Phase III Double-Blind Placebo-Controlled Trial of Conventional Concurrent Chemoradiation and Adjuvant Temozolomide Plus Bevacizumab Versus Conventional Concurrent Chemoradiation and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma

Inclusion Criteria:

- Histologically confirmed glioblastoma (gliosarcoma closed to accrual as of 07-13-10)

- WHO grade IV disease

- Tumor must have a supratentorial component

- Has undergone partial or complete surgical resection of tumor within the past 3-5
weeks

- Diagnosis must be made by surgical excision (not by stereotactic biopsy)

- No significant postoperative hemorrhage, defined as > 1 cm diameter of blood in
the tumor cavity by MRI or CT scan

- Has ≥ 1 block of tumor tissue of sufficient size available for analysis of MGMT
status and determination of molecular profile

- At least 1 cm³ of tissue composed primarily of tumor must be present

- No CUSA (Cavitron ultrasonic aspirator)-derived material

- No recurrent or multifocal malignant glioma

- No metastases detected below the tentorium or beyond the cranial vault

- Karnofsky performance status 70-100%

- Absolute neutrophil count ≥ 1,800/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)

- ALT and AST ≤ 3 times normal

- Bilirubin ≤ 2.0 mg/dL

- PT/INR < 1.4 (for patients not on warfarin)

- Creatinine ≤ 1.7 mg/dL

- Urine protein: creatinine ratio < 0.5 OR 24-hour urine protein < 1,000 mg

- BUN ≤ 30 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 6 months after
completion of study treatment

- Systolic blood pressure (BP) ≤ 160 mm Hg or diastolic BP ≤ 90 mm Hg

- No evidence of acute cardiac ischemia by electrocardiogram

- No other invasive malignancy within the past 3 years, except for nonmelanomatous skin
cancer or carcinoma in situ of the breast, oral cavity, or cervix

- No severe, active comorbidity, including any of the following:

- Unstable angina and/or congestive heart failure within the past 6 months

- Transmural myocardial infarction within the past 6 months

- Evidence of recent myocardial infarction or ischemia as indicated by ST
elevations of ≥ 2 mm by EKG

- New York Heart Association class II-IV congestive heart failure requiring
hospitalization within the past 12 months

- Stroke, cerebral vascular accident, or transient ischemic attack within the past
6 months

- Serious, inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g., aortic aneurysm or history of aortic
dissection) or clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Serious or non-healing wound, ulcer, or bone fracture

- Abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, or
significant traumatic injury within the past 28 days

- Acute bacterial or fungal infection requiring IV antibiotics

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- AIDS based on current CDC definition

- Active connective tissue disorders (e.g., lupus or scleroderma) that, in the
opinion of the treating physician, may place the patient at high risk for
radiation toxicity

- Any other major medical illness or psychiatric impairment that, in the opinion
of the investigator, would preclude study drug administration or completion of
study therapy

- Recovered from prior surgery

- No prior chemotherapy or radiosensitizers for cancer of the head and neck region

- Prior chemotherapy for a different cancer is allowed

- No prior temozolomide or bevacizumab

- No prior Gliadel wafers or any other intratumoral or intracavitary treatment

- No prior radiotherapy to the head and neck (except for T1 glottic cancer) resulting
in overlap of radiotherapy fields

- More than 28 days since prior major surgical procedure or open biopsy other than
craniotomy for tumor resection

- More than 30 days since prior and no concurrent treatment on another therapeutic
clinical trial

- No concurrent growth factors to induce elevations in neutrophil count for the
purposes of administration of temozolomide on the scheduled dosing interval; to allow
treatment with temozolomide at a higher dose; or to avoid interruption of the
treatment during concurrent radiotherapy

- No concurrent erythropoietin

- No concurrent tumor debulking surgery, other chemotherapy, immunotherapy, biologic
therapy, or additional stereotactic boost radiotherapy

- No other concurrent investigational drugs during the "blinded phase" of the study

- Concurrent full-dose anticoagulants (e.g., warfarin or low molecular weight heparin)
allowed provided both of the following criteria are met:

- No active bleeding or pathological condition that carries a high risk of
bleeding (e.g., tumor involving major vessels or known varices)

- In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a
stable dose of low molecular weight heparin