A staggered seamless dose-optimization design for co-developing monotherapy and combination therapy

2026-09-01

AI Summary

提出了一种交错无缝剂量优化设计，用于同时开发单药和联合疗法，通过适应性启动联合子试验，并使用基于毒性和早期活性的模型辅助规则来解决剂量优化问题。

Abstract

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.

Problem

• dose-optimization
• monotherapy
• combination therapy
• efficacy
• tolerability

Innovation

• staggered seamless design
• model-assisted rule
• Bayesian stopping boundaries
• optimal biological dose (OBD)
• adaptive initiation