Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy

Study Overview
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Brief Summary
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This randomized phase III trial studies 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 interfere with tumor growth by blocking the ability of tumor cells to grow and spread. Everolimus and bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor. It is not yet known whether giving everolimus together with bevacizumab is better than everolimus alone in treating patients with advanced kidney cancer that has progressed after first-line therapy.

Detailed Description
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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 vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) treatment. SECONDARY OBJECTIVES: I. To compare the progression-free survival and proportion who experience an objective response (defined as complete clinical response [cCR] + partial response [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: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive everolimus orally (PO) once daily (QD) on days 1-28. ARM II: Patients receive everolimus PO QD 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. 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.

Official Title
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Randomized Phase III Trial Comparing Everolimus Versus Everolimus Plus Bevacizumab for Advanced Renal Cell Carcinoma Progressing After Treatment With Tyrosine Kinase Inhibitors

Conditions
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Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Everolimus
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Renal cell carcinoma with some component of clear cell histology Metastatic or unresectable disease Must have been treated with at least 1 prior VEGFR tyrosine kinase inhibitor treatment and have progressed or have been intolerant to treatment No prior systemic therapy with a vascular endothelial growth factor (VEGF) binding agent (e.g., bevacizumab) No prior systemic therapy with any mechanistic target of rapamycin (mTOR) inhibitor (e.g., sirolimus, temsirolimus, everolimus) Prior cytokine therapy is allowed Any systemic therapy must be completed at least 4 weeks prior to registration >= 2 weeks since any prior radiation (including palliative) Patients must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to study registration, and must have fully recovered from any such procedure The following are not considered to be major procedures: thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies and routine dental procedures Patients must have measurable disease by RECIST criteria; lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT) scan No active brain metastases: patients with treated, stable brain metastases for at least three months are eligible as long as they meet the following criteria: Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or CT) (stable dose of anticonvulsants are allowed); treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 are not eligible Baseline brain imaging (MRI/CT) is required No serious non-healing wound, ulcer, or bone fracture No arterial thrombotic events within 6 months of registration: Including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI); patients with clinically significant peripheral artery disease (i.e., claudication on less than one block), significant vascular disease (i.e., aortic aneurysm, history of aortic dissection), or any other arterial thrombotic event are ineligible Patients who have experienced a deep venous thrombosis or pulmonary embolus within the past 6 months must be on stable therapeutic anticoagulation to be enrolled to this study Patients receiving anti-platelet agents and prophylactic anticoagulation are eligible No inadequately controlled hypertension: (defined as a blood pressure of >= 160 mmHg systolic and/or >= 90 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy No known severe impairment of lung function, defined as >= grade 2 dyspnea or cough, or either: Requirement of supplemental oxygen, or In cases where pulmonary function or pulse oximetry tests have been obtained, forced expiratory volume of the lung in one second (FEV1) or forced vital capacity (FVC) are < 50% of predicted, or single breath diffusing capacity of the lung for carbon monoxide (DLCO) is < 35% of predicted or resting room oxygen saturation is less than 90% No active or severe liver disease (e.g. acute or chronic hepatitis, cirrhosis) No positive serology for anti-hemoglobin C (HBC) or anti-hepatitis C virus (HCV) antibodies; hepatitis B virus (HBV) seropositive patients (hepatitis B surface antigen [HBsAg] positive) are eligible if they are closely monitored for evidence of active HBV infection by HBV deoxryribonucleic acid (DNA) testing and agree to receive suppressive therapy with lamivudine or other HBV-suppressive therapy until at least 4 weeks after the last dose of everolimus No New York Heart Association (NYHA) class >= 2 congestive heart failure No active bleeding or chronic hemorrhagic diathesis or increased risk for bleeding: Including but not limited to history of major bleeding within 6 months (e.g. gastrointestinal, lung, CNS sites; or required transfusion support) No history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to the initiation of treatment No ongoing immunosuppressive therapy: including chronic systemic treatment with corticosteroids (>= 10 mg/day prednisone equivalent) Archival tissue must be available for submission: though it is optional patients to choose to participate in the correlative substudies or not Patients who are pregnant or nursing are not eligible Women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration Women of child-bearing potential include: Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months) Women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35m IU/mL Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy) Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 or Karnofsky score >= 60% Granulocytes >= 1,500/μL Platelet count >= 100,000/μL Calculated creatinine clearance >= 30 mL/minute (modified Cockroft and Gault formula) Bilirubin =< 1.5 x upper limits of normal Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN) Fasting serum triglycerides =< 200 mg/dL Serum cholesterol =< 300 mg/dL Fasting serum glucose =< 1.5 x ULN Urine protein to creatinine ratio < 1.0 or urine protein =< 1+

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (everolimus)<br>Patients receive everolimus PO QD on days 1-28. | Drug: Everolimus<br>* Given PO<br>* Other names: Zortress;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Arm II (everolimus with bevacizumab)<br>Patients receive everolimus PO QD on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 15. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Everolimus<br>* Given PO<br>* Other names: Zortress;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | The time from date of randomization to date of death due to any cause, assessed up to 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | The time from randomization to disease progression or death from any cause, assessed up to 5.5 years | 
| Objective Response Rate (CR + PR) | The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. | Up to 5.5 years | 
| Toxicities, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | The number of patients reporting grade 3 or higher adverse events as graded by the NCI's Common Toxicity Criteria (CTCAE) Version 4 are reported here. A complete list of all reported adverse events is reported in the Adverse Events section of this report. | Up to 30 days after completion of study treatment |