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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00563147
Recruitment Status : Completed
First Posted : November 26, 2007
Last Update Posted : October 4, 2011
Information provided by (Responsible Party):
AVEO Pharmaceuticals, Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Drug: tivozanib (AV-951) plus temsirolimus Phase 1

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : November 2007
Actual Primary Completion Date : November 2010
Actual Study Completion Date : February 2011

Arm Intervention/treatment
Experimental: A
tivozanib (AV-951) plus temsirolimus
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
Other Name: Torisel (temsirolimus)

Primary Outcome Measures :
  1. To determine the safety and tolerability of tivozanib (AV-951) when given in combination with temsirolimus [ Time Frame: 4 weeks (1 cycle) ]

Secondary Outcome Measures :
  1. To characterize the pharmacokinetic profile of tivozanib (AV-951) and temsirolimus when administered in combination [ Time Frame: 8 weeks (2 cycles) ]
  2. To evaluate the antineoplastic activity of tivozanib (AV-951) and temsirolimus when administered in combination [ Time Frame: 8 weeks (2 cycles) ]
  3. To evaluate the effect of tivozanib (AV-951) and temsirolimus on global and targeted gene expression patterns [ Time Frame: 8 weeks (2 cycles) ]
  4. To determine the maximum tolerated dose (MTD) of tivozanib (AV-951) when administered in combination with temsirolimus [ Time Frame: 4 weeks (1 cycle) ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00563147

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United States, California
UCLA Jonsson Comprehensive Cancer Center
Los Angeles, California, United States, 90095
Stanford University
Stanford, California, United States, 94305
United States, Florida
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Nebraska
Nebraska Methodist Hospital
Omaha, Nebraska, United States, 68114
United States, Texas
The Methodist Hospital Research Institute
Houston, Texas, United States, 77030
Sponsors and Collaborators
AVEO Pharmaceuticals, Inc.
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Study Director: Joshua Zhang, M.D. AVEO Pharmaceuticals
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AVEO Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00563147    
Other Study ID Numbers: AV-951-07-102
First Posted: November 26, 2007    Key Record Dates
Last Update Posted: October 4, 2011
Last Verified: September 2011
Keywords provided by AVEO Pharmaceuticals, Inc.:
Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Kidney Diseases
Urologic Diseases
Male Urogenital Diseases
MTOR Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic