A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas

David M. Peereboom, Jeffrey G. Supko, Kathryn A. Carson, Tracy Batchelor, Surasak Phuphanich, Glenn Lesser, Tom Mikkelson, Joy Fisher, Serena Desideri, Xiaoying He, Stuart A. Grossman

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Abstract

Ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. A phase I/II and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. Adult patients received ixabepilone as a 1-h infusion daily for 5 days every 3 weeks. A modified continual reassessment method was used to escalate doses, beginning at 5.0 mg/m2, in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (EIAED). In the phase I study, the maximum tolerated dose (MTD) and pharmacokinetics of ixabepilone were determined for each group. The phase II study used a two-stage design to evaluate response rate. Secondary endpoints were survival and 6-month progression free survival. In the phase I trial, 38 patients (median age 54 years) were enrolled. The MTD was 6.8 mg/m2 for patients not taking EIAEDs and 9.6 mg/m2 for those taking EIAEDs. The dose limiting toxicities in both groups were hematologic. Twenty-three patients (median age 54 years) were enrolled in the first stage of the phase II trial. No objective responses were observed. Median overall survival was 5.8 (95% CI, 5.0-8.6) months and 6-month PFS rate was 4% (95% CI, 0-22%). The overall mean total body clearance for ixabepilone was significantly higher (P = 0.003) in patients receiving EIAEDs (36 ± 11 l/h/m2) than those not (24 ± 9.2 l/h/m2). Patients on EIAEDs had a substantially higher MTD likely due to induction of cytochrome P450. Ixabepilone had no activity in patients with recurrent high-grade gliomas.

Original languageEnglish (US)
Pages (from-to)261-268
Number of pages8
JournalJournal of neuro-oncology
Volume100
Issue number2
DOIs
StatePublished - Nov 2010

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Keywords

  • Chemotherapy
  • Ixabepilone
  • Phase II
  • Recurrent gliomas

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Peereboom, D. M., Supko, J. G., Carson, K. A., Batchelor, T., Phuphanich, S., Lesser, G., Mikkelson, T., Fisher, J., Desideri, S., He, X., & Grossman, S. A. (2010). A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas. Journal of neuro-oncology, 100(2), 261-268. https://doi.org/10.1007/s11060-010-0190-0