Chari Ajai, Htut Myo, Zonder Jeffrey A, Fay Joseph W, Jakubowiak Andrzej J, Levy Joan B, Lau Kenneth, Burt Steven M, Tunquist Brian J, Hilder Brandi W, Rush Selena A, Walker Duncan H, Ptaszynski Mieke, Kaufman Jonathan L
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
City of Hope, Duarte, California.
Cancer. 2016 Nov 15;122(21):3327-3335. doi: 10.1002/cncr.30174. Epub 2016 Jul 19.
Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study.
The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase.
With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m /day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m /day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m /day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m (duration of response, 5.2 to ≥21.2 months).
The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-3335. © 2016 American Cancer Society.
非那西布是一种驱动蛋白纺锤体蛋白抑制剂，已在复发/难治性多发性骨髓瘤患者中显示出令人鼓舞的活性。与硼替佐米的临床前协同作用是当前1期研究的理论依据。
本研究为多中心研究，初始阶段为剂量爬坡，以确定非那西布联合硼替佐米（加或不加地塞米松）两种给药方案的最大耐受剂量，随后进入剂量扩展阶段。
加用预防性非格司亭后，达到了最大计划剂量：在28天周期的第1、8和15天，硼替佐米剂量为1.3mg/m²/天加40mg地塞米松，非那西布静脉给药，剂量为1.5mg/m²/天（方案1：第1、2、15和16天）或3mg/m²/天（方案2：第1和15天）。最常见的不良事件（使用美国国立癌症研究所不良事件通用术语标准第4.0版评估严重程度）为短暂性、非累积性中性粒细胞减少和血小板减少，3/4级事件分别在44%（使用非格司亭时第1周期为16%）和29%的患者中报告。观察到非血液学3/4级毒性的总体发生率较低（≤11%）。中位有3线既往治疗史，56%的患者对蛋白酶体抑制剂难治，总体缓解率为20%（55例患者），在14例接受剂量≥1.25mg/m²非那西布治疗的蛋白酶体抑制剂难治性疾病患者中缓解率为29%（缓解持续时间为5.2至≥21.2个月）。
当前的1期研究确定了这些药物联合使用的给药方案，该方案显示出良好的安全性，非血液学毒性发生率低，血液学毒性可控。非那西布、硼替佐米和地塞米松联合使用似乎对复发/难治性多发性骨髓瘤患者具有持久活性。《癌症》2016年；122：3327 - 3335。©2016美国癌症协会。
