Phase 1/2 Study of Tivozanib in Combination With Nivolumab in Subjects With RCC

Inclusion Criteria:

1. ≥ 18-year-old
2. Histologically or cytologically documented renal cell carcinoma with a clear cell component, except in Phase 1b, where any histology will be permitted
3. Metastatic renal cell carcinoma. Measurable or evaluable disease by RECIST 1.1 criteria
4. No prior exposure to tivozanib or nivolumab
5. ECOG performance status ≤ 1 (see Appendix A) and life expectancy ≥ 3 months.
6. Signed and dated written informed consent
7. Sexually active pre-menopausal female subjects and female partners of male subjects must use adequate contraceptive measures, while on study and for at least 160 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 160 days after the last dose of study drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; or (b) 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 may be affected by cytochrome P450 interactions, and are not considered effective for this study.

Exclusion Criteria:

1. Pregnant or lactating women.
2. Subjects with symptomatic CNS metastases. Subjects with treated brain metastases that have remained stable for at least 3 months without steroids are allowed. Subjects with signs or symptoms or history of brain metastasis must have a CT or MRI scan of the brain within 1 month prior to the start of protocol therapy. Subjects with spinal cord or nerve root compression who have completed treatment at least 4 weeks before the start of protocol therapy and are stable without steroid treatment for at least one week before start of protocol therapy are allowed. Subjects with leptomeningeal metastases are not allowed.
3. Any of the following hematologic abnormalities:

   * Hemoglobin \< 9.0 g/dL
   * ANC \< 1500 per mm3
   * Platelet count \< 100,000 per mm3
4. Any of the following serum chemistry abnormalities:

   * Total bilirubin \> 1.5 × ULN (\>2.5 mg/dL in patients with Gilbert's syndrome)
   * AST or ALT \> 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)
   * Serum creatinine \> 1.5 × ULN
   * Proteinuria \> 2.5 g/24 hours or 3+ with urine dipstick
   * Any other ³ Grade 3 laboratory abnormality at baseline (other than those listed above)
5. Significant cardiovascular disease, including:

   * Clinically symptomatic heart failure. Subjects with a history of heart failure must have an ECHO or MUGA scan to document left ventricular ejection fraction (LVEF) \> 45% prior to start of protocol therapy
   * Uncontrolled hypertension: blood pressure \>150/95 mmHg on more than 2 antihypertensive medications, on two consecutive measurements obtained at least 24 hours apart. Subjects with a history of hypertension must have been on stable doses of anti-hypertensive drugs for ≥ 2 weeks prior to start of protocol therapy.
   * Myocardial infarction within 3 months prior to start of protocol therapy
6. Subjects with delayed healing of wounds, ulcers, and/or bone fractures
7. Serious/active infection or infection requiring parenteral antibiotics
8. Inadequate recovery from any prior surgical procedure; major surgical procedure within 4 weeks prior to start of protocol therapy.
9. Inability to comply with protocol requirements
10. Subjects with a "currently active" second primary malignancy other than non-melanoma skin cancers. 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.
11. Known concomitant genetic or acquired immune suppression disease such as HIV
12. Treatment with systemic hormonal therapy within 3 weeks prior to start of protocol therapy, with the exception of:

    * Hormonal therapy for appetite stimulation or contraception
    * Nasal, ophthalmic, inhaled and topical steroid preparations
    * Oral replacement therapy for adrenal insufficiency
    * Low-dose maintenance steroid therapy (equivalent of prednisone 10mg/day) for other conditions
    * Hormone replacement therapy
13. Herbal preparations/supplements (except for a daily multivitamin/mineral supplement not containing herbal components) or CYP3A4 inhibitors or inducers (see Appendix B) within 2 weeks prior to start of or during protocol therapy.