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