Randomized Phase III Trial Comparing Everolimus Versus Everolimus Plus Bevacizumab for Advanced Renal Cell Carcinoma Progressing After Treatment With Tyrosine Kinase Inhibitors
Randomized Phase III Trial Comparing Everolimus Versus Everolimus Plus Bevacizumab for Advanced Renal Cell Carcinoma Progressing After Treatment With Tyrosine Kinase Inhibitors
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.
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.
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
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:
No serious non-healing wound, ulcer, or bone fracture
No arterial thrombotic events within 6 months of registration:
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:
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:
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+
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