Tivozanib Before Surgery in Treating Patients With Localized Kidney Cancer

PRIMARY OBJECTIVES:

I. To assess the feasibility of conducting a trial of tivozanib in the neoadjuvant setting
of localized (completely resectable) renal cell cancer (RCC).

SECONDARY OBJECTIVES:

I. To evaluate the safety of tivozanib in the neoadjuvant setting. II. To compare the tissue
before and after tivozanib for pharmacodynamic purposes (tumor infiltrating lymphocytes,
myeloid derived suppressor cells, necrosis in the primary tumor after exposure to
tivozanib).

III. To assess the overall response rate of tivozanib in primary tumors and correlate the
radiographic changes, if any, to histo-pathological changes in the pathology specimen
post-nephrectomy.

IV. To compare the various growth factors (vascular endothelial growth factor [VEGF],
interleukin-8 [IL-8], placenta growth factor [P1GF]) at baseline and post treatment.

V. To assess the nephrectomy rate after applying neoadjuvant tivozanib in this primarily
resectable RCC population.

OUTLINE:

Patients receive tivozanib orally (PO) once daily (QD) on days 1-21. Treatment repeats every
28 days for 2 courses in the absence of disease progression or unacceptable toxicity. 25
days after completion of tivozanib, patients undergo curative nephrectomy.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Biopsy proven non-metastatic clear cell RCC, as per radiographic studies is T2 - T3a
based on the American Joint Committee on Cancer (AJCC) 6th edition criteria

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

- Hemoglobin >= 10 gm/dL

- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L

- Platelets >= 100 X 10^9/L

- Total bilirubin < 1.5 X upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN

- International normalization ratio (INR) < 1.5

- Activated partial thromboplastin time (aPTT) < 1.2 X ULN

- Serum creatinine < 1.5 mg/dL or if >= 1.5 mg/dL: calculated creatinine clearance
(CrCL) > 30 mL/min based on Cockroft-Gault formula

- Must have the ability to swallow and retain oral medication

- Patients of childbearing potential must agree to use acceptable contraceptive methods
(e.g., double barrier) during treatment

- Patient or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Pregnant or nursing female patients

- Unwilling or unable to follow protocol requirements

- Any condition which in the Investigator's opinion deems the patient an unsuitable
candidate to receive tivozanib (solitary kidney, multiple tumors in the same or
contralateral kidney)

- Not a candidate for surgery

- Received an investigational agent within 30 days prior to enrollment

- Non-clear cell or sarcomatoid histology

- Patients with metastatic disease at presentation

- Prior therapy with tyrosine kinase inhibitor for RCC

- A second primary malignancy (except squamous and basal cell carcinoma of skin) in the
past 3 years

- Active or chronic infections

- Significant cardiovascular disease, including:

- Clinically symptomatic left ventricular failure

- Uncontrolled hypertension: systolic blood pressure of > 150 mmHg or diastolic
blood pressure of > 100 mmHg documented on 2 consecutive measurements taken at
least 24 hours apart

- Myocardial infarction, severe angina, or unstable angina within 6 months prior
to administration of first dose of tivozanib

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation)

- Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial
fibrillation that is well controlled with anti-arrhythmic medication)

- Coronary or peripheral artery bypass graft within 6 months of screening

- History of coronary artery disease or peripheral arterial disease

- History of stroke or carotid endarterectomy

- Patients who are taking cytochrome P450 system (CYP)3A4 inducers are excluded;
patients taking CYP3A4 inducers that can be safely replaced with another agent may be
enrolled after a 5 day washout period