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

Primary Purpose

Carcinoma, Renal Cell

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tivozanib (AV-951)
Placebo comparator
Sponsored by
AVEO Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Carcinoma, Renal Cell focused on measuring Renal Cell Carcinoma, AV-951, tivozanib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

1

2

Arm Description

Tivozanib (AV-951) administered as a solid dosage form daily for three weeks per month

solid oral capsule containing excipients dosed daily for three weeks per month

Outcomes

Primary Outcome Measures

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
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.
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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
July 16, 2007
Last Updated
August 17, 2020
Sponsor
AVEO Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00502307
Brief Title
A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma
Official Title
A Phase 2, Placebo-Controlled, Randomized, Discontinuation Trial of Tivozanib (AV-951) in Patients With Renal Cell Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
October 2007 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
August 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AVEO Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Renal Cell
Keywords
Renal Cell Carcinoma, AV-951, tivozanib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
272 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Tivozanib (AV-951) administered as a solid dosage form daily for three weeks per month
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
solid oral capsule containing excipients dosed daily for three weeks per month
Intervention Type
Drug
Intervention Name(s)
Tivozanib (AV-951)
Intervention Description
solid oral dosage form taken daily for three weeks per one month cycle
Intervention Type
Drug
Intervention Name(s)
Placebo comparator
Intervention Description
solid oral capsule containing excipients dosed daily for three weeks per month
Primary Outcome Measure Information:
Title
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs)
Description
To determine the safety and tolerability of tivozanib (AV-951) with the protocol-specified dose schedule
Time Frame
28 weeks after study entry
Title
Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population)
Description
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.
Time Frame
16 weeks after study entry
Title
Percentage of Randomly Assigned Subjects Remaining Progression Free at 12 Weeks Following Random Assignment to Tivozanib (AV-951) or Placebo
Description
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.
Time Frame
28 weeks after study entry
Secondary Outcome Measure Information:
Title
Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization )
Description
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 Frame
28 weeks from study entry
Title
Overall Progression-free Survival (From Start of Treatment)
Description
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.
Time Frame
12 months from study entry
Title
Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects
Description
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.
Time Frame
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
Title
Maximum Observed Serum Concentration During a Dosing Interval at Steady State (Cmax)
Description
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.
Time Frame
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
Title
Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)]
Description
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.
Time Frame
28 weeks from study entry

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dmitriy G Nosov, M.D.
Organizational Affiliation
Russian Oncological Research Center n.a. N.N. Blokhin of the Russian Academy of Medical Sciences
Official's Role
Principal Investigator
Facility Information:
City
Vellore
State/Province
Tamil Nadu
ZIP/Postal Code
632004
Country
India
City
Kolkata
Country
India
City
Mumbai
Country
India
City
New Delhi
Country
India
City
Pune
Country
India
City
Astrakhan
Country
Russian Federation
City
Ioshkar-Ola
Country
Russian Federation
City
Kazan
Country
Russian Federation
City
Moscow
ZIP/Postal Code
125284
Country
Russian Federation
City
Moscow
ZIP/Postal Code
129128
Country
Russian Federation
City
Moscow
Country
Russian Federation
City
Novgorod
Country
Russian Federation
City
Obninsk
Country
Russian Federation
City
Pyatigorsk
Country
Russian Federation
City
Rostove-on-Don
Country
Russian Federation
City
Sochi
Country
Russian Federation
City
St. Petersburg
Country
Russian Federation
City
Tomsk
Country
Russian Federation
City
Ufa
Country
Russian Federation
City
Cherkassy
Country
Ukraine
City
Dnepropetrovsk
Country
Ukraine
City
Donetsk
Country
Ukraine
City
Kharkov
Country
Ukraine
City
Lviv
Country
Ukraine
City
Uzhgorod
Country
Ukraine
City
Zaporizzhya
Country
Ukraine

12. IPD Sharing Statement

Learn more about this trial

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

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