双重靶向抗肿瘤新药的早期临床试验设计的探讨  

Discussion of early clinical trial design for new dual-targeted antitumor drugs

作　　者：方莹莹 王兴河 FANG Ying-ying;WANG Xing-he(Phase I Clinical Trial Center,Beijing Shijitan Hospital,Capital Medical University,Bejing 100038,China)

机构地区：[1]首都医科大学附属北京世纪坛医院药物Ⅰ期临床试验研究室,北京100038

出　　处：《中国临床药理学杂志》2024年第7期1076-1079,共4页The Chinese Journal of Clinical Pharmacology

摘　　要：目的回顾性分析双重靶向抗肿瘤新药早期临床研究设计策略的特点。方法通过汇总2015-01-01-2023-10-31完成以双特异性抗体(BsAbs)和双靶点嵌合抗原受体基因修饰T细胞(CAR-T)治疗为主的早期临床试验,从起始剂量和剂量递增设计、剂量扩展试验、主要不良事件(AE)等方面进行回顾性分析。结果共纳入BsAbs早期临床试验13个,双靶点CAR-T治疗早期临床试验12个。在起始剂量选择方面,在BsAbs中,应用基于药代动力学/药效学模型方法(15.38%),应用最低预期生物效应水平方法(7.69%)。在剂量递增设计方面,BsAbs以“3+3”设计和基于模型设计为主(23.08%),双靶点CAR-T治疗以改良的“3+3”设计(25.00%)为主。在剂量扩展试验方面,BsAbs涉及剂量扩展试验设计比双靶点CAR-T治疗多(53.85%和25.00%)。BsAbs和双靶点CAR-T治疗的主要AE为细胞因子释放综合征(61.54%和50.00%)。结论双重靶向抗肿瘤新药的早期临床试验设计既需要继承传统经典设计,还需要适应性设计的不断改良和优化。Objective To retrospectively analyze the characteristics of early clinical study design strategies for dual-targeted new antitumor drugs.Methods Early clinical trials focusing on bispecific antibodies(BsAbs)and dual-targeted chimeric antigen receptor genetically modified T-cell(CAR-T)therapy were retrospectively analyzed in terms of starting dose and dose-escalation design,dose-expansion trials,and major adverse events(AEs)by pooling the completed trials from 2015-01-01 to 2023-10-31.ResultsA total of 13 early clinical trials of BsAbs and 12 early clinical trials of dual-targeted CAR-T cell therapy were included.In terms of starting dose selection,pharmacokinetic/pharmacodynamics model-based method(15.38%)and minimal anticipated biological effect level method(7.69%)were applied in BsAbs.In terms of dose-escalation design,"3+3"design and model-based design were predominant in BsAbs(23.08%);dual-targeted CAR-T cell therapy was predominant in modified"3+3"design(25.00%).In terms of dose-expansion trials,BsAbs involved more dose-expansion trial designs than dual-targeted CAR-T cell therapy(53.85%us 25.00%).The major AEs for both BsAbs and dual-targeted CAR-T cell therapy were cytokine release syndrome(61.54%us 50.00%).Conclusion The design of early clinical trials for new dual-targeted antitumor drugs would require both the inheritance of the traditional classical design and the continuous improvement and optimization of the adaptive design.

关 键 词：双特异性抗体 双靶点嵌合抗原受体基因修饰T细胞治疗 早期临床试验 研究设计 

分 类 号：R979.1[医药卫生—药品]