Treatment of Refractory Metastatic Renal Cell Carcinoma With Bevacizumab and RADOO1

Inclusion Criteria:

Patients will be included in the study based on the following criteria:

• Signed Informed Consent Form
• Histologically confirmed metastatic RCC that is predominantly clear cell
• Measurable disease, as defined by RECIST (see Appendix D)
• Age >= 18 years
• ECOG performance status of 0 or 1

• No more than one prior targeted therapy (e.g. sorafenib, sunitinib)

  o Prior cytokine therapy allowed

• No more than two prior systemic therapies
• Ability and capacity to comply with the study and follow-up procedures

Exclusion Criteria:

1. Disease-Specific Exclusions

   • RCC with predominantly sarcomatoid features
   • Radiotherapy for RCC within 28 days prior to Day 1, with the exception of single-fraction radiotherapy given for the indication of pain control
   • Prior treatment with bevacizumab or any mTOR inhibitor (temsirolimus, sirolimus, or everolimus)
   • Current need for dialysis
2. General Medical Exclusions

Subjects meeting any of the following criteria are ineligible for study entry:

• Inability to comply with study and/or follow-up procedures
• Life expectancy of less than 12 weeks

• Inadequate organ function, as evidenced by any of the following at screening:

  • Absolute neutrophil count (ANC) < 1500/uL
  • Platelet count <= 100 x 10^9/L
  • Total bilirubin >= 1.5 x ULN
  • Alkaline phosphatase, AST, and/or ALT > 2.5 x the upper limit of normal (ULN) for patients without evidence of liver metastases; > 5 X ULN for patients with documented liver metastases
  • Serum creatinine > 2.0 mg/dL
  • Hemoglobin < 9 g/dL a. may be transfused or receive epoetin alfa to maintain or exceed this level up to the hemoglobin level recommended on the current label for for epoetin alfa because of the potential increased risk of thrombotic events and increased mortality. Also, rapid increase in hemoglobin may exacerbate hypertension, i.e., a possible adverse event with bevacizumab and to a lesser extent with RAD001.
• Active infection or fever > 38.5°C within 3 days of starting treatment

• Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice an effective method of birth control.

  • Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the initial administration of RAD001 and the first day of each cycle.
  • Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective methods of birth control for this study.
• History of other malignancies within 5 years prior to Day 1 except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma, squamous-cell carcinoma of the skin, carcinoma in situ of the cervix, early-stage bladder cancer, or low-grade endometrial cancer
• Malignancies that have undergone a putative surgical cure (i.e., localized prostate cancer post-prostatectomy) within 5 years prior to Day 1 may be discussed with the Principal Investigator.
• Any other medical conditions (including mental illness or substance abuse) deemed by the clinician to be likely to interfere with a patient's ability to provide informed consent, cooperate, or participate in the study, or to interfere with the interpretation of the results.
• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study c. Bevacizumab-Specific Exclusions
• Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
• Any prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix B)
• History of myocardial infarction or unstable angina within 6 months prior to study enrollment
• History of stroke or transient ischemic attack within 6 months prior to study enrollment

• Known CNS disease, except for treated brain metastasis

  o Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; 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 3 months prior to Day 1 will be excluded

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
• Symptomatic peripheral vascular disease
• Evidence of bleeding diathesis or coagulopathy that is not intentionally pharmacologically-induced
• 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
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
• Serious, non-healing wound, ulcer, or bone fracture
• Proteinuria at screening as demonstrated by a urine protein: creatinine (UPC) ratio >= 1.0. If UPC >= 1.0, the patient must undergo a 24 hour urine collection which must demonstrate <= 1g of protein in 24 hours to be eligible.

• Known hypersensitivity to any component of bevacizumab

  d. RAD001- Specific Exclusions

• Known hypersensitivity to any component of RAD001
• Chronic treatment with systemic steroids or another immunosuppressive agent
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
• Severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air)
• If O2 saturation is <= 88% at rest on screening, pulmonary function tests (PFTs) will be ordered to confirm normal pulmonary function and eligibility.
• Fasting total cholesterol > 350 mg/dl
• Fasting triglyceride level > 400 mg/dl or >2.5x ULN
• Fasting serum glucose > 250 mg/dl
• Serum phosphorus < 2.0 mg/dl Serum corrected calcium < 8.0 mg/dL