Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM)

Inclusion Criteria:

1. Signed Informed Consent Form
2. Age \>/= 18 years
3. Histologically confirmed glioblastoma in first, second or third relapse. A pathology report constitutes adequate documentation of histology for study inclusion. Subjects with an initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy is determined to be glioblastoma. The amount of prior systemic therapy for this population is, nevertheless, restricted to three regimens, with one including temozolomide.
4. Radiographic demonstration of disease progression following prior therapy
5. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on MRI performed within 14 days prior to registration (Day 1). Baseline MRIs for subjects who underwent salvage surgery after first or second relapse must be obtained \>/= 4 weeks after the procedure. If receiving corticosteroids, subjects must be on a stable or decreasing dose of corticosteroids for \>/= 5 days prior to baseline MRI.
6. Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: 1) They have recovered from the effects of surgery. 2) Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. 3) To best assess the extent of residual measurable disease post-operatively, a MRI should be done no later than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively. .
7. An interval of \>/= 4 weeks since surgical resection is required prior to starting protocol therapy.
8. Prior standard radiation for glioblastoma
9. Prior chemotherapy: All first-relapse subjects must have received temozolomide. All second- and third-relapse subjects must have received temozolomide. Patients may not have received prior nitrosoureas.
10. Recovery from the effects of prior therapy, including the following: Four weeks from cytotoxic agents (3 weeks from procarbazine, 2 weeks from vincristine); Four weeks from any investigational agent; One week from non-cytotoxic agents(eg accutane, thalidomide); Eight weeks from radiotherapy to minimize the potential for MRI changes related to radiation necrosis that might be misdiagnosed as progression of disease, or 4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside the primary radiation field; Patients may have had gliadel wafers during their original surgery but they must be \>/= 9 months post their original surgery date.
11. Prior therapy with gamma knife or other focal high-dose radiation is allowed, but the subject must have subsequent histologic documentation of recurrence or positron emission tomography (PET) or MR Spectroscopic documentation of tumor, unless the recurrence is a new lesion outside the irradiated field
12. Patients must have adequate bone marrow function (WBC \>/= 3,000/µl, absolute neutrophil count (ANC) \>/= 1,500/mm\^3, platelet count of \>/= 100,000/mm\^3, and hemoglobin \>/= 10 gm/dl), adequate liver function (SGPT \< 3 times normal and alkaline phosphatase \< 2 times normal, bilirubin \<1.5 mg/dl), adequate renal function (creatinine \</= 1.5 mg/dL or creatinine clearance \>/= 60 cc/min/1.73 m\^2) and a urine protein:creatinine ratio of \</=1 before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
13. Patients must have a Karnofsky performance status (KPS) equal or greater than 60
14. Use of an effective means of contraception in males and in females of childbearing potential. Women of childbearing potential must have a negative β-human chorionic gonadotropin (HCG) pregnancy test documented within 14 days prior to registration. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
15. Ability to comply with study and follow-up procedures
16. Patients receiving treatment with other antiepileptic medications will not be excluded. Patients should preferably be treated with non-enzyme inducing anti-epileptic medications to avoid any potential interactions with lomustine. However, the use of non-enzyme inducing anti-epileptic medications is not mandatory. If enzyme-inducing antiepileptic drugs are used, monitoring of drug levels should be considered, as considered clinically appropriate by the treating physician.
17. Patients on the following medications will be included: Anticoagulants/Anti-platelets: Patients on stable dose anticoagulants (e.g. warfarin, low molecular-weight heparin) and in-range international normalized ratio (INR) (2-3) are eligible. Patients are allowed to take aspirin, clopidogrel, ticlopidine, Aggrenox, ibuprofen and other NSAIDS.
18. Patients must be willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while enrolled in the study.
19. This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race. Minorities will actively be recruited to participate.

Exclusion Criteria:

1. Prior treatment with anti-angiogenesis (eg bevacizumab, sorafenib, sunitinib) agent or nitrosurea (eg. lomustine, carmustine, nimustine).
2. Prior treatment with polifeprosan 20 with carmustine wafer except for the patients with gliadel wafers \>/= 9 months post their original surgery date.
3. Patients must not have received any investigational agents within 28 days prior to commencing study treatment.
4. Prior intracerebral agents
5. Need for urgent palliative intervention for primary disease (e.g., impending herniation)
6. Evidence of recent hemorrhage on baseline MRI of the brain with the following exceptions: (1) Presence of hemosiderin (2) Resolving hemorrhagic changes related to surgery (3) Presence of punctate hemorrhage in the tumor
7. Blood pressure of \> 140 mmHg systolic and \> 90 mmHg diastolic
8. History of hypertensive encephalopathy
9. New York Heart Association (NYHA) Grade II or greater chronic heart failure(CHF)
10. History of myocardial infarction or unstable angina within 6 months prior to Day 1
11. History of stroke or transient ischemic attack within 6 months prior to study enrollment
12. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to Day 1
13. Evidence of bleeding diathesis or coagulopathy or INR \>1.5 unless on a stable dose of anticoagulation therapy. History of significant bleeding disorder unrelated to cancer, including: (1) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) (2) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) (3) Ongoing or recent (\</= 3 months) significant gastrointestinal bleeding
14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1
15. History of intracerebral abscess within 6 months prior to Day 1
16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study
17. Minor surgical procedures (excluding placement of a vascular access device), stereotactic biopsy, fine needle aspirations, or core biopsies within 7 days prior to Day 1
18. Serious non-healing wound, ulcer, or bone fracture
19. Pregnancy (positive pregnancy test) or lactation
20. Known hypersensitivity to any component of bevacizumab
21. History of any other malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible
22. Pregnant or nursing females
23. Unstable systemic disease, including active infection, uncontrolled hypertension, or serious cardiac arrhythmia requiring medication
24. Subjects unable to undergo an MRI with contrast
25. Patients with a known allergy to bevacizumab, or a known allergy to nitrosoureas (eg. lomustine, carmustine, nimustine) will be excluded
26. Patient must be able to tolerate the procedures required in this study including periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study. Inability to comply with protocol or study procedures (for example, an inability to swallow tablets) will be an exclusion criteria.