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 Anne Carson, Tracy Batchelor, Surasak Phuphanich, Glenn Lesser, Tom Mikkelson, Joy Fisher, Serena Desideri, Xiaoying He, Stuart A Grossman

Research output: Contribution to journalArticle

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

Fingerprint

Glioma
Pharmacokinetics
Maximum Tolerated Dose
Epothilones
ixabepilone
Survival
Excipients
Microtubules
Anticonvulsants
Cytochrome P-450 Enzyme System
Disease-Free Survival
Enzymes

Keywords

  • Chemotherapy
  • Ixabepilone
  • Phase II
  • Recurrent gliomas

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

Cite this

A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas. / Peereboom, David M.; Supko, Jeffrey G.; Carson, Kathryn Anne; Batchelor, Tracy; Phuphanich, Surasak; Lesser, Glenn; Mikkelson, Tom; Fisher, Joy; Desideri, Serena; He, Xiaoying; Grossman, Stuart A.

In: Journal of Neuro-Oncology, Vol. 100, No. 2, 11.2010, p. 261-268.

Research output: Contribution to journalArticle

Peereboom, DM, Supko, JG, Carson, KA, Batchelor, T, Phuphanich, S, Lesser, G, Mikkelson, T, Fisher, J, Desideri, S, He, X & Grossman, SA 2010, 'A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas', Journal of Neuro-Oncology, vol. 100, no. 2, pp. 261-268. https://doi.org/10.1007/s11060-010-0190-0
Peereboom, David M. ; Supko, Jeffrey G. ; Carson, Kathryn Anne ; Batchelor, Tracy ; Phuphanich, Surasak ; Lesser, Glenn ; Mikkelson, Tom ; Fisher, Joy ; Desideri, Serena ; He, Xiaoying ; Grossman, Stuart A. / A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas. In: Journal of Neuro-Oncology. 2010 ; Vol. 100, No. 2. pp. 261-268.
@article{ffb37dce9380421eba2ccf18135e8cb7,
title = "A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas",
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.",
keywords = "Chemotherapy, Ixabepilone, Phase II, Recurrent gliomas",
author = "Peereboom, {David M.} and Supko, {Jeffrey G.} and Carson, {Kathryn Anne} and Tracy Batchelor and Surasak Phuphanich and Glenn Lesser and Tom Mikkelson and Joy Fisher and Serena Desideri and Xiaoying He and Grossman, {Stuart A}",
year = "2010",
month = "11",
doi = "10.1007/s11060-010-0190-0",
language = "English (US)",
volume = "100",
pages = "261--268",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",
number = "2",

}

TY - JOUR

T1 - A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas

AU - Peereboom, David M.

AU - Supko, Jeffrey G.

AU - Carson, Kathryn Anne

AU - Batchelor, Tracy

AU - Phuphanich, Surasak

AU - Lesser, Glenn

AU - Mikkelson, Tom

AU - Fisher, Joy

AU - Desideri, Serena

AU - He, Xiaoying

AU - Grossman, Stuart A

PY - 2010/11

Y1 - 2010/11

N2 - 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.

AB - 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.

KW - Chemotherapy

KW - Ixabepilone

KW - Phase II

KW - Recurrent gliomas

UR - http://www.scopus.com/inward/record.url?scp=79952188360&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952188360&partnerID=8YFLogxK

U2 - 10.1007/s11060-010-0190-0

DO - 10.1007/s11060-010-0190-0

M3 - Article

VL - 100

SP - 261

EP - 268

JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

IS - 2

ER -