Patupilone (Epothilone B) for Recurrent Glioblastoma: Clinical Outcome and Translational Analysis of a Single-Institution Phase I/II Trial
Patupilone (Epothilone B) for Recurrent Glioblastoma: Clinical Outcome and Translational Analysis of a Single-Institution Phase I/II Trial
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DOI：
10.1159/000339152
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发表时间：
2012-01-01
期刊：
影响因子：
3.5
通讯作者：
Hofer, Silvia
中科院分区：
文献类型：
--
作者：
Oehler, Christoph;Frei, Karl;Hofer, Silvia
背景：胶质母细胞瘤（GBM）患者在最初的多模式治疗后不可避免地出现复发或进展性疾病，从进展开始的中位生存期为6-9个月。迄今为止，对于GBM的复发或进展还没有公认的标准治疗方法。Patupilone （EPO906）是一种新型的天然微管稳定细胞毒性药物，可穿过血脑屏障，在胶质瘤模型中具有临床前活性。方法：这是一项针对肿瘤进展的GBM患者的单机构、早期I/II期试验，这些患者符合第二次手术的条件，目的是评估单药帕upilone （10mg /m(2)，每3周）的疗效和安全性。患者在第二次手术前1周接受帕哌龙治疗，此后每3周一次，直到肿瘤进展或出现毒性。主要终点是6个月的无进展生存期（PFS）和总生存期（OS）以及肿瘤组织中的patupilone浓度。次要终点是毒性、血浆中帕哌酮浓度和预测性生物标志物的转化分析。结果：在2008年6月至2010年4月期间招募了9例患者，平均年龄为54.6±8.6岁。第二次手术后的中位生存期和1年OS分别为11个月（95% CI， 5-17个月）和45% （95% CI, 14-76）。中位PFS为1.5个月（95% CI, 1.3-1.7个月），PFS6为22% (95% CI, 0-46)，其中2例患者在9.75和22个月时无复发。手术时，肿瘤组织中帕upilone浓度比血浆中高30倍。肿瘤反应不能通过测试的生物标志物来预测。治疗一般耐受良好，无血液学，但累积，虽然可逆的感觉神经病变等级
Background: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multi-modal treatment and have a median survival of 6-9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. Methods: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m(2), every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. Results: Nine patients with a mean age of 54.6 +/- 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5-17 months) and 45% (95% CI, 14-76), respectively. Median PFS was 1.5 months (95% CI, 1.3-1.7 months) and PFS6 was 22% (95% CI, 0-46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade