A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas.
A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas.
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DOI：
10.1007/s11060-010-0190-0
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发表时间：
2010-11
影响因子：
3.9
通讯作者：
New Approaches to Brain Tumor Therapy (NABTT) Consortium
中科院分区：
文献类型：
--
作者：
Peereboom DM;Supko JG;Carson KA;Batchelor T;Phuphanich S;Lesser G;Mikkelsen T;Fisher J;Desideri S;He X;Grossman SA;New Approaches to Brain Tumor Therapy (NABTT) Consortium
伊沙匹隆是一种埃博霉素，一种新型的非紫杉烷微管稳定剂。在复发性高级别胶质瘤患者中进行了伊沙匹隆的I/II期和药代动力学试验。成人患者接受伊沙匹隆作为1小时输注，每天5天，每3周。在按使用或不使用酶诱导抗癫痫药物（EIAED）分层的患者中，使用改良的连续再评估方法递增剂量，从5.0 mg/m2开始。在I期研究中，确定了各组的伊沙匹隆最大耐受剂量（MTD）和药代动力学。II期研究采用两阶段设计评价缓解率。次要终点是生存期和6个月无进展生存期。在I期试验中，入组了38例患者（中位年龄54岁）。未服用EIAED的患者的MTD为6.8 mg/m2，服用EIAED的患者为9.6 mg/m2。两组的剂量限制性毒性均为血液学毒性。23例患者（中位年龄54岁）入组II期试验的第一阶段。未观察到客观缓解。中位总生存期为5.8（95% CI，5.0-8.6）个月，6个月PFS率为4%（95% CI，0-22%）。接受EIAED的患者中伊沙匹隆的总体平均全身清除率（36 ± 11 l/h/ m2）显著高于未接受EIAED的患者（24 ± 9.2 l/h/m2）（P = 0.003）。接受EIAED治疗的患者MTD显著较高，可能是由于细胞色素P450的诱导。伊沙匹隆在复发性高级别胶质瘤患者中没有活性。
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.
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影响因子：
45.3
作者：
Fetell, MR;Grossman, SA;Piantadosi, S
通讯作者：
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