用于同步开发单药治疗与联合治疗的交错无缝剂量优化设计

中文摘要 AI 辅助

当代肿瘤药物开发日益需要高效的剂量优化策略，以评估单药治疗（Mono）和联合治疗（Combo），同时平衡活性、疗效与耐受性。针对新型药物需单独及与已上市药物联合评估的场景，我们提出一种交错无缝I/II期设计：I期先启动单药剂量探索，一旦观察到基于早期临床或生物学信息的预设联合启动信号，即可自适应开放联合治疗子试验；剂量分配采用基于毒性与早期活性的模型辅助规则，在可耐受且具潜在前景的方案中补充入组。I期结束时，基于累积毒性与治疗应答数据的效毒效用，从已评估的单药及联合方案中选定2种候选方案；II期无缝延续在选定方案治疗的患者，按需招募额外患者，应用贝叶斯无效性与疗效终止边界以确定最终推荐的最优生物剂量（OBD）。模拟研究显示，与对照设计相比，该设计缩短了I期试验时长，同时保持了具竞争力的OBD选择性能与可接受的安全性；无缝II期组件进一步减少了额外招募需求，支持高效的最终OBD选择。

英文摘要

Contemporary oncology drug development increasingly requires efficient dose-optimization strategies that evaluate monotherapy (Mono) and combination therapy (Combo) while balancing activity, efficacy, and tolerability. We propose a staggered seamless phase I/II design for settings in which a novel agent is evaluated alone and in combination with an established therapy. In phase I, Mono dose finding begins first, and Combo subtrials can be opened adaptively once a prespecified combination-initiation signal based on early clinical or biological information is observed. Dose assignment uses a model-assisted rule based on toxicity and early activity, with backfilling at tolerable and potentially promising regimens. At the end of phase I, two candidate regimens are selected from the evaluated Mono and Combo regimens using an efficacy-toxicity utility based on accumulated toxicity and treatment-response data. Phase II seamlessly carries forward patients treated at the selected regimens, enrolls additional patients as needed, and applies Bayesian futility and efficacy stopping boundaries to identify a final recommended optimal biological dose (OBD). Simulation studies showed that the proposed design shortened phase I trial duration relative to the comparator designs while maintaining competitive OBD-selection performance and acceptable safety. The seamless phase II component further reduced the need for additional enrollment and supported efficient final OBD selection.

发表机构

• Chuo University（中央大学）
• Astellas Pharma Global Development Inc.（安斯泰来全球开发公司）
• The University of Texas MD Anderson Cancer Center（德克萨斯大学安德森癌症中心）

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