Sequential Two-agent Assessment in Renal Cell Carcinoma Therapy: The START Trial

Inclusion Criteria: 1. Confirmed metastatic RCC with a clear cell component. 2. Prior radical or partial nephrectomy required. Patients whose primary tumor was treated with cryoablation or radiofrequency ablation would also be eligible. 3. Measurable disease 4. Age \>/= 18 years. Because no dosing or adverse event data are currently available on the use of these targeted agents in patients \< 18 years of age, children are excluded from this study 5. ECOG performance status 0 or 1 6. Adequate organ and marrow function within 14 days as defined below: a) Absolute neutrophil count /=\> 1,500/microL; b) Platelets \>/= 100,000/microL; c) Hgb \>/= 9.0 g/dL (transfusion allowed); d) Total bilirubin \< 1.5 mg/dl; e) Albumin \> 2.5 g/dL; f) AST and ALT \</= 2.5 X ULN for subjects without liver metastases; g) AST and ALT \< 5 X ULN for subjects with liver metastases; h) Serum creatinine \</= 2 mg/dL or CrCl \>/= 50 cc/min; i) Fasting serum cholesterol \</= 300 mg/dL or \</= 7.75 mmol/L and fasting triglycerides \</= 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication. 7. Female patients of childbearing potential must have a negative pregnancy test (serum/plasma or urine) within 7 days prior to beginning treatment on the study due to the possible teratogenic effect 8. Patients of child fathering or childbearing potential must agree to practice a form of medically acceptable birth control while on study 9. Patients must give written informed consent prior to initiation of study-related procedures. Patients with a history of major psychiatric illness must be judged able to fully understand the investigational nature of the study and the risks associated with the therapy 10. Patients must be able to swallow pills 11. Both men and women and members of all races and ethnic groups are eligible for this trial Exclusion Criteria: 1. No patient with any concurrent active malignancy, i.e. a patient requiring or receiving systemic therapy for another malignancy at the same time of treatment for RCC 2. Patients must not have received any prior targeted therapy (anti-VEGF agents or mTOR inhibitors), including adjuvant therapy, and must not have received any prior chemotherapy for mRCC. However, patients who had received prior immunotherapy, such as cytokines or vaccines, are permitted to enroll. 3. Patients must not be scheduled to receive another experimental drug while on this study. Patients are permitted to receive concomitant bisphosphonates. 4. Patients must not have multiple brain metastases or leptomeningeal disease. Patients with controlled solitary brain metastasis are eligible. 5. Patients must not have had a stroke or transient ischemic attack within 6 months. 6. Patients must not have uncontrolled infections. 7. Patients must not have clinically significant cardiovascular disease, defined as myocardial infarction (or unstable angina) within 6 months, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia refractory to medical management 8. Patients must not have uncontrolled hypertension, defined as \> 140/90 or prior history of hypertensive crisis or hypertensive encephalopathy. Treatment of hypertension with medications is permitted. 9. History of hemoptysis (\>/= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1 10. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) 11. Symptomatic peripheral vascular disease 12. Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breast-feeding should be discontinued if the mother is enrolled on this trial. 13. Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with some of these agents. 14. Patients must not have a clinical history of coagulopathy or bleeding diathesis. Patients may be on therapeutic anticoagulation preferably a low-molecular weight heparin. If the patients are on warfarin, the INR should be maintained within a therapeutic level and must be checked weekly for the first four weeks, then every 2 weeks for 4 additional weeks. Thereafter, they may be followed at the discretion of the treating provider. Antiplatelet agents are allowed. 15. Concomitant treatment with rifampin, St. John's wort, or the cytochrome p450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital) is not allowed on this study. 16. Patients with significant baseline proteinuria defined as 300 or greater by screening U/A will be excluded if they have \> 1,000 mg proteins in a 24-hour urine collection or if they have a random urine protein over creatinine (UPC) ratio \>1. 17. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study 18. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment 19. Serious, non-healing wound, ulcer, or bone fracture 20. Uncontrolled diabetes as defined by fasting serum glucose \>1.5 x ULN 21. Known hypersensitivity to any component of bevacizumab, pazopanib or everolimus. 22. Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. 23. Patients with severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air 24. Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection. 25. Patients receiving chronic, systemic treatment with steroids in pharmacological doses or immunosuppressive agents are excluded. Patients who receive steroids for physiological replacement, e.g., after adrenalectomy are not excluded. Topical or inhaled corticosteroids are also allowed.