Border Zone Stereotactic Radiosurgery With Bevacizumab in Patients With Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) is the most common primary brain tumor in adults.
Unfortunately, despite aggressive surgery, radiation therapy (RT) and chemotherapy, the
prognosis for this disease is poor. It is our hypothesis that GBM is a "local" disease
wherein treatment failure is due to failure to eradicate tumor cells in the pathways along
which the tumor eventually spreads (the "border zone").

The investigators hypothesize that treatment volume escalation will be successful at
improving overall survival in patients with GBM when appropriate targeting and precision dose
delivery is performed in a single treatment session. The 'border zone' of the tumor will be
targeted for SRS (defined as a combination of the MRI volume of gadolinium enhancement plus
up to 2 cm of the surrounding T2 volume). This represents the volume of tumor infiltrated
white matter and is the route of GBM spread. Bevacizumab, a monoclonal antibody to vascular
endothelial growth factor (VEGF), has been used with safety and clinical success with
concomitant chemotherapy in solid tumors, including GBM.

The investigators further hypothesize that a combined approach of SRS with this VEGF
inhibitor will be an effective strategy for GBM because bevacizumab will maximize the effects
of radiation in the treated volume and potentially reduce radiation toxicity in the adjacent
brain.

Inclusion Criteria:

1. Histologically confirmed glioblastoma multiforme, WHO grade IV astrocytoma.

2. Prior first-line treatment with surgery or biopsy followed by fractionated
radiotherapy with concurrent temozolomide-containing chemotherapy is required for
glioblastoma patients. Additional prior chemotherapy is allowed, without limitation on
number of recurrences.

3. An interval of at least 2 months since completion of fractionated radiotherapy.

4. Age > 18 years

5. Life expectancy of at least 12 weeks.

6. Karnofsky Performance Status score (KPS) of ≥ 60

7. Documented recurrent disease; Disease must be evaluable, but does not need to be
measurable; the target site for SRS does not need to be located in a
previously-irradiated area.

8. All patients must have no restrictions to obtaining MRI with and without gadolinium
contrast.

9. Adequate bone marrow, hepatic and renal function ; BUN < 25 and Cr < 1.7

10. Negative pregnancy test at the time of SRS in any patient who could be pregnant.

11. Willingness to forego additional therapy until evidence of disease progression

Exclusion Criteria:

1. General Medical Exclusions:

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

2. Active malignancy, other than superficial basal cell and superficial squamous (skin)
cell, or carcinoma in situ of the cervix within last 3 years.

3. Prior radiosurgery

4. Prior intracavitary irradiation or Gliadel wafers.

2. Disease-Specific Exclusions:

1. Inability to comply with protocol or study procedures

2. Prior treatment with bevacizumab.

3. Inability to undergo MRI with and without contrast administration.

3. Bevacizumab-Specific Exclusions:

1. Inadequately controlled hypertension.

2. Prior history of hypertensive crisis or hypertensive encephalopathy.

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

4. History of myocardial infarction or unstable angina within 6 months prior to Day 1.

5. History of stroke or transient ischemic attack within 6 months prior to Day 1.

6. Significant vascular disease within 6 months prior to Day 1.

7. History of hemoptysis within 1 month prior to Day 1.

8. Evidence of bleeding diathesis or significant coagulopathy

9. Major surgical procedure, open biopsy, or significant traumatic injury within 14 days
prior to Day 1 or anticipation of need for major non -cranial surgical procedure
during the course of the study.

10. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1.

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

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

13. Proteinuria

14. Known hypersensitivity to any component of bevacizumab

15. Pregnancy (positive pregnancy test) or lactation. Use of effective means of
contraception (men and women) in subjects of child-bearing potential.