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/m(2), 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/m(2) for patients not taking EIAEDs and 9.6 mg/m(2) 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/m(2)) than those not (24 ± 9.2 l/h/m(2)). 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.
authors.affiliation: Cleveland Clinic Brain Tumor and Neuro-Oncology Center, Cleveland, OH, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Peereboom
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carson
authors.forename: Tracy
authors.initials: T
authors.lastname: Batchelor
authors.forename: Surasak
authors.initials: S
authors.lastname: Phuphanich
authors.forename: Glenn
authors.initials: G
authors.lastname: Lesser
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelson
authors.forename: Joy
authors.initials: J
authors.lastname: Fisher
authors.forename: Serena
authors.initials: S
authors.lastname: Desideri
authors.forename: Xiaoying
authors.initials: X
authors.lastname: He
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D034261:Epothilones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D034261:Epothilones; C430592:ixabepilone
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