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

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)