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
Primary Purpose
Renal Cell Carcinoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
tivozanib (AV-951) plus temsirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Renal Cell Carcinoma focused on measuring tivozanib, AV-951
Eligibility Criteria
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
Sites / Locations
- UCLA Jonsson Comprehensive Cancer Center
- Stanford University
- H. Lee Moffitt Cancer Center
- Nebraska Methodist Hospital
- The Methodist Hospital Research Institute
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
A
Arm Description
tivozanib (AV-951) plus temsirolimus
Outcomes
Primary Outcome Measures
To determine the safety and tolerability of tivozanib (AV-951) when given in combination with temsirolimus
Secondary Outcome Measures
To characterize the pharmacokinetic profile of tivozanib (AV-951) and temsirolimus when administered in combination
To evaluate the antineoplastic activity of tivozanib (AV-951) and temsirolimus when administered in combination
To evaluate the effect of tivozanib (AV-951) and temsirolimus on global and targeted gene expression patterns
To determine the maximum tolerated dose (MTD) of tivozanib (AV-951) when administered in combination with temsirolimus
Full Information
NCT ID
NCT00563147
First Posted
November 21, 2007
Last Updated
September 30, 2011
Sponsor
AVEO Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT00563147
Brief 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
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 Type
Interventional
2. Study Status
Record Verification Date
September 2011
Overall Recruitment Status
Completed
Study Start Date
November 2007 (undefined)
Primary Completion Date
November 2010 (Actual)
Study Completion Date
February 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AVEO Pharmaceuticals, Inc.
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma
Keywords
tivozanib, AV-951
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Experimental
Arm Description
tivozanib (AV-951) plus temsirolimus
Intervention Type
Drug
Intervention Name(s)
tivozanib (AV-951) plus temsirolimus
Other Intervention Name(s)
Torisel (temsirolimus)
Intervention Description
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
Primary Outcome Measure Information:
Title
To determine the safety and tolerability of tivozanib (AV-951) when given in combination with temsirolimus
Time Frame
4 weeks (1 cycle)
Secondary Outcome Measure Information:
Title
To characterize the pharmacokinetic profile of tivozanib (AV-951) and temsirolimus when administered in combination
Time Frame
8 weeks (2 cycles)
Title
To evaluate the antineoplastic activity of tivozanib (AV-951) and temsirolimus when administered in combination
Time Frame
8 weeks (2 cycles)
Title
To evaluate the effect of tivozanib (AV-951) and temsirolimus on global and targeted gene expression patterns
Time Frame
8 weeks (2 cycles)
Title
To determine the maximum tolerated dose (MTD) of tivozanib (AV-951) when administered in combination with temsirolimus
Time Frame
4 weeks (1 cycle)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joshua Zhang, M.D.
Organizational Affiliation
AVEO Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
UCLA Jonsson Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
H. Lee Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Nebraska Methodist Hospital
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68114
Country
United States
Facility Name
The Methodist Hospital Research Institute
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
23726267
Citation
Fishman MN, Srinivas S, Hauke RJ, Amato RJ, Esteves B, Cotreau MM, Strahs AL, Slichenmyer WJ, Bhargava P, Kabbinavar FF. Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. Eur J Cancer. 2013 Sep;49(13):2841-50. doi: 10.1016/j.ejca.2013.04.019. Epub 2013 May 28.
Results Reference
derived
Learn more about this trial
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
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