5-year relapse free survival (RFS) in patients with high-risk uveal melanoma. (Cohort 2) III. To assess whether the combination of sunitinib and valproic acid used for 12 months improve the 2-year relapse free survival (RFS) in patients with high-risk uveal melanoma. (Cohort 3) SECONDARY OBJECTIVES: I. To assess the efficacy of adjuvant sunitinib, in terms of RFS and adjuvant valproic acid used for 6 months in preventing the development of distal metastases in patients with high risk uveal melanoma. (Cohort 1) II. To assess the efficacy of adjuvant sunitinib, in terms of OS, used for 12 months in patients with high risk uveal melanoma. (Cohort 2) III. To assess the efficacy of adjuvant sunitinib in combination with valproic acid, in terms of OS in patients with high risk uveal melanoma. (Cohort 3) IV. To confirm the safety and tolerability of 6 months of adjuvant sunitinib and adjuvant valproic acid. (Cohort 1) V. To confirm the safety and tolerability of 12 months of adjuvant sunitinib. (Cohort 2) VI. To confirm the safety and tolerability of 12 months of adjuvant sunitinib and valproic acid. (Cohort 3) TERTIARY OBJECTIVES: I. To determine whether blood myeloid-derived suppressor cells (MDSCs) concentration and other inflammatory cytokines correlates with OS and RFS. OUTLINE: Patients are assigned to 1 of 3 cohorts. COHORT 1: Participants are randomized to 1 of 2 arms. ARM I: Patients receive sunitinib malate orally (PO) daily for 6 months in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive valproic acid PO daily for 6 months in the absence of disease progression or unacceptable toxicity. COHORT 2: Patients receive sunitinib malate PO daily for 12 months in the absence of disease progression or unacceptable toxicity. COHORT 3: Patients receive sunitinib malate PO daily and valproic acid PO daily for 12 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
210
Sidney Kimmel Cancer Center at Thomas Jefferson University
Philadelphia, Pennsylvania, United States
Overall survival (Cohort 1)
OS distribution will be summarized using the method of Kaplan-Meier and the 2-year OS rate with two-sided 90% confidence interval (CI) will be provided. OS will be compared to the historic OS using a one-sample log-rank test.
Time frame: Time of definitive treatment of the primary tumor until death from any cause, assessed at 2 years
Relapse-free survival (RFS) (Cohort 2 and 3)
RFS distribution will be summarized using the method of Kaplan-Meier. 1.5-year, 2-year PFS rate will be computed with the corresponding two-sided 90% confidence intervals. OS and RFS will be compared to the null hypothesis OS or RFS using a one-sided one-sample Brookmeyer-Crowley test with alpha 0.05
Time frame: Time of definitive treatment of the primary tumor until confirmed metastatic relapse or death from any cause, assessed at 2 years
Relapse-free survival (Cohort 1)
RFS distribution will be summarized using the method of Kaplan-Meier, and two-sided 90% confidence interval (CI) will be provided.
Time frame: Time of definitive treatment of the primary tumor until confirmed metastatic relapse or death from any cause, assessed at 2 years
Overall survival (Cohort 2)
OS distribution will be summarized using the method of Kaplan-Meier and the 2-year OS rate with two-sided 90% confidence interval (CI) will be provided. OS will be compared to the historic OS using a one-sample log-rank test.
Time frame: Time of definitive treatment of the primary tumor until death from any cause, assessed at 2 years
Tolerability, defined as the proportion of patients able to complete 6 months of treatment, including those who underwent dose reduction
Proportion of patients completing six months of treatment will be summarized using descriptive statistics.
Time frame: 6 months
Incidence of toxicity assessed according to the National Institute of Health Common Terminology Criteria for Adverse Events (NIH CTCAE) version 4.0
Type and grade of toxicity will be assessed on every schedule visit and recorded based on NIH CTCAE 4.0 grading system. Descriptive statistics will be used to summarized type and grade of toxicity.
Time frame: Up to 5 years
Quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires
The FACT-G questionnaires will be scored at baseline, 1 month, 3 months, and 6 months. The difference between two treatment groups will be analyzed with standard t-test at individual evaluation points. Average QOL scores during the study will be calculated and compared between the treatment groups. To estimate the magnitude of the difference between treatment groups, the standardized effect size and minimally important difference will be used. Repeated-measures mixed-effects models with random intercepts and slopes will be used to assess treatment differences in QOL measures over time.
Time frame: Up to 6 months
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