Trial of the Combination of Bevacizumab and Everolimus in Patients With Refractory, Progressive Intracranial Meningioma

Inclusion Criteria: 1. Patients must be 18 years of age. 2. Histologic diagnosis of meningioma, WHO grade 1, 2, or 3 (benign, atypical, or malignant). In addition, patients with definitive radiologic evidence of meningioma who are unresectable, and in whom radiation therapy without biopsy is the standard treatment, are also eligible. 3. All patients must have developed recurrent disease/progression after receiving all standard treatments, which must include the following: * surgical resection, if possible; * definitive radiation therapy for unresectable meningioma, or for recurrent meningioma after resection. * patients must be at least 4 weeks post-surgery, and must be at least 2 weeks post-radiation therapy, with resolution of related toxicities. 4. All patients must have progressive symptoms judged to be directly related to their recurrent/progressive meningioma. Patients with no new symptoms, or patients with stable neurologic deficits from previous surgical resection, are not eligible. 5. Patients may have had 0 or 1 previous systemic treatment regimens. 6. ECOG performance status of 0-2. 7. Adequate bone marrow, kidney, and liver function, as follows: * Absolute neutrophil count (ANC) ≥1500/μL * Hemoglobin (Hgb) ≥9 g/dL * Platelets ≥100,000/L (≤7 days prior to treatment) * AST or ALT ≤2.5 x institutional upper limit of normal (ULN) * Total bilirubin ≤1.5 x institutional ULN * Serum creatinine ≤1.5 x institutional ULN 8. Life expectancy of at least 12 weeks. 9. Ability to swallow whole pills. 10. Patients must have measurable disease on MRI scan. 11. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately. 12. INR ≤1.5 x institutional upper limit of normal (ULN) . (Anticoagulation is allowed if target INR is ≤1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for \>2 weeks at the time of study entry). 13. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x institutional ULN. Note: In case one or both of these thresholds are exceeded, the patient can only be included in the study after initiation of appropriate lipid-lowering medication. 14. Patients must be accessible for treatment and follow-up. 15. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry. Exclusion Criteria: 1. Previous treatment with bevacizumab or any other anti-angiogenesis agents. 2. Previous treatment with m-TOR inhibitors (sirolimus, temsirolimus, everolimus). 3. Patients who have had major surgery or significant traumatic injury within 4 weeks of the start of study drugs, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia), or patients that may require major surgery during the course of the study. 4. Minor surgical procedures (with the exception of the placement of portacath or other central venous access) must be completed at least 7 days prior to beginning protocol treatment. 5. Women who are pregnant or lactating. 6. Patients with proteinuria at screening as demonstrated by either: urine protein creatinine (UPC) ratio 1.0 at screening OR urine dipstick for proteinuria 2+ (patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection, and must demonstrate 1 g of protein/24 hours to be eligible) 7. Patients with a serious non-healing wound, active ulcer, or untreated bone fracture. 8. Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). 9. Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) within 1 month prior to study enrollment. 10. History of myocardial infarction or unstable angina within 6 months of beginning treatment. 11. Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and /or diastolic blood pressure \>100 mmHg while on antihypertensive medications). 12. New York Heart Association (NYHA) class II or greater congestive heart failure (CHF). 13. Serious cardiac arrhythmia requiring medication. 14. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of treatment. 15. History of stroke or transient ischemic attack within 6 months prior to beginning treatment. 16. Any prior history of hypertensive crisis or hypertensive encephalopathy. 17. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 of beginning treatment. 18. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). 19. Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as: * unstable angina pectoris, symptomatic CHF, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease * severely impaired lung function * uncontrolled diabetes as defined by fasting serum glucose \>1.5 x ULN * active (acute or chronic) or uncontrolled severe infections * liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis. 20. Known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus), or to its excipients. 21. Immunization with attenuated live vaccines within 1 week of the study, or anytime during study treatment. 22. Chronic, systemic treatment with immunosuppressive agents. Patients who require a stable dose of corticosteroids for control of cerebral edema are eligible. Topical or inhaled steroids are also allowed. 23. Known human immunodeficiency virus (HIV) infection. 24. Grapefruits, star fruits, seville oranges, and their juices and products, should be avoided. 25. Drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A4 should be avoided. 26. Use of St. John's Wort or rifampicin. 27. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. 28. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study. 29. Use of any non-approved or investigational agent within 4 weeks of study entry. Patients may not receive any other investigational or anti-cancer treatments while participating in this study. 30. Other malignancies within the last 3 years, with the exception of adequately treated basal or squamous cell carcinomas of the skin, or carcinoma in situ of the cervix.