A Phase I Trial of Vorinostat in Combination With Bevacizumab & Irinotecan in Recurrent Glioblastoma

Drug Administration: (A cycle is 28 days) Irinotecan and bevacizumab are given IV on days 1
and 15 of each cycle. Vorinostat is given orally on days 1-7 and 15-21 of each cycle.

Vorinostat (provided in 100mg capsules) begins at a dose of 200mg/day, escalating to
300mg/day and then to a maximum of 400mg/day. Vorinostat will be taken prior to irinotecan
and bevacizumab on days 1 and 15. The drug should be administered at the same time every day
for days 2-7 and 16-21. Patients will be treated prophylactically with compazine 30 minutes
prior to vorinostat which, in turn, should be taken 30 minutes prior to a meal whenever
possible.

Irinotecan is given at a dose of 125mg/m2. Bevacizumab is given at a dose of 10mg/kg.

MTD will be defined by toxicities occurring during the first 4 weeks of therapy. Three
patients will be treated at dose level one and can be enrolled simultaneously. They must be
observed for DLT for at least 4 weeks from treatment day 1. Page 15 of the protocol outlines
the dose escalation parameters. At least 9 patients will be treated at the MTD. If DLT is
not achieved in any cohort of up to a dose level of 400mg/day of vorinostat, further dose
escalations will not be made. This dose will then become the recommended dose.

Patients demonstrating evidence of benefit may be treated up to a maximum of 24 cycles, at
the investigator's discretion.