Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase III trial is studying giving everolimus together with bevacizumab to see how well it works compared to everolimus alone in treating patients with advanced kidney cancer that progressed after first-line therapy. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Everolimus and bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor

Further Study Information

PRIMARY OBJECTIVES:

l. To compare the overall survival of patients receiving bevacizumab plus everolimus and everolimus alone among patients with advanced renal cell carcinoma progressing after first line VEGFR-TKI treatment.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival and proportion who experience an objective response (defined as cCR + PR) in patients with advanced renal cell carcinoma receiving bevacizumab plus everolimus and everolimus alone.

II. To compare grade 3 or higher toxicity in patients receiving each treatment regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to number of risk factors (i.e., Karnofsky performance status < 80%, corrected serum calcium >= 10 mg/dL, and hemoglobin =< 13 g/dL for male patients or =< 11.5 g/dL for female patients) present (0 vs 1 vs 2-3) and total duration of prior VEGFR tyrosine kinase inhibitor therapy (< 12 weeks vs >= 12 weeks). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive everolimus orally (PO) once daily on days 1-28.

ARM II: Patients receive everolimus PO once daily on days 1-28 and bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Blood, urine, and tumor tissue samples may be collected periodically for pharmacogenomic and correlative studies.

After completion of study treatment, patients are followed up every 8 weeks until disease progression and then every 6 months for up to 5.5 years.

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed renal cell carcinoma

• Some component of clear cell disease

• Metastatic or unresectable disease

• Measurable disease by RECIST criteria, defined as lesions that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan

• Treated with ≥ 1 prior VEGFR tyrosine kinase inhibitor treatment and have progressed or have been intolerant to treatment

• Available archive tissue for submission

• No active brain metastases

• Patients with treated, stable (for ≥ 3 months) brain metastases are eligible provided that they meet the following criteria:

• No ongoing requirement for steroids

• No evidence of progression or hemorrhage after treatment for ≥ 3 months as ascertained by clinical examination and brain imaging (MRI or CT scan)

• Stable doses of anticonvulsants are allowed

• Treatment may include whole-brain radiotherapy, radiosurgery (Gamma Knife, LINAC, or equivalent), or a combination as deemed appropriate by the treating physician

• Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within the past 3 months are not eligible

• Baseline brain imaging (MRI or CT scan) is required

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

• Granulocytes ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Calculated creatinine clearance ≥ 30 mL/min

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• AST ≤ 2.5 times ULN

• Fasting serum triglycerides ≤ 200 mg/dL

• Serum cholesterol ≤ 300 mg/dL

• Fasting serum glucose ≤ 1.5 times ULN

• Urine protein to creatinine ratio < 1.0 OR urine protein ≤ 1+

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy

• No arterial thrombotic events within the past 6 months, including any of the following:

• Transient ischemic attack

• Cerebrovascular accident

• Peripheral arterial thrombus

• Unstable angina or angina requiring surgical or medical intervention within the past 6 months

• Myocardial infraction

• Clinically significant peripheral artery disease (i.e., claudication on < 1 block)

• Significant vascular disease (i.e., aortic aneurysm, history of aortic dissection)

• Any other arterial thrombotic event

• Patients who experienced a deep venous thrombosis or pulmonary embolus within the past 6 months are eligible provided that they are on stable therapeutic anticoagulation

• No inadequately controlled hypertension (defined as a BP of ≥ 160 mm Hg systolic and/or ≥ 90 mm Hg diastolic on medication) or any history of hypertensive crisis or hypertensive encephalopathy

• No NYHA class II-IV congestive heart failure

• No known severe impairment of lung function, defined as dyspnea or cough ≥ grade 2 and meeting 1 of the following criteria:

• Requirement for supplemental oxygen

• In cases where pulmonary function or pulse oximetry tests have been obtained, FEV1 or forced vital capacity is < 50% of predicted, or single breath DLCO is < 35% of predicted, or resting room oxygen saturation is < 90%

• No active or severe liver disease (e.g., acute or chronic hepatitis, cirrhosis)

• No positive serology for anti-hepatitis B core or anti-hepatitis C virus antibodies

• Hepatitis B virus (HBV) seropositive patients (HB surface antigen positive) are eligible provided that they are closely monitored for evidence of active HBV infection by HBV DNA testing and agree to receive suppressive therapy with lamivudine or other HBV-suppressive therapy until ≥ 4 weeks after the last dose of everolimus

• No active bleeding or chronic hemorrhagic diathesis or increased risk for bleeding including, but not limited to, history of major bleeding within the past 6 months (e.g., gastrointestinal [GI], lung, or CNS sites or required transfusion support)

• No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 6 months

• No serious non-healing wound, ulcer, or bone fracture

• No significant traumatic injury within the past 4 weeks

• No concurrent hormones or other chemotherapeutic agents except for steroids given for adrenal failure, suspected drug-induced pneumonitis, or other allergic reactions; hormones administered for non-disease-related conditions (e.g., insulin for diabetes); and intermittent use of dexamethasone as an antiemetic or to treat cough associated with everolimus pneumonitis

• Concurrent antiplatelet agents and prophylactic anticoagulation allowed

• No prior systemic therapy with a VEGF-binding agent (e.g., bevacizumab)

• No prior systemic therapy with any mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus)

• Prior cytokine therapy allowed

• At least 4 weeks since prior systemic therapy

• At least 4 weeks since prior major surgical procedure* or open biopsy and fully recovered

• At least 2 weeks since prior radiotherapy (including palliative) and no concurrent radiotherapy

• A symptomatic lesion or one which may produce disability (e.g., unstable femur) may be irradiated before study initiation, provided other measurable or evaluable disease is present

• No concurrent immunosuppressive therapy, including chronic systemic treatment with corticosteroids (≥ 10 mg/day prednisone equivalent)

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

George Philips

Principal Investigator

U.S.A.
California
	Los Angeles
	Kaiser Permanente Medical Center - Los Angeles
		Han A Koh	Ph: 626-564-3455
	San Diego
	Kaiser Permanente - Mission
		Han A Koh	Ph: 626-564-3455
	Santa Clara
	Kaiser Permanente Medical Center - Santa Clara Homestead Campus
		Louis Fehrenbacher	Ph: 626-564-3455
Florida
	Orange Park
	Integrated Community Oncology Network - Orange Park
		Linda Struhar-Sylvester	Ph: 904-861-8574
			Email: info@icononcology.com
Hawaii
	Aiea
	Kapiolani Medical Center at Pali Momi
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Honolulu
	Cancer Research Center of Hawaii
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Hawaii Medical Center - East
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Kapiolani Medical Center for Women and Children
		Jeffrey L. Berenberg	Ph: 808-586-2979
	OnCare Hawaii, Incorporated - Kuakini
		Jeffrey L. Berenberg	Ph: 808-586-2979
	OnCare Hawaii, Incorporated - Lusitana
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Queen's Cancer Institute at Queen's Medical Center
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Straub Clinic and Hospital, Incorporated
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Kailua
	Castle Medical Center
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Lihue
	Kauai Medical Clinic
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Wailuku
	Maui Memorial Medical Center
		Jeffrey L. Berenberg	Ph: 808-586-2979
	Pacific Cancer Institute - Maui
		Jeffrey L. Berenberg	Ph: 808-586-2979
Indiana
	Beech Grove
	St. Francis Hospital and Health Centers - Beech Grove Campus
		Howard M. Gross	Ph: 765-983-3000
	Fort Wayne
	Fort Wayne Medical Oncology and Hematology
		Sreenivasa Rao Nattam	Ph: 260-484-8830
			Email: ledgar@fwmoh.com
	Radiation Oncology Associates Southwest
		Bharat H. Barai	Ph: 219-736-2800
North Carolina
	Concord
	Batte Cancer Center at Northeast Medical Center
		James Grier Wall	Ph: 704-355-2884
	Durham
	Duke Cancer Institute
		Jeffrey Crawford	Ph: 888-275-3853
North Dakota
	Bismarck
	Bismarck Cancer Center
		John T Reynolds	Ph: 701-323-5760
			Email: tfischer@mohs.org
Oregon
	Clackamas
	Clackamas Radiation Oncology Center
		Alison K Conlin	Ph: 503-215-6412
	Milwaukie
	Providence Milwaukie Hospital
		Alison K Conlin	Ph: 503-215-6412
	Newberg
	Providence Newberg Medical Center
		Alison K Conlin	Ph: 503-215-6412
	Oregon City
	Willamette Falls Hospital
		Alison K Conlin	Ph: 503-215-6412
	Portland
	CCOP - Columbia River Oncology Program
		Alison K Conlin	Ph: 503-215-6412
	Providence Cancer Center at Providence Portland Medical Center
		Alison K Conlin	Ph: 503-215-6412
	Providence St. Vincent Medical Center
		Alison K Conlin	Ph: 503-215-6412
Pennsylvania
	Abington
	Rosenfeld Cancer Center at Abington Memorial Hospital
		Willard G. Andrews	Ph: 215-481-2402
	Bryn Mawr
	Bryn Mawr Hospital
		Paul B. Gilman	Ph: 484-476-2649
			Email: wellenbachj@mlhs.org
	Paoli
	Cancer Center of Paoli Memorial Hospital
		Paul B. Gilman	Ph: 484-476-2649
			Email: wellenbachj@mlhs.org
	Wynnewood
	CCOP - Main Line Health
		Paul B. Gilman	Ph: 484-476-2649
			Email: wellenbachj@mlhs.org
	Lankenau Cancer Center at Lankenau Hospital
		Paul B. Gilman	Ph: 484-476-2649
			Email: wellenbachj@mlhs.org
Washington
	Vancouver
	Southwest Washington Medical Center Cancer Center
		Alison K Conlin	Ph: 503-215-6412
West Virginia
	Huntington
	Edwards Comprehensive Cancer Center at Cabell Huntington Hospital
		Maria-Rosalia B. Tria Tirona	Ph: 304-399-6617
Wisconsin
	Appleton
	Fox Valley Hematology and Oncology - East Grant Street
		Avi Bar-Lev	Ph: 920-749-1171

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01198158
Information obtained from ClinicalTrials.gov on February 25, 2013

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