A Randomized Phase ll Study of Adjuvant Sunitinib or Valproic Acid in High-Risk Patients With Uveal Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 210
- 试验地点
- 1
- 主要终点
- Relapse-free survival (RFS) (Cohort 2 and 3)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >= 18 years old
- •Histologically-confirmed primary uveal melanoma
- •Definitive local treatment for primary tumor, including surgical resection (enucleation) or radiation therapy (radioactive plaque or external proton beam)
- •High risk for distal recurrence defined as any of the following conditions: A) Confirmed both monosomy 3 and 8q amplification; B) Class II tumor
- •Less than 6 months from the date that local treatment (surgical or radiation) of the primary tumor was finalized
- •Karnofsky performance status (PS) scores of 70 or greater
- •If female, no pregnancy
- •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 (sunitinib malate) (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
- •Absolute neutrophil count (ANC) >= 1500/mm^3
- •Platelets >= 100,000/mm^3
- •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
- •Serum albumin > 2.0 g/dl
- •Adequate cardiac function (ejection fraction [EF] > 50%) based on multi gated acquisition (MUGA) scan or 2 dimensional-echocardiogram (2D-Echo)
- •Life expectancy of at least 5 years
排除标准
- •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
- •Metastatic uveal melanoma
- •History of severe allergic reaction to sunitinib or valproic acid; inability to receive sunitinib or valproic acid
- •Previous treatment with sunitinib or valproic acid for uveal melanoma
- •Active treatment with valproic acid for non-oncological conditions, if this cannot be safely switched to an alternative agent
- •Active epilepsy or convulsive conditions that require continuous use of anticonvulsants
- •Patients with known urea cycle disorders (i.e.: ornithine transcarbamylase deficiency)
- •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
- •Active liver disease (i.e., cirrhosis, viral or autoimmune hepatitis, etc.)
- •Pregnancy or unwillingness to stop breast-feeding
- •Prior myelosuppressive chemotherapy or other investigational drug therapy within the last 6 months prior to initiation of sunitinib or valproic acid
- •Current evidence of hematemesis, melena or gross hematuria
- •History or presence of any significant bleeding disorders
- •Concurrent use of a strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitor or inducer; 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
- •Chronic usage of aspirin greater than 81 mg/day
- •Unable to render informed consent and to follow protocol requirements
- •Any other medical condition(s) that, at the discretion of the principal investigator (PI), would make the patient inappropriate for this study
研究组 & 干预措施
Sunitinib- (Cohort 1, Arm I)
Patients receive sunitinib malate PO daily for 6 months in the absence of disease progression or unacceptable toxicity
Quality-of-Life Assessment-Ancillary studies
- Laboratory Biomarker Analysis-Correlative studies
干预措施: Sunitinib (Drug)
Sunitinib Malate + Valproic Acid (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.
Quality-of-Life Assessment-Ancillary studies
Laboratory Biomarker Analysis-Correlative studies
干预措施: Sunitinib Malate + Valproic Acid (Drug)
Valproic acid- (Cohort 1, Arm II)
Patients receive valproic acid PO daily for 6 months in the absence of disease progression or unacceptable toxicity
Quality-of-Life Assessment-Ancillary studies
Laboratory Biomarker Analysis-Correlative studies
干预措施: Valproic Acid (Drug)
Sunitinib Malate (Cohort 2)
Patients receive sunitinib malate PO daily for 12 months in the absence of disease progression or unacceptable toxicity
Quality-of-Life Assessment-Ancillary studies
Laboratory Biomarker Analysis-Correlative studies
干预措施: Sunitinib Malate (Drug)
结局指标
主要结局
Relapse-free survival (RFS) (Cohort 2 and 3)
时间窗: Time of definitive treatment of the primary tumor until confirmed metastatic relapse or death from any cause, assessed at 2 years
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
Overall survival (Cohort 1)
时间窗: Time of definitive treatment of the primary tumor until death from any cause, assessed at 2 years
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.
次要结局
- Tolerability, defined as the proportion of patients able to complete 6 months of treatment, including those who underwent dose reduction(6 months)
- Relapse-free survival (Cohort 1)(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)(Time of definitive treatment of the primary tumor until death from any cause, assessed at 2 years)
- Incidence of toxicity assessed according to the National Institute of Health Common Terminology Criteria for Adverse Events (NIH CTCAE) version 4.0(Up to 5 years)
- Quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires(Up to 6 months)