Richardson Paul G, Zimmerman Todd M, Hofmeister Craig C, Talpaz Moshe, Chanan-Khan Asher A, Kaufman Jonathan L, Laubach Jacob P, Chauhan Dharminder, Jakubowiak Andrzej J, Reich Steven, Trikha Mohit, Anderson Kenneth C
Dana-Farber Cancer Institute, Boston, MA;
School of Medicine, University of Chicago, Chicago, IL;
Blood. 2016 Jun 2;127(22):2693-700. doi: 10.1182/blood-2015-12-686378. Epub 2016 Mar 23.
Marizomib (MRZ) is a novel, irreversible proteasome inhibitor in clinical development for the treatment of relapsed or relapsed and refractory multiple myeloma (RRMM). MRZ inhibits the 3 proteolytic activities of the 20S proteasome with specificity distinct from bortezomib and carfilzomib. Study NPI-0052-101 Part 1 enrolled relapsed or RRMM patients into an open-label, dose-escalation design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of MRZ administered intravenously on 2 different schedules: schedule A (0.025-0.7 mg/m(2) once weekly on days 1, 8, and 15 of 4-week cycles) and schedule B (0.15-0.6 mg/m(2) twice weekly on days 1, 4, 8, and 11 of 3-week cycles; concomitant dexamethasone was allowed with schedule B). Patients had received an average of 4.9 and 7.3 prior treatment regimens (schedules A and B, respectively). MRZ schedule A was administered to 32 patients, and the RP2D was established as 0.7 mg/m(2) infused over 10 minutes. Schedule B was administered to 36 patients, and the RP2D was determined to be 0.5 mg/m(2) infused over 2 hours. The most common (>20% of patients) related adverse events were fatigue, headache, nausea, diarrhea, dizziness, and vomiting. Six patients achieved clinical benefit responses (defined as minimal response or better), including 5 partial responses (1 patient on schedule A and 4 on schedule B; 3 of these 4 patients received concomitant dexamethasone). MRZ was generally well tolerated, and results suggest activity in previously treated RRMM patients. Combination studies using pomalidomide and dexamethasone are now underway. The trial was registered at www.clinicaltrials.gov as #NCT00461045.
马立佐米（MRZ）是一种新型的不可逆蛋白酶体抑制剂，正处于临床开发阶段，用于治疗复发或复发难治性多发性骨髓瘤（RRMM）。MRZ抑制20S蛋白酶体的3种蛋白水解活性，其特异性与硼替佐米和卡非佐米不同。研究NPI - 0052 - 101的第1部分将复发或RRMM患者纳入开放标签、剂量递增设计，以确定在2种不同给药方案下静脉注射MRZ的最大耐受剂量和推荐的2期剂量（RP2D）：方案A（0.025 - 0.7 mg/m²，在4周周期的第1、8和15天每周一次）和方案B（0.15 - 0.6 mg/m²，在3周周期的第1、4、8和11天每周两次；方案B允许同时使用地塞米松）。患者平均分别接受了4.9种和7.3种先前的治疗方案（方案A和方案B）。32例患者接受了方案A治疗，RP2D确定为0.7 mg/m²，在10分钟内输注。36例患者接受了方案B治疗，RP2D确定为0.5 mg/m²，在2小时内输注。最常见的（>20%的患者）相关不良事件为疲劳、头痛、恶心、腹泻、头晕和呕吐。6例患者获得临床获益反应（定义为最小反应或更好），包括5例部分缓解（方案A中有1例患者，方案B中有4例患者；这4例患者中有3例同时接受了地塞米松治疗）。MRZ总体耐受性良好，结果表明其对先前治疗的RRMM患者有活性。目前正在进行使用泊马度胺和地塞米松的联合研究。该试验已在www.clinicaltrials.gov上注册，编号为#NCT00461045。
