Phase i and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas

Academic Article

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 pharma- cokinetics 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 +EIASD 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 +EIASD 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 camp- tothecin analogue, has little activity in recurrent MG. Copyright 2008 by the Society for Neuro-Oncology.
  • Published In

  • Neuro-Oncology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Grossman SA; Carson KA; Phuphanich S; Batchelor T; Peereboom D; Nabors LB; Lesser G; Hausheer F; Supko JG
  • Start Page

  • 608
  • End Page

  • 616
  • Volume

  • 10
  • Issue

  • 4