Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial
Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial
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DOI：
10.1200/jco.2015.65.4889
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发表时间：
2016-04-20
影响因子：
45.3
通讯作者：
Mosse, Yael P.
中科院分区：
文献类型：
--
作者：
DuBois, Steven G.;Marachelian, Araz;Mosse, Yael P.
目的Alisertib是一种口服Aurora A激酶抑制剂，在神经母细胞瘤中具有临床前活性。伊立替康和替莫唑胺在晚期神经母细胞瘤患者中具有活性。本I期研究的目的是确定最大耐受剂量（MTD）的alisertib与伊立替康和替莫唑胺在这个population.Patients和MethodsPatients年龄1至30岁的复发性或难治性神经母细胞瘤有资格。患者在第1 - 7天接受45、60和80 mg/m2/天剂量水平的alisertib片剂，沿着伊立替康50 mg/m2静脉给药，第1 - 5天口服替莫唑胺100 mg/m2。alisertib的剂量递增遵循滚动6设计。药代动力学和药物基因组学testing.ResultsTwenty-three患者入组，22个合格的剂量递增和可评价的样品。共开办了244门课程。alisertib的MTD为60 mg/m2，需要强制性骨髓生长因子支持和头孢菌素预防腹泻。在大多数疗程中观察到任何级别的血小板减少和中性粒细胞减少（分别为84%和69%）。55%的疗程中腹泻和54%的疗程中恶心是最常见的非血液学毒性。总体缓解率为31.8%，在MTD时观察到50%的缓解率。每例患者的中位疗程数为8个（范围为2 - 32个）。2年无进展生存率为52.4%。药代动力学测试没有显示伊立替康和alisertib.ConclusionAlisertib 60 mg/m2每剂量7天之间的药物-药物相互作用的证据是耐受的标准伊立替康和替莫唑胺骨干，并具有良好的响应和无进展生存率。该方案的II期试验正在进行中。(C)2016年美国临床肿瘤学会
PurposeAlisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population.Patients and MethodsPatients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained.ResultsTwenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m(2), with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib.ConclusionAlisertib 60 mg/m(2) per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing. (C) 2016 by American Society of Clinical Oncology