Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma
Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma
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DOI：
10.1182/blood-2014-01-548941
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发表时间：
2014-08-14
期刊：
影响因子：
20.3
通讯作者：
Niesvizky, Ruben
中科院分区：
文献类型：
--
作者：
Kumar, Shaji K.;Bensinger, William I.;Niesvizky, Ruben
蛋白酶体抑制是多发性骨髓瘤的有效治疗策略。随着生存率的提高，人们越来越关注给药的便利性和毒性特征。Ixazomib是一种正在研究的口服20S蛋白酶体抑制剂。60例复发和/或难治性多发性骨髓瘤患者参加了这项1期试验，以评估安全性和耐受性，并确定单药口服伊沙唑米的最大耐受剂量（MTD），每周给予3至4周。在确定MTD后，根据复发/难治性状态和先前的硼替佐米和卡非佐米暴露将患者纳入4个不同的队列。测定其MTD为2.97 mg/m(2)。剂量限制性毒性为2例3级恶心、呕吐和腹泻，1例3级皮疹。常见的药物相关不良事件有血小板减少（43%）、腹泻（38%）、恶心（38%）、疲劳（37%）和呕吐（35%）。观察到的周围神经病变发生率为20%，仅报道了1例3级事件。9名（18%）患者达到部分缓解或更好，包括30名可评估患者中的8名（27%）在MTD治疗。药代动力学研究表明，终末半衰期较长，为3.6至11.3天，支持每周一次给药。该试验在www.clinicaltrials.gov注册为#NCT00963820。
Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.