文章：

静脉注射伊沙佐米（一种研究性蛋白酶体抑制剂）治疗复发/难治性淋巴瘤的I期剂量递增研究

Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma

原文发布日期：2014-10-17

DOI: 10.1038/bcj.2014.71

类型: Original Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

伊沙佐米是一种正处于研究阶段的蛋白酶体抑制剂，其在淋巴瘤临床前模型中已显示出活性。这项Ⅰ期研究评估了静脉注射伊沙佐米在既往接受过≥2线治疗的复发/难治性淋巴瘤患者中的安全性、耐受性、最大耐受剂量（MTD）、药代动力学、药效学及初步活性。共入组30例不同组织学类型的患者，在28天治疗周期的第1、8和15天接受0.125-3.11 mg/m²的伊沙佐米治疗。患者接受的中位治疗周期数为2（范围1-36）。确定MTD为2.34 mg/m²。最常见的药物相关不良事件包括疲劳（43%）、腹泻（33%）、恶心、呕吐和血小板减少症（各27%）。药物相关≥3级不良事件包括中性粒细胞减少症（20%）、血小板减少症（13%）和腹泻（10%）。4例（13%）患者出现药物相关周围神经病变，无≥3级事件报告。在0.5-3.11 mg/m²剂量范围内，血浆暴露量随剂量比例增加；多次给药后终末半衰期为4-12天。在26例可评估患者中，5例获得应答：11例滤泡性淋巴瘤患者中的4例（1例完全应答和3例部分应答）以及4例外周T细胞淋巴瘤患者中的1例（部分应答）。在两名经过大量预治疗的滤泡性淋巴瘤患者中，观察到接受≥32个周期治疗后的持续应答。结果表明每周静脉注射伊沙佐米通常耐受性良好，且在复发/难治性淋巴瘤中可能具有临床活性。

原文链接：

Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma