Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Special Category: CTSU trial

Objectives

Primary

1. Compare progression-free survival (PFS) of patients with advanced renal cell carcinoma treated with different combinations of bevacizumab, sorafenib tosylate, and temsirolimus vs bevacizumab alone.

Secondary

1. Assess the significance of changes in tumor size over early time points as a predictor of PFS of patients treated with these regimens.
2. Compare the number and percentage of patients with stable disease at 6 months of therapy (failure to progress).
3. Compare the safety of these regimens in these patients.
4. Compare overall survival of patients treated with these regimens.
5. Compare the objective response rate in patients treated with these regimens.
6. Assess pathology, angiogenesis histology, and activation status of MAP kinase and VEGFR2 pathways and relate to clinical outcome.

Entry Criteria

Disease Characteristics:

• Histologically confirmed clear cell renal cell carcinoma
  • Primary or metastatic lesion
  • Less than 25% of any other histology (papillary, chromophobe, or oncocytic)
• Sufficient pathology material available for diagnostic review
  • Core-needle biopsy allowed
  • No fine-needle aspirations as only source for diagnosis
• Measurable metastatic disease
  • Lesions that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as > 20 mm (2.0 cm) with conventional techniques or as ≥ 10 mm (1.0 cm) with spiral CT scan
• Not curable by standard radiotherapy or surgery
• Prior nephrectomy required, with the following exceptions:
  • Primary tumor ≤ 5 cm
  • Extensive liver metastases (> 30% of liver parenchymal) or multiple (> 5) bone metastases
  • Unresectable primary tumor due to invasion into adjacent organs or encasing the aorta or vena cava
• No history or clinical evidence of CNS disease, including primary brain tumor or brain metastases

Prior/Concurrent Therapy:

• See Disease Characteristics
• No prior cytotoxic chemotherapy
• No prior antiangiogenic therapy including, but not limited to, sunitinib malate, ZD6474, or VEGF Trap
• No prior bevacizumab, mTOR inhibitors (including, but not limited to, temsirolimus), or sorafenib tosylate
• Prior thalidomide or interferon alfa allowed as adjuvant therapy or for metastatic disease
• More than 4 weeks since prior immunotherapy and recovered
  • No more than 1 prior vaccine or cytokine-based immunotherapy regimen for metastatic disease
• More than 2 weeks since prior radiotherapy and recovered
• More than 4 weeks since prior major surgery or open biopsy
• No concurrent major surgery
• No concurrent or recent full-dose anticoagulants or thrombolytic agents (unless required to maintain patency of pre-existing or permanent indwelling IV catheters)
• No concurrent cytochrome P450 enzyme-inducing drugs including any of the following:
  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Rifampin
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer therapies or investigational agents
• No concurrent prophylactic hematopoietic colony-stimulating factors

Patient Characteristics:

• ECOG performance status 0-1
• Life expectancy > 3 months
• WBC ≥ 3,000/mm³
• Absolute granulocyte count ≥ 1,200/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9.0 g/dL (transfusions allowed)
• Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 55 mL/min
• Bilirubin ≤ 1.5 times ULN
• AST/ALT ≤ 2.5 times ULN (5.0 times ULN in the presence of liver metastases)
• INR ≤ 1.5 and aPTT normal
• Fasting cholesterol < 350 mg/dL
• Fasting triglycerides < 400 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• No seizures not controlled with standard medical therapy
• No stroke within the past 12 months
• No other malignancies within the past 5 years except basal cell skin cancer, squamous cell skin cancer, carcinoma in situ of the cervix, or ductal or lobular carcinoma in situ of the breast
• 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 tosylate, temsirolimus, or bevacizumab
• No history of bleeding diathesis or coagulopathy
• No condition that impairs ability to swallow pills
• No significant traumatic injury within the past 28 days
• No clinically significant cardiovascular disease, including any of the following:
  • Uncontrolled hypertension
    • Blood pressure must be ≤ 150/100 mm Hg on a stable antihypertensive regimen
  • Myocardial infarction or unstable angina within the past 6 months
  • New York Heart Association class II-IV congestive heart failure
  • Serious cardiac arrhythmia requiring medication
  • Unstable angina pectoris
  • Peripheral vascular disease ≥ grade 2
• No serious, nonhealing wound, ulcer, or bone fracture
• No significant proteinuria
  • If urine protein:creatinine ratio > 0.5, 24-hour urine protein must be < 1,000 mg
• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parental antibiotics on day 0 or psychiatric illness or social situations that would preclude compliance with study requirements

Expected Enrollment

A total of 360 patients will be accrued for this study.

Outcomes

Progression-free survival

Safety
Overall survival as assessed by the Kaplan-Meier method
Objective response rate
Number and percentage of patients with stable disease at 6 months

Outline

This is a randomized, multicenter study. Patients are stratified according to prior cytokine or vaccine therapy (no vs yes) and Motzer risk category (low vs intermediate vs high). Patients are randomized to 1 of 4 treatment arms.

• Arm A: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15.
• Arm B: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and bevacizumab as in arm A.
• Arm C: Patients receive bevacizumab as in arm A and oral sorafenib tosylate twice daily on days 1-28.
• Arm D: Patients receive temsirolimus as in arm B and sorafenib tosylate as in arm C.

In all arms treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

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

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Keith Flaherty, MD, Protocol chair		Ph: 215-662-7402
David McDermott, MD, Protocol co-chair		Ph: 617-667-9920

Registry Information
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 [BeST]
Trial Start Date		2007-09-14
Trial Completion Date		2012-05-25 (estimated)
Registered in ClinicalTrials.gov		NCT00378703
Date Submitted to PDQ		2006-07-24
Information Last Verified		2010-12-13
NCI Grant/Contract Number		CA21115

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