Phase II Study of Bi-Weekly Temozolomide Plus Bevacizumab for Adult Patients With Recurrent Glioblastoma Multiforme

Inclusion Criteria:

Patients must have histologically confirmed diagnosis of a glioblastoma
multiforme/gliosarcoma and:

- Must have completed at least 2 cycles of adjuvant chemotherapy

- Age > 18 years

- Karnofsky > 60%

- Hematocrit > 29%, ANC > 1,500 cells/dl, platelets > 125,000 cells/dl

- Serum creatinine < 1.5 mg/dl, BUN < 25 mg/dl, serum SGOT and bilirubin < 1.5 times
upper limit of normal

- If on corticosteroids, must be on a stable dose for 1 week prior to entry; if
clinically possible, the dose should not be escalated over entry dose level

- Signed informed consent approved by the Institutional Review Board prior to study
entry

- If sexually active, will take contraceptive measures for the duration of the
treatments

Exclusion Criteria:

- Prior toxicity grade ≥ 3 with TMZ

- Prior treatment with bevacizumab

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential not employing an effective method of birth control

- Concurrent severe and/or uncontrolled medical disease that could compromise
participation in the study

- Acute or chronic liver disease (i.e., hepatitis, cirrhosis)

- Confirmed diagnosis of HIV infection

- Have received investigational drugs less than 4 weeks prior to entry on this study or
who have not recovered from the toxic effects of such therapy

- Have received chemotherapy within 2 weeks prior (6 weeks for nitrosourea) to entry on
this study, or who have not recovered from the toxic effects of such therapy

- Have received biologic, immunotherapeutic or cytostatic agents within 1 week prior to
entry on this study or who have not recovered from the toxic effects of such therapy

- Less than 5 years free of another primary malignancy except: if the other primary
malignancy is not currently clinically significant

- Have received radiation therapy within 2 weeks prior to entry on this study or who
have not recovered from the toxic effects of such therapy.

- Surgical resection of brain tumor within 4 weeks prior to entry on this study or who
have not recovered from side effects of such therapy

- Have had any surgery other than resection of a brain tumor within 4 weeks prior to
entry on this study or who have not recovered from side effects of such therapy

- Unwilling to or unable to comply with the protocol

- Evidence of tumor progression within on immediate post radiation brain imaging

- Have not received at least 2 cycles of adjuvant chemotherapy

- Life expectancy of less than 12 weeks

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study

Bevacizumab-Specific Exclusions:

- Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
and/or diastolic blood pressure > 100 mmHg)

- Prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure (see
Appendix E)

- History of myocardial infarction or unstable angina within 6 months

- History of stroke or transient ischemic attack within 6 months

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1 or anticipation of need for major surgical procedure during the course
of the study

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days

- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1

- Serious, non-healing wound, active ulcer, or untreated bone fracture.

- Proteinuria as demonstrated by a UPC ratio greater than or equal to 1.0 at screening

- Known hypersensitivity to any component of bevacizumab