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

Renal Cell Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00563147
• Other study ID #: AV-951-07-102
• Status: Completed
• Phase: Phase 1
• First received: November 21, 2007
• Last updated: September 30, 2011
• Start date: November 2007
• Est. completion date: February 2011

Study information

• Verified date: September 2011
• Source: AVEO Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: February 2011
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Renal Cell Carcinoma

Intervention

Drug:
• tivozanib (AV-951) plus temsirolimus
ascending doses of tivozanib (AV-951) capsules administered orally for 21 days with discontinuation for 7 days; ascending doses of temsirolimus administered intravenously every 7 days

Locations

Country	Name	City	State
United States	The Methodist Hospital Research Institute	Houston	Texas
United States	UCLA Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Stanford University	Stanford	California
United States	H. Lee Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AVEO Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the safety and tolerability of tivozanib (AV-951) when given in combination with temsirolimus		4 weeks (1 cycle)	Yes
Secondary	To characterize the pharmacokinetic profile of tivozanib (AV-951) and temsirolimus when administered in combination		8 weeks (2 cycles)	No
Secondary	To evaluate the antineoplastic activity of tivozanib (AV-951) and temsirolimus when administered in combination		8 weeks (2 cycles)	No
Secondary	To evaluate the effect of tivozanib (AV-951) and temsirolimus on global and targeted gene expression patterns		8 weeks (2 cycles)	No
Secondary	To determine the maximum tolerated dose (MTD) of tivozanib (AV-951) when administered in combination with temsirolimus		4 weeks (1 cycle)	Yes