Mount Sinai Medical Center, New York, NY 10029, USA.
Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. doi: 10.1016/j.clml.2012.08.003.
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.
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.
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.
The primary endpoint of best ORR 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.
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).
卡非佐米是一种新型选择性蛋白酶体抑制剂，可与靶标不可逆结合，在硼替佐米耐药的多发性骨髓瘤（MM）患者中显示出单药活性。PX-171-003-A0 是一项开放标签、单臂、多中心的 II 期临床试验，纳入了 46 例至少接受过 2 种治疗（包括硼替佐米和免疫调节剂[沙利度胺或来那度胺]）且对进入研究前最后一个治疗方案耐药的复发性 MM 患者。
患者接受卡非佐米 20mg/m2 静脉滴注，第 1、2、8、9、15 和 16 天，每 28 天为 1 个周期，最多接受 12 个周期的治疗。根据国际骨髓瘤工作组统一缓解标准评估 42 例可评估患者的缓解情况，根据欧洲血液和骨髓移植协会（EBMT）标准评估微小缓解情况。
最佳总体缓解率（ORR）为 16.7%，包括 7 例部分缓解。缓解持续时间的中位数为 7.2 个月。临床获益反应（CBR）率为 23.8%，缓解持续时间的中位数为 13.8 个月。最常见的任何级别治疗相关不良事件（AE）是贫血（73.9%）、疲劳（69.6%）和血小板减少（50.0%）。值得注意的是，周围神经病变和与神经病变相关的 AE 通常为轻度和罕见。
这项 I 期单药试验是首次使用卡非佐米开展的 II 期研究。基于这些发现，研究方案进行了修订，在另外 250 例患者中测试了更高剂量的卡非佐米（PX-171-003-A1）。
