人双微体2抑制剂（MK-8242）用于难治性/复发性急性髓系白血病（AML）患者的I期试验。
A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML).
作者信息
Ravandi Farhad, Gojo Ivana, Patnaik Mrinal M, Minden Mark D, Kantarjian Hagop, Johnson-Levonas Amy O, Fancourt Craig, Lam Raymond, Jones Mary Beth, Knox Clayton D, Rose Shelonitda, Patel Payal Shah, Tibes Raoul
机构信息
The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Johns Hopkins University, Baltimore, MD, United States.
出版信息
Leuk Res. 2016 Sep;48:92-100. doi: 10.1016/j.leukres.2016.07.004. Epub 2016 Jul 25.
OBJECTIVE
Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML.
METHODS
MK-8242 was dosed p.o. QD (30-250mg) or BID (120-250mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300mg BID).
RESULTS
26 subjects enrolled (24 evaluable for response); 5/26 discontinued due to AEs. There were 7 deaths; 1 (fungal pneumonia due to marrow aplasia) possibly drug-related. With the 7on/7off regimen, 2 subjects had DLTs in the 250mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210mg BID or 300mg BID (doses>300mg not tested). Best responses were: 1/24 PR (11 weeks;120mg QD, 7on/7off); 1/24 CRi (2 weeks;210mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250mg BID, 7on/7off). PK on Day7 at 210mg BID revealed AUC0-12h 8.7μM·h,Cmax 1.5μM (n=5,Tmax, 2-6h),T1/2 7.9h, CLss/F 28.8L/h, and Vss/F 317L.
CONCLUSIONS
The 7on/14off regimen showed a more favorable safety profile; no MTD was established. Efficacy was seen using both regimens providing impetus for further study of HDM2 inhibitors in subjects with AML.
目的
评估MK-8242在难治性/复发性急性髓系白血病（AML）患者中的安全性/耐受性/疗效。
方法
MK-8242口服给药，每日一次（30 - 250mg）或每日两次（120 - 250mg），每28天周期中服药7天停药7天。给药方案改为每21天周期中服药7天停药14天（210或300mg每日两次）。
结果
26名受试者入组（24名可评估疗效）；26名中有5名因不良事件停药。有7例死亡；1例（由于骨髓再生障碍导致的真菌性肺炎）可能与药物相关。在7天服药/7天停药方案中，250mg每日两次组有2名受试者出现剂量限制性毒性（均为骨髓衰竭和长期血细胞减少）。在7天服药/14天停药方案中，210mg每日两次或300mg每日两次未观察到剂量限制性毒性（未测试剂量>300mg的情况）。最佳疗效为：24例中有1例部分缓解（11周；每日一次120mg，7天服药/7天停药）；24例中有1例形态学无白血病状态（4周；每日两次250mg，7天服药/7天停药）。210mg每日两次时第7天的药代动力学显示AUC0 - 12h为8.7μM·h，Cmax为1.5μM（n = 5，达峰时间为2 - 6小时），半衰期为7.9小时，稳态清除率/表观分布容积为28.8L/h，稳态分布容积/表观分布容积为317L。
结论
7天服药/14天停药方案显示出更有利的安全性；未确定最大耐受剂量。两种方案均显示出疗效，为进一步研究HDM2抑制剂治疗AML患者提供了动力。
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