title: Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas.
abstract: Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m(2)/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m(2) in daggerEIASD patients and 1.5 mg/m(2) in -EIASD patients. The mean (+/-SD) total body clearance of karenitecin was 15.9 +/- 9.6 liters/h/m(2) in daggerEIASD patients and 10.2 +/- 3.5 liters/h/m(2) in -EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231-1000, USA. grossman@jhmi.edu
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carson
authors.forename: Surasak
authors.initials: S
authors.lastname: Phuphanich
authors.forename: Tracy
authors.initials: T
authors.lastname: Batchelor
authors.forename: David
authors.initials: D
authors.lastname: Peereboom
authors.forename: L Burt
authors.initials: LB
authors.lastname: Nabors
authors.forename: Glenn
authors.initials: G
authors.lastname: Lesser
authors.forename: Fredrick
authors.initials: F
authors.lastname: Hausheer
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; C406143:cositecan; D002166:Camptothecin