Bevacizumab With or Without Sunitinib in Sunitinib-Refractory Renal Cell Carcinoma

• Participants will receive one of two treatment possibilities. Since no one knows which of the study options is best, participants will be "randomized" to one fo the three treatment groups.
• Group 1 will stop their current treatment with sunitinib and receive a dose of bevacizumab once every 2 weeks. Group 2 will receive the standard treatment of sunitinib with the addition of bevacizumab.
• All study participants will undergo the same study procedures. These study procedures will include the following at intervals specified in the protocol: medical history review; vital signs; physical exam; urine analysis; EKG and CT scan.

• Drug: Sunitinib
  Sunitinib orally once daily
  Other Name: sutent
• Drug: Bevacizumab
  Intravenously every 14 days
  Other Name: avastin

• Active Comparator: 1
  Bevacizumab monotherapy 10 mg/kg IV q2 weeks
  Intervention: Drug: Bevacizumab
• Active Comparator: 2
  Combination Sunitinib & Bevacizumab Bevacizumab 10 mg/kg IV q2 weeks Sunitinib 50 mg PO QD on 4/2 schedule
  Interventions:

  • Drug: Sunitinib
  • Drug: Bevacizumab

Inclusion Criteria:

• Histologically confirmed metastatic renal cell carcinoma with clear cell histology
• Patients must be off sunitinib for 14 days prior to day 1 of treatment on protocol
• Evidence of unidimensionally measurable disease based on RECIST criteria, with at least 1 measurable lesion
• Radiographic evidence of disease progression defined by RECIST during or within 6 weeks of completion of sunitinib treatment
• Participants must have received at least 14 doses of sunitinib therapy
• Participants must enroll within 3 months of the last dose of sunitinib
• Males or females, age of 18 years or older
• ECOG Performance status 0-2
• Resolution of all acute toxic effects of prior therapy, radiotherapy or surgical procedures to NCI CTCAE version 3.0 grade 1 or less
• Laboratory values as defined in protocol
• 4 weeks or more must have elapsed from the time of major surgery and subjects must have recovered from the procedure prior to day 1 of randomization
• No anticipated need for major surgical procedure during the course of the study
• 2 weeks or more must have elapsed from the time of minor surgery and subjects must have recovered from the procedure prior to day 1 of randomization
• 4 weeks of more must have elapsed from the time of major radiotherapy prior to day 1 of randomization

Exclusion Criteria:

• Prior treatment with bevacizumab
• Unacceptable toxicity on prior sunitinib therapy at 37.5mg or lower
• Prior systemic therapy for RCC with > 2 regimens
• Systemic therapy other than sunitinib within 4 weeks of starting the study treatment
• Uncontrolled high blood pressure
• Any prior history of hypertensive crisis or hypertensive encephalopathy
• History of abdominal fistula, gastrointestinal perforation or intraabdominal abscess within 3 months prior to day 0
• Any of the following within the 6 months prior to sudy drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, symptomatic congestive heart failure, or ejection fraction < 30%
• Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range without medication
• History of or known brain metastases or spinal cord compression
• NCI CTCAE grade 2 or above hemorrhage within 4 weeks of starting study treatment
• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
• Symptomatic peripheral vascular disease
• Grade 3 or higher cardiac dysrhythmia or QT prolongation
• Concurrent use of proarrhythmic medications including terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and flecainide
• Pregnancy or breastfeeding or inadequate contraception
• Significant thromboembolic event within 6 months
• Evidence of bleeding diathesis or coagulopathy
• Serious, non-healing wound, ulcer or bone fracture
• Proteinuria at screening
• Known hypersensitivity to any component of bevacizumab
• Psychiatric illness/social situation that would limit compliance with study requirements
• Previous or concurrent malignancy requiring active systemic therapy

• Beth Israel Deaconess Medical Center
• Pfizer