Clinical trial NCT00502307: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Renal Cell
Keywords: Renal Cell Carcinoma
AV-951
tivozanib
Lead sponsor: AVEO Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2007-07-17
Enrollment: 272
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs)
timeFrame: 28 weeks after study entry
measure: Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population)
timeFrame: 16 weeks after study entry
measure: Percentage of Randomly Assigned Subjects Remaining Progression Free at 12 Weeks Following Random Assignment to Tivozanib (AV-951) or Placebo
timeFrame: 28 weeks after study entry
Secondary outcomes:
measure: Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization )
timeFrame: 28 weeks from study entry
measure: Overall Progression-free Survival (From Start of Treatment)
timeFrame: 12 months from study entry
measure: Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects
timeFrame: 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
measure: Maximum Observed Serum Concentration During a Dosing Interval at Steady State (Cmax)
timeFrame: 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
measure: Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)]
timeFrame: 28 weeks from study entry
Other outcomes:
Locations:
city: Vellore
country: India
state: Tamil Nadu
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
country: Russian Federation
city: Moscow
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
Study officials:
affiliation: Russian Oncological Research Center n.a. N.N. Blokhin of the Russian Academy of Medical Sciences
name: Dmitriy G Nosov, M.D.
role: PRINCIPAL_INVESTIGATOR
References: