Bevacizumab, Sorafenib Tosylate, and Temsirolimus in Treating Patients With Metastatic Kidney Cancer

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Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIBiomarker/Laboratory analysis, TreatmentClosed18 and overNCINCI-2009-00533
CDR0000499788, E2804, U10CA180820, U10CA021115, ECOG-E2804, NCT00378703

Trial Description


This randomized phase II trial studies different combinations of bevacizumab, temsirolimus, and sorafenib tosylate to see how well they work compared with bevacizumab alone in treating patients with metastatic kidney cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab and sorafenib tosylate may stop the growth of tumor cells by blocking blood flow to the tumor. Temsirolimus and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving different combinations of bevacizumab, sorafenib tosylate, and temsirolimus may be more effective than bevacizumab alone in treating metastatic kidney cancer.

Further Study Information


I. To assess progression-free survival on each arm of combination targeted therapy (CTT) compared to that of bevacizumab alone.


I. To assess the significance of changes in tumor size over early time points as a predictor of progression-free survival (PFS).

II. To quantify the number and percent of patients who have stable disease at 6 months of therapy (failure to progress) in each treatment arm of CTT in patients with metastatic renal cell carcinoma (RCC).

III. To evaluate the safety of each treatment arm of CTT in patients with metastatic RCC.

IV. To assess overall survival in each arm of the study. V. To assess the objective response rate in each treatment arm of CTT in patients with metastatic RCC.

VI. To assess pathology, angiogenesis histology and to assess activation status of mitogen activated protein (MAP) kinase and vascular endothelial growth factor receptor 2 (VEGFR2) pathways and relate to clinical outcome.


I. To analyze the pharmacokinetic and pharmacogenetic properties of sorafenib (sorafenib tosylate) including angiogenesis, monooxygenases polymorphisms and multi-drug resistance (MDR).

II. To relate changes in tumor perfusion and vascular permeability on serial dynamic contrast-enhanced magnetic resonance imaging (MRI) to clinical outcome and radiologic regression detected by other standard methods.

III. To assess the potential of dynamic contrast-enhanced (DCE)-MRI imaging as a biomarker for response to therapy and/or as a prognostic indicator of disease progression.

IV. To assess site readiness and ability in acquiring DCE-MRI data. V. To determine the relationship between tumor and blood biomarkers and clinical outcomes of patients treated with the combination of targeted agents.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM A: Patients receive bevacizumab 10 mg/kg intravenously (IV) over 30-90 minutes on days 1 and 15.

ARM B: Patients receive temsirolimus 25 mg IV over 30 minutes on days 1, 8, 15, and 22 and bevacizumab as in Arm A.

ARM C: Patients receive bevacizumab 5 mg/kg IV over 30-90 minutes on days 1 and 15 and sorafenib tosylate 200 mg orally (PO) twice daily (BID) on days 1-5, 8-12, 15-19, and 22-26.

ARM D: Patients receive sorafenib tosylate 200 mg PO BID on days 1-28 and temsirolimus as in Arm B.

In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 5 years.

Eligibility Criteria

Inclusion Criteria:

  • Clear cell variant of renal cell carcinoma with less than 25% of any other histology (including, but not limited to, papillary or chromophobe or oncocytic); there must be histologic confirmation by treating center of either primary or metastatic lesion
  • Measurable metastatic disease that is not curable by standard radiation therapy or surgery; all sites must be assessed within 4 weeks prior to study entry
  • Previous nephrectomy is required with the following exceptions:
  • Primary tumor =< 5 cm, or
  • Extensive liver (> 30% of liver parenchymal) or multiple (> 5) bone metastases, making nephrectomy a clinically questionable procedure
  • Unresectable primary tumor due to invasion into adjacent organs or encasing the aorta or vena cava
  • Prior radiation therapy is permitted, but toxicities from radiation must have resolved and a minimum of 2 weeks must pass prior to randomization
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy of greater than 12 weeks
  • Hemoglobin (Hgb) >= 9.0 g/dL (transfusions allowed prior to enrollment)
  • White blood count (WBC) >= 3,000/mm^3
  • Absolute granulocyte count (AGC) >= 1,200/mm^3
  • Platelet count >= 100,000/mm^3
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 55 ml/min
  • Total bilirubin =< 1.5 x ULN
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (or =< 5.0 x ULN in the presence of liver metastases)
  • International normalized ratio (INR) =< 1.5
  • Fasting cholesterol < 350 mg/dL (9.0 mmol/L)
  • Fasting triglycerides < 400 mg/dL (4.56 mmol/L)
  • Patients with hypertension and blood pressure =< 150/100 mm/Hg on stable antihypertensive regimen are eligible

Exclusion Criteria:

  • Prior cytotoxic chemotherapy; a maximum of one prior regimen of either vaccine or cytokine-based immunotherapy disease is permitted
  • Prior anti-angiogenic therapy including, but not limited to, SU11248, ZD6474 or VEGF Trap;
  • Prior therapy with bevacizumab, mammalian target of rapamycin (mTOR) inhibitors (including, but not limited to, temsirolimus), or sorafenib; thalidomide or interferon alpha (IFNalpha) are allowed either for adjuvant therapy or stage IV disease
  • Immunotherapy within 4 weeks of randomization; toxicities from immunotherapy must have resolved and a minimum of two weeks must pass prior to enrollment
  • History or clinical evidence of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastasis, or history of stroke within the past 48 weeks
  • Other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for >= 5 years prior to the time of randomization
  • History of allergic reactions attributed to Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biologic composition to sorafenib, temsirolimus or bevacizumab
  • History of bleeding diathesis or coagulopathy
  • Any condition that impairs patient's ability to swallow pills
  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization
  • Anticipated need for major surgery during the course of the study
  • Current or recent (within 4 weeks of enrollment) use of full-dose of anticoagulants or thrombolytic agents (except as required to maintain patency of preexisting or permanent indwelling IV catheters, for those patients receiving warfarin, INR must be =< 1.5)
  • Clinically significant cardiovascular disease, defined as one of the following:
  • Uncontrolled hypertension (blood pressure > 150/100 mm/Hg at the time of enrollment);
  • Myocardial infarction or unstable angina < 24 weeks prior to registration
  • New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris
  • Grade II or greater peripheral vascular disease
  • Serious, non-healing wound, ulcer, or bone fracture
  • Significant proteinuria at baseline; urine protein must be screened within 2 weeks prior to randomization by urine analysis for urine protein creatinine (UPC) ratio; if UPC ratio is > 0.5, 24-hour urine protein is to be obtained and the level must be < 1000 mg for patient enrollment
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics on day 0 or psychiatric illness/social situations that would limit compliance with study requirements
  • Patients currently taking any of the following cytochrome P450 enzyme-inducing drugs are ineligible:
  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Rifampin
  • Pregnant or breastfeeding
  • Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

    Keith Flaherty, M.D., Study Chair

    Link to the current record.
    NLM Identifier NCT00378703 processed this data on May 04, 2015

    Note: Information about this trial is from the database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the record to standardize the names of study sponsors, sites, and contacts. only lists sites that are recruiting patients for active trials, whereas lists all sites for all trials. Questions and comments regarding the presented information should be directed to