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

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

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