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