A Study of Gliadel Followed by Avastin + Irinotecan for Glioblastoma Multiforme (GBM)

This is a phase II study of the combination of Gliadel followed by Avastin and irinotecan in
grade IV malignant glioma patients. The study will have survival and toxicity endpoints.
Subjects will be identified by the investigator as those patients who have histologically
documented grade IV malignant glioma (glioblastoma multiforme or gliosarcoma) with recurrent
or progressive disease who are able to undergo a GTR (gross total resection).

Phase I: Gliadel wafer- 1-8 wafers inserted at time of gross total resection. Treatment
cycle is 42 days in length. For patients with ≥ Grade 1 toxicity will allow 84 days prior to
beginning therapy with Avastin and CPT-11.

Phase II: Avastin Plus Irinotecan (Cycles 1-12) consists of the following (cycle length is 6
weeks):

- Irinotecan 125 mg/m2 (not taking EIAEDs) or 340 mg/m2 (taking EIAEDs) given every two
weeks on days 1, 15, 29, etc.;

- If the patient has the UGT 1A1 polymorphism (7/7), they do not metabolize the
irinotecan normally, so these patients will start out at a two dose level reduction;
For patients on an EIAED, the starting dose will be 275 mg/M2, and for patients not on
an EIAED, the starting dose will be 75 mg/M2;

- Avastin 10 mg/kg immediately after the irinotecan given every 2 weeks on days 1, 15,
29, etc.

The primary objective of this phase II study is to determine whether the administration of
Gliadel wafers followed by Avastin and irinotecan to patients with recurrent GBM is a
treatment regimen worthy of further investigation in a randomized clinical trial. The basis
for making this decision will be the proportion of patients who survive at least 24 weeks
after initiation of protocol treatment.

In the initial Phase I and II clinical trials, four potential Avastin-associated safety
signals were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage.
The two major toxicities associated with irinotecan are myelosuppression and diarrhea. Side
effects associated with Gliadel are seizures, brain edema (swelling), healing abnormalities,
wound infection and body pain.