Avastin in Combination With Radiation (XRT) & Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma (GBM) and Gliosarcomas

Inclusion Criteria:

• Patients must have histologically confirmed diagnosis of World Health Organization (WHO) grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma).Patients have to be within 4 weeks of the last major surgical procedure.

• Age > 18 years.

• An interval of at least 2 weeks and not > 6 weeks between prior major surgicalprocedure and study enrollment.

• No prior radiotherapy or chemotherapy for a brain tumor

• Karnofsky ≥ 60 percent.

• Hemoglobin ≥ 9.0 g/deciliter (dl), absolute neutrophil count (ANC) ≥ 1,500 cells/microliter, platelets ≥ 125,000 cells/microliter.

• Serum creatinine ≤ 1.5 mg/dl, serum serum glutamic-oxaloacetic transaminase (SGOT) andbilirubin ≤ 1.5 times upper limit of normal (ULN).

• For patients on corticosteroids, they must be on a stable or decreasing dose for 1week prior to entry, and the dose should not be escalated over entry dose level, ifclinically possible.

• Signed informed consent approved by the Institutional Review Board

• No evidence of > grade 1 central nervous system (CNS) hemorrhage on the baseline MRIor CT scan.

• If sexually active, patients will take contraceptive measures for the duration oftreatment as stated in the informed consent.

Exclusion Criteria:

• Pregnancy or breast feeding.

• Co-medication that may interfere with study results; e.g. immuno-suppressive agentsother than corticosteroids.

• Active infection requiring intravenous (IV) antibiotics.

• Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective ofthe grade of the tumor.

• Evidence of > grade 1 CNS hemorrhage on baseline MRI on CT scan. Avastin-Specific Concerns: Subjects meeting any of the following criteria are ineligible for study entry:

• Current, recent (within 4 weeks of the first infusion of this study), or plannedparticipation in an experimental drug study

• Blood pressure of 150/100 mmHg

• Unstable angina

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of myocardial infarction within 6 months

• History of stroke within 6 months

• Clinically significant peripheral vascular disease

• Evidence of bleeding diathesis

• Coagulopathy (prothrombin time (PT) or partial thromboplastin time (PTT) >1.5x normalor a history of > three grade 2 or greater hemorrhages)

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 daysprior to first Avastin infusion during XRT/Temodar or anticipation of need for majorsurgical procedure during the course of the study

• Minor surgical procedures, fine needle aspirations or core biopsies within 7 daysprior to first Avastin infusion during XRT/Temodar

• Pregnant (positive pregnancy test) or lactating

• Urine protein >1.0 + at screening

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesswithin 6 months prior to first Avastin infusion during XRT/Temodar

• Serious, non-healing wound, ulcer, or bone fractures.

• Inability to comply with study and/or follow-up procedures.