title: Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma.
abstract: In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade > or =3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%-29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%-27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. reard003@mc.duke.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Quinn
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: James
authors.initials: J
authors.lastname: Vredenburgh
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: James M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: Amy
authors.initials: A
authors.lastname: Walker
authors.forename: Michael
authors.initials: M
authors.lastname: Badruddoja
authors.forename: Sandra
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Dowell
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: Steven
authors.initials: S
authors.lastname: Silverman
authors.forename: Cindy
authors.initials: C
authors.lastname: Bohlin
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
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 / Q000008:administration & dosage*; D001254:Astrocytoma / Q000188:drug therapy / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002330:Carmustine / Q000008:administration & dosage; D016001:Confidence Intervals; 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; D009837:Oligodendroglioma / Q000188:drug therapy / Q000473:pathology
chemical_list: D000077146:Irinotecan; D002330:Carmustine; D002166:Camptothecin