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