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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00378703
First received: September 19, 2006
Last updated: July 23, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Clear Cell Renal Cell Carcinoma
Recurrent Renal Cell Cancer
Stage IV Renal Cell Cancer
Drug: sorafenib tosylate
Drug: temsirolimus
Biological: bevacizumab
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The BeST Trial: A Randomized Phase II Study of VEGF, RAF Kinase, and mTOR Combination Targeted Therapy (CTT) With Bevacizumab, Sorafenib and Temsirolimus in Advanced Renal Cell Carcinoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Time from randomization to clinical evidence of disease progression or death without progression, assessed up to 5 years ] [ Designated as safety issue: No ]
    Each combination therapy will also be evaluated in comparison to a historical control rate of 9 months using a one-sample exponential test with one-sided type I error of 10%.


Secondary Outcome Measures:
  • Incidence of serious adverse events, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after the last study procedure ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: From the date of entry on study, assessed up to 5 years ] [ Designated as safety issue: No ]
    Estimated on each arm and characterized using the method of Kaplan and Meier.

  • Objective response rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: From the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression, or until death without progression, assessed up to 6 months ] [ Designated as safety issue: No ]
  • Tumor burden, defined as the percent change in the sum of the longest diameter of target lesions from baseline [ Time Frame: Baseline to up to 5 years ] [ Designated as safety issue: No ]
    Mixed models will be used to examine these changes in tumor burden over time for each arm. If there is a high proportion of missing data at later time points, a joint model of survival or progression-free survival and tumor burden will be constructed using the method described by Schluchter.

  • Measures of angiogenesis, including microvessel density and the proportion of immature vessels [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association between these measures of angiogenesis and response will be examined using Fisher's exact test.

  • Level of mutation/activity indicators of epidermal growth factor receptor, VEGF, retrovirus-associated deoxyribonucleic acid sequence, v-raf-1 murine leukemia viral oncogene homolog 1 and phosphatidylinositol 3 kinase-protein kinase B pathways [ Time Frame: Baseline to up to 5 years ] [ Designated as safety issue: No ]
    To identify relationships among relevant indicators and clinical outcomes (e.g. objective response rate, 6-month PFS, overall PFS, overall survival) relationships will be summarized using contingency tables, box plots, and/or scatter plots. Correlations between molecular profiles and clinical outcome for combinations and individual agents will be sought across and within tumor types. Clinical outcomes for subsets of patients defined by the biomarker variables calculated using Kaplan-Meier curves, plotted in appropriate groupings, and tested for equality using log rank tests when appropriate.


Other Outcome Measures:
  • DCE-MRI parameters, including initial transfer coefficient (Ktrans) and the change in tumor Ktrans at the end of cycle one [ Time Frame: Up to day 28 of course 1 ] [ Designated as safety issue: No ]
    The predictive accuracy of Ktrans and change in Ktrans for time to progression will be estimated by constructing a time dependent receiver operating characteristic (ROC) curve.

  • DCE-MRI parameters, including initial Ktrans and the change in tumor Ktrans, assessed using kinetic analysis [ Time Frame: Up to day 28 of course 1 ] [ Designated as safety issue: No ]
    The predictive accuracy of Ktrans and change in Ktrans for time to progression will be estimated by constructing a time dependent ROC curve.


Enrollment: 363
Study Start Date: September 2007
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A (bevacizumab)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15.
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Correlative studies
Other Name: DCE-MRI
Experimental: Arm B (bevacizumab and temsirolimus)
Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and bevacizumab as in Arm A.
Drug: temsirolimus
Given IV
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Correlative studies
Other Name: DCE-MRI
Experimental: Arm C (bevacizumab and sorafenib tosylate)
Patients receive bevacizumab as in Arm A and sorafenib tosylate PO BID on days 1-5, 8-12, 15-19, and 22-26.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Correlative studies
Other Name: DCE-MRI
Experimental: Arm D (sorafenib tosylate and temsirolimus)
Patients receive sorafenib tosylate PO BID on days 1-28 and temsirolimus as in Arm B.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: temsirolimus
Given IV
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Correlative studies
Other Name: DCE-MRI

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients will be required to have the 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
  • Patients will be required to have 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
  • No prior cytotoxic chemotherapy; a maximum of one prior regimen of either vaccine or cytokine-based immunotherapy disease is permitted
  • No prior anti-angiogenic therapy including, but not limited to, SU11248, ZD6474 or VEGF Trap; no prior therapy with bevacizumab, mammalian target of rapamycin (mTOR) inhibitors (including, but not limited to, temsirolimus), or sorafenib will be allowed; thalidomide or interferon alpha (IFNalpha) are allowed either for adjuvant therapy or stage IV disease
  • No immunotherapy within 4 weeks of randomization; toxicities from immunotherapy must have resolved and a minimum of two weeks must pass prior to enrollment
  • Prior radiation therapy is permitted, but toxicities from radiation must have resolved and a minimum of 2 weeks must pass prior to randomization
  • No 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
  • 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
  • Activated partial thromboplastin time (aPTT) within normal limits
  • Fasting cholesterol < 350 mg/dL (9.0 mmol/L)
  • Fasting triglycerides < 400 mg/dL (4.56 mmol/L)
  • Patients must not have 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
  • No 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
  • No history of bleeding diathesis or coagulopathy
  • Any condition that impairs patient's ability to swallow pills will make patient ineligible
  • No major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization
  • No anticipated need for major surgery during the course of the study
  • No 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)
  • No clinically significant cardiovascular disease, defined as one of the following:

    • Patients with uncontrolled hypertension (blood pressure > 150/100 mm/Hg at the time of enrollment); patients with hypertension and blood pressure =< 150/100 mm/Hg on stable antihypertensive regimen are eligible
    • 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
  • No serious, non-healing wound, ulcer, or bone fracture
  • No 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

    • NOTE: UPC ratio of spot urine is an estimation of the 24 urine protein excretion; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm
  • No 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 and breastfeeding women are excluded from the study; breastfeeding should be discontinued while receiving therapy; patients must have pregnancy test within 7 days prior to patient randomization if woman is of child-bearing capacity
  • Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00378703

  Show 505 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Keith Flaherty ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00378703     History of Changes
Other Study ID Numbers: NCI-2009-00533, NCI-2009-00533, ECOG-E2804, CDR0000499788, E2804, E2804, U10CA180820, U10CA021115
Study First Received: September 19, 2006
Last Updated: July 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Antibodies
Antibodies, Monoclonal
Sirolimus
Everolimus
Bevacizumab
Sorafenib
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Anti-Bacterial Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents

ClinicalTrials.gov processed this record on July 29, 2014