Invest New Drugs. 2013 Dec;31(6):1530-8. doi: 10.1007/s10637-013-0026-9.
The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity.
This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin's lymphoma, or non-Hodgkin's lymphoma. EMD 534085 (starting dose 2 mg/m²/day) was administered intravenously every 3 weeks. Doses were escalated in 100% steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50% until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25%. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients.
Forty-four patients received EMD 534085. Median treatment duration was 43 days (range, 21-337). Thirty-eight patients (86%) received ≥2 cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135 mg/m²/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135 mg/m²/day). The maximum tolerated dose (MTD) was 108 mg/m²/day. The most common treatment-related adverse events were asthenia (50%) and neutropenia (32%). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52%).
EMD 534085 appeared to be well tolerated; MTD was 108 mg/m²/day. Preliminary antitumor results suggested limited activity in monotherapy.
驱动蛋白纺锤体蛋白 Eg5 参与有丝分裂，其抑制可促进有丝分裂停滞。强效、可逆的 Eg5 抑制剂 EMD 534085 在临床前表现出显著的抗肿瘤活性。
这是一项首次在人体中进行的、单中心、开放标签、I 期剂量递增研究（3 + 3 设计），研究了 EMD 534085 在难治性实体瘤、霍奇金淋巴瘤或非霍奇金淋巴瘤中的安全性、药代动力学和抗肿瘤活性。EMD 534085（起始剂量 2mg/m²/天）每 3 周静脉输注一次。在连续的 3 名患者队列中，以 100%的递增剂量进行剂量递增，直到出现 2 级毒性，然后以 50%的剂量递增，直到出现首次剂量限制性毒性（DLT）。如果 6 名患者中 <2 名出现 DLT，则进一步增加 25%的剂量。如果 6 名患者中有≥2 名出现 DLT，则停止剂量递增。
44 名患者接受了 EMD 534085 治疗。中位治疗持续时间为 43 天（范围为 21-337）。38 名患者（86%）接受了 ≥2 个周期的治疗。DLT 为 4 级中性粒细胞减少症（1 名患者在 108 和 135mg/m²/天时）和 3 级急性冠状动脉综合征伴肌钙蛋白 I 升高（1 名患者在 135mg/m²/天时）。最大耐受剂量（MTD）为 108mg/m²/天。最常见的治疗相关不良事件是乏力（50%）和中性粒细胞减少症（32%）。EMD 534085 表现出线性药代动力学。在配对的治疗前和治疗期间活检中磷酸组蛋白 H3 阳性细胞的增加表明存在靶标调节的证据。未观察到完全或部分缓解。最佳反应是 23 名患者（52%）的疾病稳定。
EMD 534085 似乎具有良好的耐受性；MTD 为 108mg/m²/天。初步的抗肿瘤结果表明，单药治疗活性有限。
