A Phase 2, Placebo-Controlled, Randomized, Discontinuation Trial of Tivozanib (AV-951) in Patients With Renal Cell Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 272
- 主要终点
- Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs)
研究概览
简要总结
This phase 2 trial is evaluating the antineoplastic activity of tivozanib (AV-951) in treating patients with recurrent or metastatic renal cell cancer. Tivozanib (AV-951) is a VEGF-receptor tyrosine kinase inhibitor, and may stop the growth of tumor cells by blocking blood flow to the tumor.
详细描述
Approximately 200 patients will be enroled into the initial, 16 week, open-label period using 1.5 mg/day dosing. Patients will receive tivozanib (AV-951) continuously for 3 weeks followed by 1 week off study drug. Patients will undergo disease assessment at baseline and after Cycles 2 and 4 and response will be determined by RESIST criteria.
After the initial, 16 week open-label period, disease status will be assessed and compared to baseline using modified RECIST criteria:
- Patients with greater than or equal to 25% tumor shrinkage will continue on their current dose of tivozanib (AV-951)
- Patients with less than 25% tumor change (growth or shrinkage) will be randomly assigned to double-blind tivozanib (AV-951) or matching placebo for 12 weeks
- Patients with greater than or equal to 25% tumor growth will be discontinued
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
- Triple (Participant, Care Provider, Investigator)
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
- •≥ 18 year old males or females
- •Patients with recurrent or metastatic renal cell carcinoma (RCC) or primary RCC that is not amendable to surgical intervention
- •Histologically or cytologically confirmed renal cell carcinoma
- •Measurable disease
- •No more than one prior systemic treatment (chemotherapy or immunotherapy) for RCC.
- •No active brain metastases
- •Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months
- •No childbearing potential, or use of effective contraception during the study and for 4 weeks after the last dose of study drug
- •Archival paraffin embedded tumor tissue, if available.
- •Ability to give written informed consent
排除标准
- •Pregnant or lactating women
- •Primary CNS malignancies; active CNS metastases
- •Hematologic malignancies (includes: leukemia, any form; lymphoma; and multiple myeloma)
- •Any of the following hematologic abnormalities:
- •Hemoglobin ≤ 9.0 g/dL
- •ANC < 1500 per mm3
- •Platelet count < 100,000 per mm3
- •Any of the following serum chemistry abnormalities:
- •Total bilirubin > 1.5 × the ULN
- •AST or ALT ≥ 2.5 × the ULN
- •Serum albumin < 3.0 g/dL
- •Creatinine > 1.7 × ULN (or calculated CLCR <50 mL/min/1.73 m2)
- •Proteinuria > 2.5 g/24 hours or 4+ with urine dipstick
- •Significant cardiovascular disease, including:
- •Active clinically symptomatic left ventricular failure
- •Active HTN (diastolic blood pressure > 100 mmHg). Patients with a history of hypertension must have been on stable doses of anti-hypertensive drugs for ≥ 4 weeks
- •Uncontrolled hypertension: Blood pressure >140/90 mmHg on more than 2 antihypertensive medications.
- •Myocardial infarction within 3 months prior to administration of first study dose
- •Unhealed wounds (including active gastric ulcers)
- •Serious/active infection; infection requiring parenteral antibiotics
- •Inadequate recovery from prior antineoplastic therapy
- •Inadequate recovery from any prior surgical procedure; major surgical procedure within 4 weeks prior to study entry
- •Life-threatening illness or organ system dysfunction compromising safety evaluation
- •Psychiatric disorder, altered mental status precluding informed consent or necessary testing
- •Inability to comply with protocol requirements
研究组 & 干预措施
1
Tivozanib (AV-951) administered as a solid dosage form daily for three weeks per month
干预措施: Tivozanib (AV-951) (Drug)
2
solid oral capsule containing excipients dosed daily for three weeks per month
干预措施: Placebo comparator (Drug)
结局指标
主要结局
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs)
时间窗: 28 weeks after study entry
To determine the safety and tolerability of tivozanib (AV-951) with the protocol-specified dose schedule
Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population)
时间窗: 16 weeks after study entry
The ORR is defined as the rate of (CR+PR). Objective response rates following the 16-week, open-label period (investigator assessment and IRR assessment) were estimated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and was assessed by magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Overall Response (OR) = CR + PR.
Percentage of Randomly Assigned Subjects Remaining Progression Free at 12 Weeks Following Random Assignment to Tivozanib (AV-951) or Placebo
时间窗: 28 weeks after study entry
Percentages of subjects remaining progression-free at 12 weeks post-randomization were compared across the 2 treatment arms in the ITT population. A Cochran-Mantel- Haenszel (CMH) test of general association was used, stratifying by country to evaluate the null hypothesis that treatment arm is not associated with subjects remaining progression-free. Non-completers were treated as failures. Progression is defined using RECIST v1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
次要结局
- Overall Progression-free Survival (From Start of Treatment)(12 months from study entry)
- Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization )(28 weeks from study entry)
- Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects(Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose)
- Maximum Observed Serum Concentration During a Dosing Interval at Steady State (Cmax)(Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose)
- Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)](28 weeks from study entry)