Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors
Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors
复制标题
DOI：
10.1158/1078-0432.ccr-15-1338
复制
发表时间：
2016-02-15
影响因子：
11.5
通讯作者：
Harvey, R. Donald
中科院分区：
文献类型：
--
作者：
Sarantopoulos, John;Shapiro, Geoffrey I.;Harvey, R. Donald
目的：确定试验用NEDD 8激活酶（NAE）抑制剂pevonedistat的剂量限制性毒性（DLT）和最大耐受剂量（MTD）（TAK-924/MLN 4924），并在晚期非血液系统恶性肿瘤患者中研究pevonedistat的药代动力学和药效学。Pevonedistat在21天周期的第1 - 5天（方案A，n = 12）或第1、3和5天（方案B，n = 17和C，n = 19）通过60分钟静脉输注给药。方案B包括每次pevonedistat给药前口服地塞米松8 mg。使用贝叶斯连续再评估方法进行剂量递增。采用RECIST 1.0评估肿瘤缓解情况。结果：A方案的MTD为50 mg/m2;根据观察到的肝毒性的严重程度，终止该方案。方案B和C的MTD分别为50和67 mg/m2。这两种方案的DLT包括高胆红素血症和天冬氨酸转氨酶升高。方案B或C中未报告≥ 3级治疗相关严重不良事件。方案B和C的23例（74%）可评价患者病情稳定。间断使用地塞米松对pevonedistat的药代动力学无显著影响。通过IHC检测pevonedistat-NEDD 8加合物和肿瘤活检组织中Cullin-RING连接酶底物CDT 1和NRF 2的蓄积，在多种肿瘤类型中证明了pevonedistat对NAE的抑制作用。结论：Pevonedistat在每3周一次的第1、3、5天给药方案中通常耐受良好，MTD在50 mg/m（2）和67 mg/m（2）之间。DLT主要为肝酶升高。药效学研究表明，pevonedistat可抑制肿瘤中的NAE。(C)2015年AACR。
Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies.Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0.Results: Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade >= 3 treatmentrelated serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies.Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with anMTDbetween 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. (C) 2015 AACR.