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

• To determine the safety of tivozanib (AV-951) with this dose schedule [ Time Frame: 28 weeks after study entry ] [ Designated as safety issue: Yes ]
• To determine objective response (CR + PR) rate at 16 weeks [ Time Frame: 16 weeks after study entry ] [ Designated as safety issue: No ]
• To determine the percentage of randomly assigned patients remaining progression free at 12 weeks following random assignment to tivozanib (AV-951) or placebo [ Time Frame: 28 weeks after study entry ] [ Designated as safety issue: No ]

• Determine the progression free-survival after random assignment (randomized sub-set only) [ Time Frame: 28 weeks from study entry ] [ Designated as safety issue: No ]
• Overall progression-free survival (from start of treatment) [ Time Frame: 12 months from study entry ] [ Designated as safety issue: No ]
• Characterization of pharmacokinetic and pharmacodynamic (PD) profiles of tivozanib (AV-951) in a subset of patients [ Time Frame: 28 weeks from study entry ] [ Designated as safety issue: No ]

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.

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

• Drug: Tivozanib (AV-951)
  solid oral dosage form taken daily for three weeks per one month cycle
• Drug: Placebo comparator
  solid oral capsule containing excipients dosed daily for three weeks per month

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

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