A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

Inclusion Criteria

• ≥ 18 year old males or females
• Subjects with unresectable locally recurrent or metastatic renal cell carcinoma (RCC)
• Histologically or cytologically confirmed clear cell renal cell carcinoma (≥ 50% clear cell) or non-clear cell RCC (all histologies)
• Subjects must have undergone prior nephrectomy (complete or partial) for excision of the primary tumor.
• Measurable disease per RECIST criteria Version 1.1 (see Appendix A)
• Treatment naïve subjects or subjects who have received no more than one prior systemic treatment (immunotherapy, including interferon-alfa or interleukin-2 based therapy, chemotherapy, hormonal therapy or an investigational agent) for metastatic RCC.
• Eastern Cooperative Oncology Group performance status of 0 or 1, and life expectancy ≥ 3 months
• If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment
• Willingness to provide archival paraffin embedded tumor tissue, if available.
• Ability to give written informed consent and comply with protocol requirements

Exclusion Criteria

• Any prior vascular endothelial growth factor (VEGF)-directed therapy including VEGF antibody (eg, bevacizumab), VEGF receptor tyrosine kinase inhibitor (eg, sunitinib, sorafenib, axitinib, pazopanib, etc.), VEGF trap (eg, aflibercept), or any other agent or investigational agent targeting the VEGF pathway.
• Any prior therapy with an agent targeting the mechanistic target of rapamycin pathway (eg, temsirolimus, everolimus, etc)
• Primary central nervous system (CNS) malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis have been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
• Any of the following hematologic abnormalities:
• Hemoglobin 1.5 or partial thromboplastin time >1.5 × upper limit of normal (ULN)
• Any of the following serum chemistry abnormalities:
• Total bilirubin > 1.5 × ULN (or > 2.5 × ULN for subjects with Gilbert's syndrome)
• Aspartate aminotransferase or alanine aminotransferase > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis)
• Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis)
• Creatinine > 2.0 × ULN
• Proteinuria > 3+ by urinalysis or urine dipstick
• Significant cardiovascular disease, including:
• Active clinically symptomatic left ventricular failure.
• Uncontrolled hypertension: Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on 2 or more antihypertensive medications, 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 study drug.
• History of serious ventricular arrhythmia (ie, 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
• Non-healing wound, bone fracture, or skin ulcer.
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug
• Serious/active infection or infection requiring parenteral antibiotics.
• Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
• Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to:
• Deep vein thrombosis
• Pulmonary embolism
• Cerebrovascular accident (CVA) or transient ischemic a