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

This is a Phase 2, open-label, single arm, multi-center, study of orally administered tivozanib to approximately 100 subjects with advanced renal cell carcinoma (RCC). This study is designed to evaluate biomarkers in blood and archived tissue samples, and their correlation with clinical activity and/or treatment-related toxicity in subjects with advanced RCC, and estimate the percentage of tivozanib-treated subjects who are progression-free at 6 months, overall response rate (ORR), progression free survival (PFS), safety and tolerability, and pharmacokinetics (PK). Subjects will be stratified by histology (clear cell vs. non-clear cell). Enrollment of non-clear cell subjects will be limited to ≤ 30% of the entire study population.

Study enrollment is anticipated to complete in approximately 9 months. Treatment duration is estimated to last approximately 6 months from the subject's first dose of tivozanib with a follow-up period of 30 days. After 6 months, treatment with tivozanib may continue by participation in a rollover protocol (AV-951-09-901). Maximum duration of subject participation in this Phase 2 study is approximately 8 months.

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 < 9.0 g/dL
• Absolute neutrophil count (ANC) < 1500 per mm3
• Platelet count < 100,000 per mm3
• International Normalized Ratio >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 attack (TIA)
• Peripheral arterial ischemia > Grade 2 (per CTCAE Version 3.0)
• Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to.

• Hematemesis, hematochezia, melena or other gastrointestinal bleeding Grade 2 (per CTCAE Version 3.0)
• Hemoptysis or other pulmonary bleeding Grade 2 (per CTCAE Version 3.0)
• Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast. Subjects are not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for >2 years.
• Pregnant or lactating females.
• History of genetic or acquired immune suppression disease such as HIV; subjects on immune suppressive therapy for organ transplant.
• Life-threatening illness or organ system dysfunction compromising safety evaluation.
• Requirement for hemodialysis or peritoneal dialysis.
• Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of tivozanib, major resection of the stomach or small bowel, or gastric bypass procedure.
• Psychiatric disorder or altered mental status precluding informed consent or protocol-related testing.
• Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug. All fertile male and female subjects must agree to use a highly effective method of contraception (including their partner). Effective birth control includes:

• intrauterine device plus one barrier method or 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). (Note: Oral,implantable, or injectable contraceptives