Kantarjian Hagop M, Schuster Michael W, Jain Nitin, Advani Anjali, Jabbour Elias, Gamelin Erick, Rasmussen Erik, Juan Gloria, Anderson Abraham, Chow Vincent F, Friberg Gregory, Vogl Florian D, Sekeres Mikkael A
Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
Medical Hematology/Oncology Stony Brook University School of Medicine, Stony Brook, New York, USA.
Am J Hematol. 2017 Jul;92(7):660-667. doi: 10.1002/ajh.24736. Epub 2017 Jun 5.
Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.
极光激酶参与了包括急性髓系白血病（AML）在内的多种癌症的病理生理过程。在这项1期研究中，我们调查了AMG 900（一种口服的、高效、选择性的极光激酶A和B小分子抑制剂）对AML患者的安全性和疗效。纳入了病理确诊为AML且拒绝标准治疗或对先前治疗复发或难治的患者。采用改良的3+3+3设计评估了两种每2周一次的剂量递增方案：AMG 900每日给药4天，休息10天（4/10方案），以及AMG 900每日给药7天，休息7天（7/7方案）。在9个不同剂量水平纳入了35例患者：22例采用4/10方案（每日剂量为15至100 mg），13例采用7/7方案（每日剂量为30至50 mg）。两种方案均可耐受；恶心（31%）、腹泻（29%）、发热性中性粒细胞减少（29%）和疲劳（23%）是最常见的治疗相关不良事件。3例患者（9%）达到完全缓解但血细胞计数未完全恢复。在一项探索性生物标志物分析中，一组特定通路相关基因（BIRC5、AURKA、TTK、CDC2和CCNB1）基线表达较高的患者更有可能产生反应。AMG 900在一般AML人群中耐受性良好，且通路特异性生物标志物确定了一个潜在的目标人群。未来的研究工作将致力于进一步探索反应生物标志物以及AMG 900与其他抗癌药物的联合应用。
