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

Phase Type Status Age Sponsor Protocol IDs Phase II Treatment Active 18 and over NCI ECOG-E2804 E2804, NCT00378703

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.

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



• 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



• No history or clinical evidence of CNS disease, including primary brain tumor or brain metastases

Prior/Concurrent Therapy:

• See Disease Characteristics
• No more than 1 prior regimen containing vaccine- or cytokine-based immunotherapy for advanced disease
• 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 stage IV disease
• More than 4 weeks since prior immunotherapy
• 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 I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15.



• Arm II: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and bevacizumab as in arm I.



• Arm III: Patients receive bevacizumab as in arm I and oral sorafenib tosylate twice daily on days 1-28.



• Arm IV: Patients receive temsirolimus as in arm II and sorafenib tosylate as in arm III.

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: 215-662-8624
David McDermott, MD, Protocol co-chair		Ph: 617-667-9920

U.S.A.
Illinois
	Elgin
	Sherman Hospital
		James Wade, MD	Ph:  217-876-6600
Indiana
	Indianapolis
	Indiana University Melvin and Bren Simon Cancer Center
		Clinical Trials Office - Indiana University Cancer Center	Ph:  317-274-2552
	Veterans Affairs Medical Center - Indianapolis
		Theodore Logan, MD	Ph:  317-554-0000 888-878-6889
	William N. Wishard Memorial Hospital
		Theodore Logan, MD	Ph:  317-639-6671
Iowa
	Cedar Rapids
	Cedar Rapids Oncology Associates
		Clinical Trials Office - Cedar Rapids Oncology Associates	Ph:  319-363-2690
	Mercy Regional Cancer Center at Mercy Medical Center
		Martin Wiesenfeld, MD	Ph:  319-398-6011
	Des Moines
	CCOP - Iowa Oncology Research Association
		Roscoe Morton, MD, FACP	Ph:  515-244-7586
	John Stoddard Cancer Center at Iowa Lutheran Hospital
		Clinical Trials Office - John Stoddard Cancer Center at Iowa Lutheran Hospital	Ph:  515-241-8704
	John Stoddard Cancer Center at Iowa Methodist Medical Center
		Clinical Trials Office - John Stoddard Cancer Center at Iowa Methodist Medical Center	Ph:  515-241-6727
	Medical Oncology and Hematology Associates at John Stoddard Cancer Center
		Roscoe Morton, MD, FACP	Ph:  515-244-7586
	Medical Oncology and Hematology Associates at Mercy Cancer Center
		Roscoe Morton, MD, FACP	Ph:  515-244-7586
	Mercy Cancer Center at Mercy Medical Center - Des Moines
		Roscoe Morton, MD, FACP	Ph:  515-244-7586
	Mercy Capitol Hospital
		Roscoe Morton, MD, FACP	Ph:  515-244-7586
Kansas
	Chanute
	Cancer Center of Kansas, PA - Chanute
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Dodge City
	Cancer Center of Kansas, PA - Dodge City
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	El Dorado
	Cancer Center of Kansas, PA - El Dorado
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Independence
	Cancer Center of Kansas-Independence
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Kingman
	Cancer Center of Kansas, PA - Kingman
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Liberal
	Southwest Medical Center
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Newton
	Cancer Center of Kansas, PA - Newton
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Parsons
	Cancer Center of Kansas, PA - Parsons
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Pratt
	Cancer Center of Kansas, PA - Pratt
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Salina
	Cancer Center of Kansas, PA - Salina
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Wellington
	Cancer Center of Kansas, PA - Wellington
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Wichita
	Associates in Womens Health, PA - North Review
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Cancer Center of Kansas, PA - Wichita
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Cancer Center of Kansas, PA - Medical Arts Tower
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	CCOP - Wichita
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Via Christi Cancer Center at Via Christi Regional Medical Center
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Winfield
	Cancer Center of Kansas, PA - Winfield
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
Ohio
	Bellefontaine
	Mary Rutan Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Chillicothe
	Adena Regional Medical Center
		Clinical Trials Office - Adena Regional Medical Center	Ph:  877-779-7585
	Columbus
	CCOP - Columbus
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Doctors Hospital at Ohio Health
		Clinical Trials Office - Doctors Hospital at Ohio Health	Ph:  614-566-3275
	Grant Medical Center Cancer Care
		Clinical Trials Office - Grant Medical Center Cancer Care	Ph:  614-566-4475
	Riverside Methodist Hospital Cancer Care
		Clinical Trials Office - Riverside Methodist Hospital Cancer Care	Ph:  614-566-4475
	Delaware
	Grady Memorial Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Lancaster
	Fairfield Medical Center
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Marietta
	Strecker Cancer Center at Marietta Memorial Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Newark
	Licking Memorial Cancer Care Program at Licking Memorial Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Springfield
	Community Hospital of Springfield and Clark County
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Mercy Medical Center
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Westerville
	Mount Carmel St. Ann's Cancer Center
		J. Philip Kuebler, MD, PhD	Ph:  614-488-2118
	Zanesville
	Genesis - Good Samaritan Hospital
		Clinical Trials Office - Genesis - Good Samaritan Hospital	Ph:  740-454-5232
Tennessee
	Knoxville
	Thompson Cancer Survival Center
		Clinical Trials Office - Thompson Cancer Survival Center	Ph:  865-541-1812

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		2008-09-08 (estimated)
Registered in ClinicalTrials.gov		NCT00378703
Date Submitted to PDQ		2006-07-24
Information Last Verified		2008-09-24
NCI Grant/Contract Number		CA21115