甲硫氨酰肽酶2（MetAP2）在肿瘤血管生成过程中对内皮细胞的生长和增殖至关重要。M8891是一种新型口服可利用、高效、选择性可逆的MetAP2抑制剂，经过临床前研究显示具有抗血管生成和抗肿瘤活性。我们进行了一项I期、首次人体应用、多中心、开放标签、单臂、剂量递增的研究（NCT03138538），评估了M8891单药治疗的安全性、耐受性、药代动力学和药效学。晚期实体瘤患者在21天的周期内每天一次接受7-80毫克M8891的治疗。主要终点是第一周期内的剂量限制性毒性（DLT），目的是确定最大可耐受剂量（MTD）。共有27名患者在六个剂量水平上纳入研究。报告了两起DLT（血小板减少），分别在每天60和80毫克M8891剂量下，治疗停药后恢复正常。最大可耐受剂量未确定。最常见的治疗相关不良事件是血小板减少。M8891的血浆浓度在35毫克以下剂量内呈剂量线性增加，并具有低至中度的变异性；观察到依赖剂量的甲基化延伸因子1α（MetAP2底物）在肿瘤内的积累，表明MetAP2的抑制作用。药代/药效学反应数据显示，在安全和可耐受的剂量下，达到了临床前研究中所定义的用于体内疗效所需的靶标水平。7名患者（25.9%）的疾病稳定持续42-123天。我们得出结论，M8891显示出可管理的安全性，剂量与曝光呈比例关系，互患者间变异性低至中度；在35毫克以下的M8891每天一次剂量下，达到了目标药代/药效学水平。据此数据，建议M8891单药治疗的II期剂量为每天一次35毫克。本研究为未来M8891在单药和联合研究中的进一步发展奠定了基础。M8891代表了一类新型可逆的MetAP2抑制剂，并显示出临床前的抗肿瘤活性。该剂量递增研究评估了M8891对晚期实体瘤患者的治疗效果。M8891表现出有利的药代动力学特性、肿瘤靶点结合和可管理的安全性，因此代表一种新颖的抗肿瘤策略，值得进一步开展临床研究。© 2023作者；美国癌症研究协会出版。

Methionine aminopeptidase 2 (MetAP2) is essential to endothelial cell growth and proliferation during tumor angiogenesis. M8891 is a novel orally bioavailable, potent, selective, reversible MetAP2 inhibitor with antiangiogenic and antitumor activity in preclinical studies. The safety, tolerability, pharmacokinetics, and pharmacodynamics of M8891 monotherapy were assessed in a phase I, first-in-human, multicenter, open-label, single-arm, dose-escalation study (NCT03138538). Patients with advanced solid tumors received 7-80 mg M8891 once daily in 21-day cycles. The primary endpoint was dose-limiting toxicity (DLT) during cycle 1, with the aim to determine the maximum tolerated dose (MTD). Twenty-seven patients were enrolled across six dose levels. Two DLTs (platelet count decrease) were reported, one each at 60 and 80 mg/once daily M8891, resolving after treatment discontinuation. MTD was not determined. The most common treatment-emergent adverse event was platelet count decrease. M8891 plasma concentration showed dose-linear increase up to 35 mg and low-to-moderate variability; dose-dependent tumor accumulation of methionylated elongation factor 1α, a MetAP2 substrate, was observed, demonstrating MetAP2 inhibition. Pharmacokinetic/pharmacodynamic response data showed that preclinically defined target levels required for in vivo efficacy were achieved at safe, tolerated doses. Seven patients (25.9%) had stable disease for 42-123 days. We conclude that M8891 demonstrates a manageable safety profile, with dose-proportional exposure and low-to-moderate interpatient variability at target pharmacokinetic/pharmacodynamic levels at ≤35 mg M8891 once daily. On the basis of the data, 35 mg M8891 once daily is the recommended phase II dose for M8891 monotherapy. This study forms the basis for future development of M8891 in monotherapy and combination studies.M8891 represents a novel class of reversible MetAP2 inhibitors and has demonstrated preclinical antitumor activity. This dose-escalation study assessed M8891 treatment for patients with advanced solid tumors. M8891 demonstrated favorable pharmacokinetics, tumoral target engagement, and a manageable safety profile, and thus represents a novel antitumor strategy warranting further clinical studies.© 2023 The Authors; Published by the American Association for Cancer Research.