title: Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.
abstract: OBJECTIVE
  We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG.
  
  
  METHODS
  For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined.
  
  
  RESULTS
  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. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression.
  
  
  CONCLUSIONS
  This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA. quinn008@mc.duke.edu
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Quinn
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Jon
authors.initials: J
authors.lastname: Weingart
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: James
authors.initials: J
authors.lastname: Vredenburgh
authors.forename: Jeremy
authors.initials: J
authors.lastname: Rich
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pegg
authors.forename: Robert C
authors.initials: RC
authors.lastname: Moschel
authors.forename: Robert
authors.initials: R
authors.lastname: Birch
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: James M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: Janet E
authors.initials: JE
authors.lastname: Dancey
authors.forename: Jill
authors.initials: J
authors.lastname: Maxwell
authors.forename: Sandra
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018450:Disease Progression; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077204:Temozolomide
chemical_list: C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D000077204:Temozolomide