title: Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study.
abstract: This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m(2) i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m(2) increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m(2) of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the 2, but no relationship dosage range of 350 to 800 mg/m between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m(2) dose, the AUC for CPT-11 (21.6 microg x h/ml) matched the AUC (21.6 microg x h/ml) in the non-EIAED group treated with 350 mg/m(2) of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m(2) when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.
authors.affiliation: Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA 94143, USA. pradosm@neurosurg.ucsf.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: W K A
authors.initials: WK
authors.lastname: Yung
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jaeckle
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: M Kelly
authors.initials: MK
authors.lastname: Nicholas
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Harry S
authors.initials: HS
authors.lastname: Greenberg
authors.forename: Larry
authors.initials: L
authors.lastname: Junck
authors.forename: Karen L
authors.initials: KL
authors.lastname: Fink
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: John
authors.initials: J
authors.lastname: Kuhn
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D000077146:Irinotecan; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy*; D009656:North America; D018709:Statistics, Nonparametric
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin