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

Stuart A Grossman, Kathryn Anne Carson, Surasak Phuphanich, Tracy Batchelor, David Peereboom, L. Burt Nabors, Glenn Lesser, Fredrick Hausheer, Jeffrey G. Supko

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)608-616
Number of pages9
JournalNeuro-Oncology
Volume10
Issue number4
DOIs
StatePublished - Aug 2008

Fingerprint

Glioma
Pharmacokinetics
Enzymes
Maximum Tolerated Dose
Pharmaceutical Preparations
Camptothecin
Clinical Trials, Phase I
Lactones
Glioblastoma
cositecan
Neutropenia
Thrombocytopenia
Disease Progression
Appointments and Schedules
Hydrolysis
Drug Therapy
Therapeutics

Keywords

  • Brain cancer
  • Cancer therapy
  • Drug interactions
  • Glioblastoma multiforme
  • Karenitecin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Phase i and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas. / Grossman, Stuart A; Carson, Kathryn Anne; Phuphanich, Surasak; Batchelor, Tracy; Peereboom, David; Nabors, L. Burt; Lesser, Glenn; Hausheer, Fredrick; Supko, Jeffrey G.

In: Neuro-Oncology, Vol. 10, No. 4, 08.2008, p. 608-616.

Research output: Contribution to journalArticle

Grossman, SA, Carson, KA, Phuphanich, S, Batchelor, T, Peereboom, D, Nabors, LB, Lesser, G, Hausheer, F & Supko, JG 2008, 'Phase i and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas', Neuro-Oncology, vol. 10, no. 4, pp. 608-616. https://doi.org/10.1215/15228517-2008-030
Grossman, Stuart A ; Carson, Kathryn Anne ; Phuphanich, Surasak ; Batchelor, Tracy ; Peereboom, David ; Nabors, L. Burt ; Lesser, Glenn ; Hausheer, Fredrick ; Supko, Jeffrey G. / Phase i and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas. In: Neuro-Oncology. 2008 ; Vol. 10, No. 4. pp. 608-616.
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