A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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A Phase 2, Placebo-Controlled, Randomized, Discontinuation Trial of Tivozanib (AV-951) in Patients With Renal Cell Carcinoma

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Tivozanib (AV-951)
* Drug: Placebo comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Tivozanib (AV-951) administered as a solid dosage form daily for three weeks per month | Drug: Tivozanib (AV-951)<br>* solid oral dosage form taken daily for three weeks per one month cycle<br>|
| Placebo Comparator: 2<br>solid oral capsule containing excipients dosed daily for three weeks per month | Drug: Placebo comparator<br>* solid oral capsule containing excipients dosed daily for three weeks per month<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) | To determine the safety and tolerability of tivozanib (AV-951) with the protocol-specified dose schedule | 28 weeks after study entry | 
| Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population) | 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. | 16 weeks after study entry | 
| Percentage of Randomly Assigned Subjects Remaining Progression Free at 12 Weeks Following Random Assignment to Tivozanib (AV-951) or Placebo | 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. | 28 weeks after study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization ) | PFS after randomization in the ITT population was described using the Kaplan-Meier methodology. PFS was compared across treatment arms using the log-rank test. | 28 weeks from study entry | 
| Overall Progression-free Survival (From Start of Treatment) | Number of subjects with Overall PFS (from start of treatment) was estimated using the Kaplan-Meier methodology. Subjects randomized to receive placebo were censored at randomization. Withdrawals are also censored. An alternative analysis was conducted in which PFS for subjects randomized to receive tivozanib was weighted more heavily to compensate for the information loss from randomization of other subjects to receive placebo. Additional analyses in which withdrawal was considered a PFS event were also conducted. | 12 months from study entry | 
| Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects | Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. | 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) | Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. | 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)] | Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. | 28 weeks from study entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Cell Carcinoma, AV-951, tivozanib