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

This is a Phase 1b, open-label, dose-finding study of tivozanib (AV-951) in combination with temsirolimus to include approximately 36 subjects with metastatic renal cell carcinoma (mRCC). This study is designed to evaluate the safety, tolerability, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic, pharmacogenomic, and antineoplastic activity of tivozanib (AV-951) when administered in combination with temsirolimus. Tivozanib (AV-951) will be administered once daily for 3 weeks beginning on Day 1 of Cycle 1, followed by 1 week off (1 cycle = 4 weeks). Temsirolimus will be administered intravenously once weekly starting on Day 8 of Cycle 1.

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