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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

Phase 1
18 Years
Not Enrolling
Renal Cell Carcinoma

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Trial Information

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

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.

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

- 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

- 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

Type of Study:


Study Design:

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

Outcome Measure:

To determine the safety and tolerability of tivozanib (AV-951) when given in combination with temsirolimus

Outcome Time Frame:

4 weeks (1 cycle)

Safety Issue:


Principal Investigator

Joshua Zhang, M.D.

Investigator Role:

Study Director

Investigator Affiliation:

AVEO Pharmaceuticals


United States: Food and Drug Administration

Study ID:




Start Date:

November 2007

Completion Date:

February 2011

Related Keywords:

  • Renal Cell Carcinoma
  • tivozanib
  • AV-951
  • Carcinoma, Renal Cell
  • Carcinoma



Stanford UniversityStanford, California  94305
Nebraska Methodist HospitalOmaha, Nebraska  68114
H. Lee Moffitt Cancer CenterTampa, Florida  33612
The Methodist Hospital Research InstituteHouston, Texas  77030
UCLA Jonsson Comprehensive Cancer CenterLos Angeles, California  90095