A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia
A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia
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DOI：
10.1182/blood-2016-11-750158
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发表时间：
2017-06-15
期刊：
影响因子：
20.3
通讯作者：
Stone, Richard
中科院分区：
文献类型：
--
作者：
Garzon, Ramiro;Savona, Michael;Stone, Richard
Selinexor是一种新型的、一流的选择性核输出化合物抑制剂，它可以阻断输出蛋白1 （XPO1）的功能，导致肿瘤抑制蛋白的核积累，并诱导癌细胞死亡。一项1期剂量递增研究启动，以检查selinexor在晚期血液系统恶性肿瘤患者中的安全性和有效性。2013年1月至2014年6月期间，95名复发或难治性急性髓性白血病（AML）患者入组，在21天或28天的周期内接受4、8或10剂selinexor。AML患者中最常见的不良事件（ae）是1级或2级体质和胃肠道毒性，通常在支持治疗下是可控的。唯一的非血液学3/4级AE，发生在bb0.5 %的患者群体中，是疲劳（14%）。没有剂量限制性毒性的报告或累积毒性的证据。推荐的2期剂量为60mg（类似于35mg /m(2)），基于总体安全性和有效性数据，每周两次，为期4周。总体而言，81名可评估患者中有14%达到了客观缓解（OR）， 31%的患者骨髓母细胞较基线减少了50%。与无反应患者相比，获得OR的患者在中位无进展生存期（PFS） （5.1 vs 1.3个月；P = 0.008；风险比[HR]， 3.1）和总生存期（9.7 vs 2.7个月；P = 0.01； HR, 3.1）方面有显著改善。这些发现表明，selinexor作为单药治疗复发或难治性AML患者是安全的，并为后续的2期临床开发提供了信息。该试验在www.clinicaltrials.gov注册为#NCT01607892。
Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21-or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (similar to 35 mg/m(2)) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed similar to 50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.