Phase II trial of Gliadel plus O(6)-benzylguanine (O(6)-BG) for patients with recurrent glioblastoma multiforme.

Published

Journal Article

1568 Background. The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) which removes chloroethylation or methylation damage from the O(6)-position of guanine. O(6)-BG is an AGT substrate that inhibits AGT by suicide inactivation. A previous phase III randomized, placebo-controlled trial has shown that Gliadel wafer significantly prolongs 6-month survival (55.5% for Gliadel vs. 35.6% for placebo) and median survival (28 weeks for Gliadel vs. 20 weeks for placebo) in patients with recurrent glioblastoma multiforme (GBM) (Brem et al 1995). Despite the success of Gliadel in prolonging survival we may be able to improve on this success by depleting AGT. METHODS: 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 O(6)-BG in patients with recurrent GBM. In a prior study the O(6)-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m(2) over 1 hour followed by a continuous infusion of 30 mg/m(2)/d for 48 hours. In order to guarantee depletion of tumor AGT activity for at least 5 days after Gliadel placement, this O(6)-BG bolus was repeated on days 3 and 5 while continuing the infusion. RESULTS: 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 survival is 68% and the median survival is 36 weeks. 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 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. CONCLUSIONS: Thus far, this data demonstrates an increase in the efficacy of Gliadel when combined with O(6)-BG. Twenty-six additional patients will be enrolled for a total accrual of 50 patients. [Table: see text].

Full Text

Duke Authors

Cited Authors

  • Quinn, JA; Vredenburgh, JJ; Rich, JN; Reardon, DA; Desjardins, A; Gururangan, S; Friedman, AH; Lavin, K; Sathornsumetee, S; Threatt, S; Friedman, HS

Published Date

  • June 20, 2006

Published In

Volume / Issue

  • 24 / 18_suppl

Start / End Page

  • 1568 -

PubMed ID

  • 27952495

Electronic International Standard Serial Number (EISSN)

  • 1527-7755

Language

  • eng

Conference Location

  • United States