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

Phase 2

Completed

• Conditions: Carcinoma, Renal Cell
• Interventions: Drug: Placebo comparator; Drug: Tivozanib (AV-951)

• Registration Number: NCT00502307
• Lead Sponsor: AVEO Pharmaceuticals, Inc.

Brief Summary

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

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

Study Timeline

• Study First Submitted: 2007-07-16
• Study First Submitted QC: 2007-07-16
• Study First Posted: 2007-07-17
• Study Start: 2007-10
• Primary Completion: 2010-08
• Study Completion: 2010-08
• Disposition First Submitted: 2012-06-01
• Disposition First Submitted QC: 2012-06-06
• Disposition First Posted: 2012-06-08
• Results First Submitted: 2020-07-06
• Status Verified: 2020-08
• Results First Submitted QC: 2020-08-17
• Last Update Submitted: 2020-08-17
• Results First Posted: 2020-09-01
• Last Update Posted: 2020-09-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 272

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Placebo comparator	solid oral capsule containing excipients dosed daily for three weeks per month
1	Tivozanib (AV-951)	Tivozanib (AV-951) administered as a solid dosage form daily for three weeks per month

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs)	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)	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	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.

Secondary Outcome Measures

Name	Time	Method
Overall Progression-free Survival (From Start of Treatment)	12 months from study entry	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.
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	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.
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	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.
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	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.
Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)]	28 weeks from study entry	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.