文章：

基于剂量限制性毒性归因的自适应分配I期药物联合研究设计

Design of a Phase I Drug Combination Study with Adaptive Allocation Based on Dose-Limiting Toxicity Attribution

原文发布日期：20 March 2025

DOI: 10.3390/cancers17061038

类型: Article

开放获取: 是

英文摘要：

Background:This article describes the adaptation of a Phase I drug combination method to incorporate dose-limiting toxicity (DLT) attribution in dose assignments. The study is motivated by the Embolden trial (NCT03240211), a Phase Ib, multicenter trial at the UVA Comprehensive Cancer Center evaluating pembrolizumab with pralatrexate (Arm A), decitabine (Arm C), or both (Arm B) in relapsed/refractory peripheral and cutaneous T cell lymphomas.Methods:While Arms A and C used monotherapy dose escalation, Arm B required simultaneous escalation of both agents, integrating drug-specific DLT attribution to guide dosing.Results:We adapted the partial order continual reassessment method (POCRM) to incorporate this attribution, ensuring appropriate de-escalation of the offending agent. Given the trial’s complexity, software modifications were necessary to evaluate design performance through simulations.Conclusions:This work underscores the importance of novel dose-finding strategies in early-phase trials and aims to promote their broader adoption for improved trial efficiency and transparency.

摘要翻译： 

背景：本文介绍了一种将剂量限制性毒性（DLT）归因纳入剂量分配的第一阶段药物联合方案的调整方法。该研究基于Embolden试验（NCT03240211）的设计需求，该试验是由弗吉尼亚大学综合癌症中心开展的一项Ib期多中心研究，旨在评估帕博利珠单抗联合普拉曲沙（A组）、地西他滨（C组）或两者联用（B组）治疗复发/难治性外周及皮肤T细胞淋巴瘤的疗效。 方法：A组和C组采用单药剂量递增方案，而B组需要同时递增两种药物剂量，并通过整合药物特异性DLT归因来指导用药。 结果：我们改良了偏序连续重评估方法（POCRM），将药物特异性毒性归因纳入设计框架，确保对引发毒性的药物进行合理降级。鉴于试验设计的复杂性，本研究通过软件修改进行模拟以评估方案性能。 结论：这项工作凸显了创新剂量探索策略在早期临床试验中的重要性，旨在推动其更广泛的应用，从而提升试验效率与透明度。

原文链接：

Design of a Phase I Drug Combination Study with Adaptive Allocation Based on Dose-Limiting Toxicity Attribution