双重靶向抗肿瘤新药的早期临床试验设计的探讨OA北大核心CSTPCD

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.Results A 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％vs 25.00％).The major AEs for both BsAbs and dual-targeted CAR-T cell therapy were cytokine release syndrome(61.54％vs 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.