可穿透血脑屏障的微管抑制剂:TPI287
  • TPI 287是三代紫杉烷类药物,可规避P-糖蛋白介导的外排,克服血脑屏障阻碍药物积累;
  • 24例GBM患者(7个递增剂量组)参与确定TPI 287联合BEV治疗GBM时,TPI 287最佳剂量(一期临床实验);
  • 中位随访时间为28个月,20例疗效评估,23例生存率评估;
  • 8例(9例中)存在MGMT基因启动子甲基化;
  • 无DLT,唯一相关AE:骨髓抑制(3例,3-4级);
  • 联合BEV,TPI 287剂量高达220 mg/m2依然安全且耐受良好,最终生存结果可与历史对照媲美。
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Final results from the dose-escalation stage of a phase 1/2 trial of TPI 287, a brain penetrable microtubule inhibitor, plus bevacizumab in patients with recurrent glioblastoma

一/二期临床实验中剂量递增阶段结果:TPI 287(可穿透血脑屏障的微管抑制剂)联合阿瓦斯汀治疗复发性胶质母细胞瘤

2017-05-05

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Background: Microtubule inhibitors, including taxanes, are active in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by poor blood-brain barrier (BBB) accumulation. TPI 287, a third-generation taxane designed to evade P-glycoprotein mediated efflux, readily penetrates the BBB and overcomes this limitation. CB-017 is a multi-center phase 1/2 trial designed to determine the optimal dose of TPI 287 and potential efficacy in patients treated with this drug plus bevacizumab (BEV) for treatment of recurrent GBM. Final results of the dose escalation Phase 1 stage of this trial are reported.
Methods: GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks via IV infusion. MRIs were obtained every six weeks with response assessed via RANO criteria. TPI 287 dose escalation was based on a traditional 3+3 design.
Results: Twenty-four patients were enrolled in 7 TPI 287 dose-escalation cohorts (140-220 mg/m2) from 6 U.S. centers. Twenty and 23 patients were evaluable for response and survival, respectively. Median follow-up was 28 months. Results are shown in the table below. Of the 9 patients from which biomarker data was available, tumors from 8 patients (89%) harbored an unmethylated MGMT promoter, an established negative prognostic indicator for survival. No DLTs were reported and myelosuppression (n=3) was the only drug-related grade 3/4 adverse event.
Conclusions: TPI 287 in combination with BEV is safe and well tolerated at doses up to 220 mg/m2. Final survival results from the Phase 1 portion of this study compare favorably with historical controls and support further investigation of TPI 287 plus BEV for treatment of recurrent GBM.

All Authors:
Samuel Aaron Goldlust

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