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

Inclusion Criteria

• Signed Informed Consent Form
• Age >/= 18 years
• 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.
• Radiographic demonstration of disease progression following prior therapy
• 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.
• 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. .
• An interval of >/= 4 weeks since surgical resection is required prior to starting protocol therapy.
• Prior standard radiation for glioblastoma
• 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.
• 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.
• 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
• 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 /= 60 cc/min/1.73 m^2) and a urine protein:creatinine ratio of /= 9 months post their original surgery date.
• Patients must not have received any investigational agents within 28 days prior to commencing study treatment.
• Prior intracerebral agents
• Need for urgent palliative intervention for primary disease (e.g., impending herniation)
• 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
• Blood pressure of > 140 mmHg systolic and > 90 mmHg diastolic
• History of hypertensive encephalopathy
• New York Heart Association (NYHA) Grade II or greater chronic heart failure(CHF)
• History of myocardial infarction or unstable angina within 6 months prior to Day 1
• History of stroke or transient ischemic attack within 6 months prior to st