A Phase 1b, Open-Label, Dose-Finding Study to Evaluate the Safety of Tivozanib (AV-951) in Combination With Temsirolimus in Subjects With Metastatic Renal Cell Carcinoma

Inclusion Criteria: * ≥ 18-year-old males or females * Histologically confirmed renal cell carcinoma with a clear cell component * Documented progressive disease * Measurable disease by RECIST criteria * No more than 1 prior VEGF receptor targeted therapy; no prior treatment with temsirolimus or other drugs targeting the mTOR pathway * Karnofsky performance status \> 70%; life expectancy ≥ 3 months * Ability to give written informed consent Exclusion Criteria: * Known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component of the temsirolimus formulation * Primary CNS malignancies; active CNS metastases * Hematologic malignancies (including leukemia in 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: * Fasting serum cholesterol \> 350 mg/dL * Fasting triglycerides \> 400 mg/dL * Total bilirubin \> 1.5 × ULN * AST or ALT \> 2.5 × ULN (or \> 5 x ULN in subjects with liver metastasis) * Serum albumin \< 3.0 g/dL * Creatine \> 1.5 × ULN (or calculated CLCR \<50 mL/min/1.73 m2) * Proteinuria \> 2.5 g/24 hours or 3+ with urine dipstick * Significant cardiovascular disease, including: * Active clinically symptomatic left ventricular failure * Active hypertension (diastolic blood pressure \> 100 mmHg). Subjects 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 2 or more antihypertensive medications * Myocardial infarction within 3 months prior to administration of first dose of study drug * Subjects with delayed healing of wounds, ulcers, and/or bone fractures * Pulmonary hypertension or pneumonitis * Serious/active infection; infection requiring parenteral antibiotics * Inadequate recovery from any prior surgical procedure; major surgical procedure within 6 weeks prior to study entry * Uncontrolled psychiatric disorder, altered mental status precluding informed consent or necessary testing * Inability to comply with protocol requirements * Ongoing hemoptysis or history of clinically significant bleeding * Cerebrovascular accident within 12 months of study entry, or peripheral vascular disease with claudication on walking less than 1 block * Deep venous thrombosis or pulmonary embolus within 6 months of study entry and/or ongoing need for full-dose oral or parenteral anticoagulation * 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 are considered by their physician to be \< 30% risk of relapse. * Pregnant or lactating women * Known concomitant genetic or acquired immune suppression disease such as HIV Prohibited medications: * VEGF receptor (VEGFR) targeted therapy within 4 weeks prior to and during study * Other signal transduction inhibitors, monoclonal antibodies, etc., within 4 weeks prior to and during study * Immunotherapy or biological response modifiers within 4 weeks prior to and during study * Systemic hormonal therapy within 4 weeks prior to and during study, with the exception of: * Hormonal therapy for appetite stimulation or contraception * Nasal, ophthalmic, and topical glucocorticoid preparations * Oral replacement therapy for adrenal insufficiency * Low-dose maintenance steroid therapy for other conditions * Herbal preparations/supplements (except for a daily multivitamin/mineral supplement not containing herbal components) within 2 weeks prior to or during study * Any experimental therapy 4 weeks prior to and during study * Radiotherapy: * At least 2 weeks since prior local radiation therapy (ie, involving \<25% of bone marrow) at the time of study entry * At least 4 weeks since prior radiation therapy involving ≥ 25% of bone marrow * Treatment with CYP3A4 inducers or inhibitors during the study