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

• Progression-free survival (PFS) [ Time Frame: The time from randomization to disease progression or death from any cause, assessed up to 6.5 years ] [ Designated as safety issue: No ]
  The stratified log-rank statistic will be the primary analysis to compare the two treatment arms on PFS adjusting on the stratification factors (number of negative prognostic factors (0, 1, 2-3) and prior VEGFR-TKI therapy (< 12 weeks, >= 12 weeks). The Kaplan-Meier product-limit estimator will be used to estimate the PFS distribution. In addition, the proportional hazards model will be used to assess the importance of the treatment arm adjusting on patient characteristics, stratification variables and other important covariates in predicting PFS.
• Objective response rate (defined as confirmed complete response plus partial response) [ Time Frame: Up to 6.5 years ] [ Designated as safety issue: No ]
  Furthermore, the Cochran-Mantel-Haenszel test will be used to compare the two arms on the proportion of patients who experience an objective response (defined as either a confirmed CR or a PR) adjusting on the stratification factors (number of negative prognostic features and prior VEGFR-TKI therapy.
• Toxicities, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  The Fisher exact test will be used to compare the two treatment arms on the proportion of patients with unacceptable treatment related grade 3 or higher toxicity.

• Progression-free survival [ Designated as safety issue: No ]
• Objective response rate (defined as confirmed complete response plus partial response) [ Designated as safety issue: No ]
• Toxicity [ Designated as safety issue: Yes ]

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

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.

• Clear Cell Renal Cell Carcinoma
• Recurrent Renal Cell Cancer
• Stage III Renal Cell Cancer
• Stage IV Renal Cell Cancer

• Drug: everolimus
  Given orally
  Other Names:

  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
• Biological: bevacizumab
  Given IV
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

• Active Comparator: Arm I (everolimus)
  Patients receive everolimus PO once daily on days 1-28.
  Intervention: Drug: everolimus
• Experimental: Arm II (everolimus with bevacizumab)
  Patients receive everolimus PO once daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 15.
  Interventions:

  • Drug: everolimus
  • Biological: bevacizumab

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)