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

AVEO Pharmaceuticals

Status and phase

Completed

Phase 1

Conditions

Renal Cell Carcinoma

Treatments

Drug: tivozanib (AV-951) plus temsirolimus

Study type

Interventional

Funder types

Industry

Identifiers

NCT00563147

AV-951-07-102

Details and patient eligibility

About

The purpose of this study is to test the safety and tolerability of tivozanib (AV-951) and Torisel™ given in combination for renal cell cancer. The study will also assess the effects of the combination of tivozanib (AV-951) and Torisel™ on the tumor. Tivozanib (AV-951) is a VEGF-receptor tyrosine kinase inhibitor, and may stop the growth of tumor cells by blocking blood flow to the tumor. Temsirolimus is an mTOR inhibitor which is approved for the treatment of advanced renal cell carcinoma.

Full description

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.

Enrollment

28 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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