This is a Phase II, open-label, multicenter, randomized, non comparative study consisting of two concurrent single-arms. Approximately 160 subjects will be randomized in a 1:1 ratio to Arm 1 (bevacizumab alone) or Arm 2 (bevacizumab + irinotecan).

Inclusion Criteria:

• Signed Informed Consent Form
• Age ≥ 18 years
• Histologically confirmed GBM in first or second relapse
• 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 first treatment (Day 0)
• An interval of ≥ 4 weeks since prior surgical resection
• Prior standard radiation for GBM
• Prior chemotherapy: first-relapse subjects
• Prior chemotherapy: second-relapse subjects
• Recovery from the effects of prior therapy, including the following: 4 weeks from cytotoxic agents (except 6 weeks from nitrosoureas, 3 weeks from procarbazine, 2 weeks from vincristine); 4 weeks from any investigational agent; 1 week from non-cytotoxic agents; 8 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
• Prior therapy with gamma knife or other focal high-dose radiation is allowed but the subject must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field
• Karnofsky performance status ≥ 70
• Life expectancy > 12 weeks
• Use of an effective means of contraception in males and in females of childbearing potential
• Ability to comply with study and follow-up procedures

Exclusion Criteria:

• Prior treatment with irinotecan, bevacizumab, or another VEGF or VEGFR-targeted agent
• Prior treatment with prolifeprospan 20 with carmustine wafer
• 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: Presence of hemosiderin; Resolving hemorrhagic changes related to surgery; Presence of punctate hemorrhage in the tumor
• Received more than two treatment regimens for Grade III and/or Grade IV glioma
• Blood pressure of > 150 mmHg systolic and > 100 mmHg diastolic
• History of hypertensive encephalopathy
• New York Heart Association (NYHA) Grade II or greater CHF
• History of myocardial infarction or unstable angina within 6 months prior to Day 0
• History of stroke or transient ischemic attack within 6 months prior to study enrollment
• Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to Day 0
• Evidence of bleeding diathesis or coagulopathy
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0
• History of intracerebral abscess within 6 months prior to Day 0
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study
• Minor surgical procedures (excluding placement of a vascular access device), stereotactic biopsy, fine needle aspirations, or core biopsies within 7 days prior to Day 0
• Serious non-healing wound, ulcer, or bone fracture
• Pregnancy (positive pregnancy test) or lactation
• Known hypersensitivity to any component of bevacizumab
• History of any other malignancy within 5 years (except non-melanoma skin cancer or carcinoma in situ of the cervix)
• Pregnant or nursing females
• Unstable systemic disease, including active infection, uncontrolled hypertension, or serious cardiac arrhythmia requiring medication
• Subjects unable to undergo an MRI with contrast