title: Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma.
abstract: Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. quinn008@mc.duke.edu
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Quinn
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: James
authors.initials: J
authors.lastname: Vredenburgh
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: James M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: Amy
authors.initials: A
authors.lastname: Walker
authors.forename: Holly
authors.initials: H
authors.lastname: Schweitzer
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Sandra
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Affronti
authors.forename: Susanne
authors.initials: S
authors.lastname: Jackson
authors.forename: Deborah
authors.initials: D
authors.lastname: Allen
authors.forename: Karen
authors.initials: K
authors.lastname: Ziegler
authors.forename: Cindy
authors.initials: C
authors.lastname: Bohlin
authors.forename: Christy
authors.initials: C
authors.lastname: Lentz
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001254:Astrocytoma / Q000188:drug therapy / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009837:Oligodendroglioma / Q000188:drug therapy / Q000473:pathology
chemical_list: D000077146:Irinotecan; D002330:Carmustine; D002166:Camptothecin