Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma.
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.
Quinn
Jennifer A
JA
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. quinn008@mc.duke.edu
Reardon
David A
DA
Friedman
Allan H
AH
Rich
Jeremy N
JN
Sampson
John H
JH
Vredenburgh
James
J
Gururangan
Sridharan
S
Provenzale
James M
JM
Walker
Amy
A
Schweitzer
Holly
H
Bigner
Darell D
DD
Tourt-Uhlig
Sandra
S
Herndon
James E
JE
Affronti
Mary Lou
ML
Jackson
Susanne
S
Allen
Deborah
D
Ziegler
Karen
K
Bohlin
Cindy
C
Lentz
Christy
C
Friedman
Henry S
HS
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
D000077146:Irinotecan; D002330:Carmustine; D002166:Camptothecin