PRIMARY OBJECTIVES:
1) To assess the efficacy of adjuvant sunitinib malate or adjuvant valproic acid used for 6
months to improve overall survival (OS) at 2 years in patients with high-risk uveal melanoma.
SECONDARY OBJECTIVES:
1. To assess the efficacy of adjuvant sunitinib malate and adjuvant valproic acid used for
6 months in preventing the development of distal metastases (relapse-free survival, RFS)
in patients with high-risk uveal melanoma.
2. To confirm the safety and tolerability of 6 months of adjuvant sunitinib and adjuvant
valproic acid in patients with high-risk uveal melanoma.
3. To assess the quality of life during the adjuvant treatment.
TERTIARY OBJECTIVES:
1) To determine whether blood myeloid-derived suppressor cells (MDSCs) concentration and
other inflammatory cytokines correlates with OS and RFS.
OUTLINE: Patients are randomized to 1 of 2 treatment 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.
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.
Inclusion Criteria:
1. Age >= 18 years old.
2. Histologically-confirmed primary uveal melanoma.
3. Definitive local treatment for primary tumor, including surgical resection
(enucleation) or radiation therapy (radioactive plaque or external proton beam).
4. High risk for distal recurrence defined as any of the following conditions: A) -
Confirmed both monosomy 3 and 8q amplification; B) - Class II tumor.
5. Less than 6 months from the date that local treatment (surgical or radiation) of the
primary tumor was finalized.
6. Karnofsky performance status (PS) scores of 70 or greater.
7. If female, no pregnancy.
8. If of child-bearing potential (< one year post-menopausal), must agree to practice an
effective method of avoiding pregnancy (including oral or implanted contraceptives,
intrauterine device, condom, diaphragm with spermicidal, cervical cap, abstinence or
sterile sex partner) from the time informed consent is signed (women only) or the time
of initiation of sunitinib (men only); both men and women must agree to continue using
such precautions while receiving sunitinib or valproic acid and for 30 days after the
final dose.
9. Adequate organ function that has been determined within 2 weeks prior to the study
entry, defined as:
- Absolute neutrophil count (ANC) ≥ 1500/mm3, platelets ≥ 100,000/mm3, and
hemoglobin ≥ 8 g/dl
- Serum creatinine < 1.5 times upper limit of normal range (ULN) or creatinine
clearance ≥ 40 ml/min
- Serum bilirubin < 1.5 times ULN and serum albumin > 2.0 g/dl
- Adequate cardiac function (EF> 50%) based on MUGA scan
Exclusion Criteria:
1. Other malignancy within 5 years, except curatively treated non-melanomatous skin
cancer, curatively treated carcinoma in situ of the uterine cervix, or early stage
(stage I or IIa) prostate cancer.
2. Metastatic uveal melanoma.
3. History of severe allergic reaction to sunitinib or valproic acid; inability to
receive sunitinib or valproic acid.
4. Previous treatment with sunitinib or valproic acid for uveal melanoma.
5. Active treatment with valproic acid for non-oncological conditions, if this cannot be
safely switched to an alternative agent.
6. Active epilepsy or convulsive conditions that require continuous use of
anticonvulsants.
7. Patients with known urea cycle disorders (i.e.: ornithine transcarbamylase
deficiency).
8. Severe cardiovascular disease within 6 months, including myocardial infarction,
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebro-vascular accident or transient ischemic attack,
pulmonary embolism, life threatening arrhythmias, uncontrollable hypertension or QT
prolongation syndrome.
9. History of active liver disease (i.e. cirrhosis, viral or autoimmune hepatitis, etc.).
10. Pregnancy or unwillingness to stop breast-feeding.
11. Prior myelosuppressive chemotherapy or other investigational drug therapy within the
last 6 months prior to initiation of sunitinib or valproic acid.
12. Current evidence of hematemesis, melena or gross hematuria.
13. History or presence of any significant bleeding disorders.
14. Concurrent use of a strong CYP3A4 inhibitor or inducer (refer to Section 7). These
medications should be discontinued or switched to a different medication with a weaker
CYP3A4 interaction prior to enrollment into the study. If patients need to continue
the same medication(s), they are excluded from the study.
15. Chronic usage of aspirin greater than 81 mg/day.
16. Unable to render informed consent and to follow protocol requirements.
