An Open-Label Single-Arm Pilot Phase II Study (PX-171-003-A0) of Low-Dose, Single-Agent Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma
An Open-Label Single-Arm Pilot Phase II Study (PX-171-003-A0) of Low-Dose, Single-Agent Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma
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DOI：
10.1016/j.clml.2012.08.003
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发表时间：
2012-10-01
影响因子：
2.7
通讯作者：
Siegel, David S.
中科院分区：
文献类型：
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作者：
Jagannath, Sundar;Vij, Ravi;Siegel, David S.
对46例复发和难治性多发性骨髓瘤(MM)患者进行了新一代选择性蛋白酶体抑制剂carfilzomib的开放式单臂多中心试验II期研究。总有效率(ORR)为16.7%，中位有效时间为7.2个月。这项先导性研究是卡菲佐米进行的第一个II期单剂试验。背景：卡菲佐米是一种下一代选择性蛋白酶体抑制剂，它不可逆地结合其靶点，并已证明在对博替佐米耐药的多发性骨髓瘤(MM)患者中具有单药活性。PX-171-003-A0是一项开放标签的单臂多中心试验II期研究，纳入了46名复发性多发性骨髓瘤患者，这些患者以前接受过包括波特佐米和免疫调节剂(沙利度胺或来那度胺)在内的两种治疗方法，但对进入研究前的最后一种治疗方案无效。方法：卡非佐米20 mg/m(2)静脉滴注，第1、2、8、9、15、16天，每28天一次，共12个周期。根据国际骨髓瘤工作组的统一反应标准对42名可评估患者的反应进行评估，根据欧洲血液和骨髓移植组织(EBMT)的标准评估最低反应。结果：BEST OAR的主要终点为16.7%，包括7个部分反应。中位有效时间为7.2个月。临床受益缓解率为23.8%，中位缓解期为13.8个月。最常见的急性不良反应(AEs)是贫血(73.9%)、乏力(69.6%)和血小板减少(50.0%)。值得注意的是，周围神经病和神经病相关的AEs一般较轻且不常见。结论：这项先导性研究是使用卡菲佐米进行的第一个II期单药试验。基于这些发现，这项研究被修改为在另外250名患者中测试更高剂量的卡菲佐米(PX-171-003-A1)。
An open-label single-arm multicenter pilot phase II study of the next-generation selective proteasome inhibitor carfilzomib was conducted in 46 patients with relapsed and refractory multiple myeloma (MM) after >= 2 previous therapies. The best overall response rate (ORR) was 16.7%, with a median duration of response of 7.2 months. This pilot study was the first phase II single-agent trial conducted with carfilzomib.Background: Carfilzomib is a next-generation selective proteasome inhibitor that irreversibly binds its target and has demonstrated single-agent activity in patients with bortezomib-resistant multiple myeloma (MM). PX-171-003-A0, an open-label single-arm multicenter pilot phase II study, enrolled 46 patients with relapsed MM after >= 2 previous therapies including bortezomib and an immunomodulator (thalidomide or lenalidomide) and disease refractory to the last treatment regimen preceding study entry. Methods: Patients received carfilzomib 20 mg/m(2) intravenously on days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles. Responses in 42 evaluable patients were assessed per International Myeloma Working Group Uniform Response Criteria, with minimal response assessed per European Group for Blood and Marrow Transplantation (EBMT) criteria. Results: The primary endpoint of best OAR was 16.7%, including 7 partial responses. Median duration of response was 7.2 months. Clinical benefit response (CBR) rate was 23.8% with a median duration of response of 13.8 months. The most common treatment-emergent adverse events (AEs) of any grade were anemia (73.9%), fatigue (69.6%), and thrombocytopenia (50.0%). Notably, peripheral neuropathy and neuropathy-related AEs were generally mild and infrequent. Conclusion: This pilot study was the first phase II single-agent trial conducted with carfilzomib. Based on these findings, the study was amended to test a higher carfilzomib dose in an additional 250 patients (PX-171-003-A1).