Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.
Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.
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DOI：
10.1038/bcj.2014.71
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发表时间：
2014-10-17
影响因子：
12.8
通讯作者：
Martin P
中科院分区：
文献类型：
--
作者：
Assouline SE;Chang J;Cheson BD;Rifkin R;Hamburg S;Reyes R;Hui AM;Yu J;Gupta N;Di Bacco A;Shou Y;Martin P
Ixazomib是一种正在研究的蛋白酶体抑制剂，已在淋巴瘤模型中显示出临床前活性。这项第1阶段的研究评估了静脉注射(IV)ixazomib在接受过⩾2治疗的复发/难治性淋巴瘤患者中的安全性、耐受性、最大耐受量、药代动力学、药效学和初步活性。30名组织学不同的患者在28天周期的第1、8和15天接受Ixazomib 0.125−3.11 /m2治疗。患者接受治疗的中位数为两个周期(范围1−36)。测得MTD值为2.34 mg/m2。最常见的药物相关不良事件包括乏力(43%)、腹泻(33%)、恶心、呕吐和血小板减少(各占27%)。与药物相关的⩾3级不良反应包括中性粒细胞减少(20%)、血小板减少(13%)和腹泻(10%)。4例(13%)患者发生药物相关的周围神经病变；没有⩾3级事件的报道。血浆暴露剂量从0.5−增加到3.11 mg/m2，终末半衰期为4−。在26例可评价的患者中，有5例有效：4/11例滤泡性淋巴瘤患者(1例完全缓解，3例部分缓解)和1/4外周T细胞淋巴瘤患者(部分缓解)。对两例高度治疗的滤泡性淋巴瘤患者进行了32个周期的⩾治疗，观察到持续的反应。结果表明，每周静脉注射ixazomib一般耐受性良好，可能在临床上对复发/难治性淋巴瘤有效。
Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125−3.11 mg/m2 on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1−36). MTD was determined to be 2.34 mg/m2. Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾3 events were reported. Plasma exposure increased dose proportionally from 0.5−3.11 mg/m2; terminal half-life was 4−12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.