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Phase II Trial of Gliadel Plus O6-Benzylguanine (O6-BG) for Patients With Recurrent Glioblastoma Multiforme


Posted on: 06/06/2006

Phase II Trial of Gliadel Plus O6-Benzylguanine (O6-BG) for Patients With Recurrent Glioblastoma Multiforme
Jennifer A. Quinn, James J. Vredenburgh, Jeremy N. Rich, David A. Reardon, Annick Desjardins, Sridharan Gururangan, Allan H. Friedman, Darell D. Bigner, Kyle Lavin, Sith Sathornsumetee, Stevie Threatt, and Henry S. Friedman; Duke University Medical Center, Durham NC 27710.
 
The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) which removes chloroethylation or methylation damage from the O6-position of guanine. O6-BG is an AGT substrate that inhibits AGT by suicide inactivation. A previous placebo-controlled trial has shown that Gliadel wafer significantly prolongs 6-month survival (55.5% for Gliadel vs. 35.6 for placebo) in patients with recurrent glioblastoma multiforme (GBM). Despite the success of Gliadel in prolonging survival we may be able to improve on this success by depleting AGT. Thus, we have designed a phase 2 trial where we define the activity and the toxicity of Gliadel in combination with a 5-day infusion of O6-BG in patients with recurrent GBM. In a prior study the O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. In order to guarantee depletion of tumor AGT activity for at least 5 days, this O6-BG bolus was repeated on days 3 and 5 while continuing the infusion. To date, 24 patients have been enrolled out of a planned accrual of 50 patients. Seventeen of these patients received prior nitrosourea therapy. The 6-month progression free survival is 68%. The adverse events include the following: 2 episodes of CSF leak (8%), 4 episodes of wound infection at craniotomy site (16%), 5 episodes of grade ³ 3 seizures (21%) and 3 episodes of hyponatremia (12%). These adverse events were similar in frequency to those seen in patients receiving Gliadel in prior placebo-controlled Gliadel trials. Thus far, this data demonstrates an increase in the efficacy of Gliadel when combined with O6-BG. Twenty-six additional patients will be enrolled for a total accrual of 50 patients. 

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