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

September 30, 2011 updated by: AVEO Pharmaceuticals, Inc.
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

28

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90095
        • UCLA Jonsson Comprehensive Cancer Center
      • Stanford, California, United States, 94305
        • Stanford University
    • Florida
      • Tampa, Florida, United States, 33612
        • H. Lee Moffitt Cancer Center
    • Nebraska
      • Omaha, Nebraska, United States, 68114
        • Nebraska Methodist Hospital
    • Texas
      • Houston, Texas, United States, 77030
        • The Methodist Hospital Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • Torisel (temsirolimus)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AVEO Pharmaceuticals, Inc.

Investigators

  • Study Director: Joshua Zhang, M.D., AVEO Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2007

Primary Completion (Actual)

November 1, 2010

Study Completion (Actual)

February 1, 2011

Study Registration Dates

First Submitted

November 21, 2007

First Submitted That Met QC Criteria

November 21, 2007

First Posted (Estimate)

November 26, 2007

Study Record Updates

Last Update Posted (Estimate)

October 4, 2011

Last Update Submitted That Met QC Criteria

September 30, 2011

Last Verified

September 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AV-951-07-102

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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