title: Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial.
abstract: OBJECTIVE
  This phase I trial was designed to (1) establish the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite.
  
  
  METHODS
  The first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT).
  
  
  RESULTS
  Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4 micromol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 micromol/L.
  
  
  CONCLUSIONS
  Systemically administered O6-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.
authors.affiliation: New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Weingart
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carson
authors.forename: Joy D
authors.initials: JD
authors.lastname: Fisher
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: Mark L
authors.initials: ML
authors.lastname: Rosenblum
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.forename: Kevin
authors.initials: K
authors.lastname: Judy
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Tatter
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000008:administration & dosage; D016503:Drug Delivery Systems; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C453779:carmustine with prolifeprosan 20; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine