A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer
A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer
复制标题
DOI：
10.1016/j.ejca.2018.05.007
复制
发表时间：
2018-09-01
影响因子：
8.4
通讯作者：
Tuereci, Ozlem
中科院分区：
文献类型：
--
作者：
Sahin, Ugur;Schuler, Martin;Tuereci, Ozlem
简介：IMAB 362（Zolbetuximab）是一种嵌合单克隆抗体，可与癌细胞特异性靶抗原Claudin-18.2结合。在体外，IMAB 362通过抗体依赖性细胞毒性和补体依赖性细胞毒性介导细胞死亡;因此，IMAB 362可以作为一种有效的靶向免疫抑制剂。这项首次人体I期研究将患有晚期胃癌或胃食管连接部癌的成年患者（N = 15）纳入5个连续单次剂量递增队列（33、100、300、600和1000 mg/m2）。安全性/耐受性，包括确定最大耐受剂量和推荐的II期剂量，是主要目的;次要目的包括评估IMAB 362药代动力学特征、免疫原性和抗肿瘤活性（通过实体瘤疗效评价标准v1.0评估）。IMAB 362在所有剂量下通常耐受良好，胃肠道毒性是最常见的治疗相关不良事件。由于在治疗4周内未观察到剂量限制性毒性，因此未确定最大耐受剂量。IMAB 362的药代动力学特征似乎在剂量范围内成比例;平均半衰期范围为13至24天。虽然大多数患者在单次静脉注射IMAB 362后4-5周表现出疾病进展，但600 mg/m2剂量组中的1例患者在注射后约2个月达到并维持疾病稳定。结论：本研究的结果表明，IMAB 362通常耐受良好，并支持对胃/胃食管交界处癌患者进行进一步评估。(C)2018爱思唯尔有限公司版权所有。
Introduction: IMAB362 (Zolbetuximab) is a chimeric monoclonal antibody that binds to Claudin-18.2, a target antigen specific to cancer cells. In vitro, IMAB362 mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; thus, IMAB362 may serve as a potent, targeted immunotherapeutic agent.Methods: This first-in-human phase I study enroled adult patients (N = 15) with advanced gastric or gastro-oesophageal junction cancer into five sequential single dose-escalation cohorts (33, 100, 300, 600, and 1000 mg/m(2)) following a 3 + 3 design. Safety/tolerability, including determination of maximum tolerated dose and recommended phase II dose, were the primary objectives; secondary objectives included assessment of the IMAB362 pharmacokinetic profile, immunogenicity, and antitumour activity (assessed by Response Evaluation Criteria in Solid Tumors v1.0).Results: IMAB362 was generally well tolerated at all doses, with gastrointestinal toxicities being the most commonly observed treatment-related adverse events. As dose-limiting toxicity was not observed within 4 weeks of treatment, a maximum tolerated dose was not established. The pharmacokinetic profile of IMAB362 appeared to be proportional across the dose range; and mean half-life ranged from 13 to 24 d. While most patients showed progressive disease at weeks 4-5 after a single intravenous IMAB362 infusion, one patient in the 600 mg/m(2) dose group achieved and maintained stable disease for approximately 2 months postinfusion.Conclusions: Findings from this study demonstrate that IMAB362 is generally well tolerated and support further evaluation in patients with gastric/gastro-oesophageal junction cancer. (C) 2018 Elsevier Ltd. All rights reserved.