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

doi:10.1007/s11060-010-0190-0

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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 language	English (US)
Pages (from-to)	261-268
Number of pages	8
Journal	Journal of neuro-oncology
Volume	100
Issue number	2
DOIs	https://doi.org/10.1007/s11060-010-0190-0
State	Published - Nov 2010

Keywords

Chemotherapy
Ixabepilone
Phase II
Recurrent gliomas

ASJC Scopus subject areas

Oncology
Neurology
Clinical Neurology
Cancer Research

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10.1007/s11060-010-0190-0

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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 A.} 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.}",

note = "Funding Information: Acknowledgments This study was performed by the New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD, USA, and supported in part by National Cancer Institute UO1 Grant CA62475 (NABTT Central Office). Kathryn A. Carson{\textquoteright}s work on the manuscript was supported by National Center for Research Resources grant UL1 RR 025005. We are grateful to Kimberly Busby for her support of this clinical trial development and manuscript.",

year = "2010",

month = nov,

doi = "10.1007/s11060-010-0190-0",

language = "English (US)",

volume = "100",

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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 A.

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.

N1 - Funding Information: Acknowledgments This study was performed by the New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD, USA, and supported in part by National Cancer Institute UO1 Grant CA62475 (NABTT Central Office). Kathryn A. Carson’s work on the manuscript was supported by National Center for Research Resources grant UL1 RR 025005. We are grateful to Kimberly Busby for her support of this clinical trial development and manuscript.

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

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KW - Recurrent gliomas

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

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