Richardson Paul G, Baz Rachid, Wang Michael, Jakubowiak Andrzej J, Laubach Jacob P, Harvey R Donald, Talpaz Moshe, Berg Deborah, Liu Guohui, Yu Jiang, Gupta Neeraj, Di Bacco Alessandra, Hui Ai-Min, Lonial Sagar
Dana-Farber Cancer Institute, Boston, MA;
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
Blood. 2014 Aug 14;124(7):1038-46. doi: 10.1182/blood-2014-01-548826. Epub 2014 Jun 11.
Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade ≥3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.
伊沙佐米是首个进入临床研究阶段的口服蛋白酶体抑制剂。在这项1期试验中，60例复发/难治性多发性骨髓瘤患者（先前治疗的中位数为4线；分别有88%、88%、62%和5%的患者接受过硼替佐米、来那度胺、沙利度胺以及卡非佐米/马立佐米治疗）接受单药伊沙佐米治疗，剂量为0.24至2.23mg/m²（第1、4、8、11天给药；每21天为一个周期）。在2.23mg/m²剂量时发生了2例剂量限制性毒性反应（3级皮疹；4级血小板减少症）。最大耐受剂量为2.0mg/m²，40例患者在4个扩展队列中接受了该剂量。患者接受治疗的中位数为4个周期（范围为1 - 39个周期）；18%的患者接受了≥12个周期的治疗。88%的患者出现了与药物相关的不良事件，包括恶心（42%）、血小板减少症（42%）、疲劳（40%）和皮疹（40%）；与药物相关的≥3级事件包括血小板减少症（37%）和中性粒细胞减少症（17%）。12%的患者出现了1/2级与药物相关的周围神经病变（无≥3级病例）。两名患者在研究期间死亡（均被认为与治疗无关）。伊沙佐米的终末半衰期为3.3至7.4天；血浆暴露量随剂量成比例增加（0.48 - 2.23mg/m²）。在55例可评估疗效的患者中，15%达到了部分缓解或更好的疗效（76%病情稳定或更好）。这些研究结果为伊沙佐米在多发性骨髓瘤后续的临床开发提供了依据。该试验已在www.clinicaltrials.gov上注册，注册号为#NCT00932698。
