A rapidly increasing number of Phase I dose-finding studies, those based on the standard 3+3 design in particular, are being prolonged with the inclusion of dose expansion cohorts (DEC) to better characterize the toxicity profiles of experimental agents and to study disease-specific cohorts. These trials consist of two phases: the usual dose escalation phase that aims to establish the maximum tolerated dose (MTD), and the dose expansion phase that accrues additional patients, often with different eligibility criteria, and where additional information is collected. Currently, not all protocols specify whether and how the MTD will be updated in the light of new data accumulated from the DEC. Here, we propose methods that allow monitoring of safety in the DEC by reevaluating the MTD in light of additional information. Our working assumption is that, regardless of the design being used for dose escalation, during the DEC we are experimenting in the neighborhood of a target dose with an acceptable rate of toxicity. We refine our initial estimate of the MTD by continuing experimentation in the immediate vicinity of the initial estimate of the MTD. The auxiliary information provided by such an evaluation will include toxicity, pharmacokinetic, efficacy, and other endpoints. We consider approaches specifically focused on the aims of DEC that examine efficacy alone or simultaneously with safety. Simulations provide further insight into the behavior of the proposed tests. Supplementary materials for this article are available online.

随着剂量扩展队列 (DEC) 的纳入，I 期剂量探索研究的数量迅速增加，特别是基于标准 3+3 设计的研究，这些研究正在延长，以更好地表征实验药物的毒性特征并研究疾病-特定群体。这些试验由两个阶段组成：通常的剂量递增阶段，旨在确定最大耐受剂量（MTD）；剂量扩展阶段，招募更多患者，通常具有不同的资格标准，并收集额外的信息。目前，并非所有协议都指定 MTD 是否以及如何根据 DEC 积累的新数据进行更新。在这里，我们提出了通过根据附加信息重新评估 MTD 来监控 DEC 安全性的方法。我们的工作假设是，无论用于剂量递增的设计如何，在 DEC 期间，我们都在具有可接受的毒性率的目标剂量附近进行实验。我们通过在 MTD 初始估计附近继续进行实验来完善 MTD 的初始估计。这种评估提供的辅助信息将包括毒性、药代动力学、功效和其他终点。我们考虑专门针对 DEC 目标的方法，即单独检查功效或与安全性同时检查。模拟可以进一步深入了解所提出的测试的行为。本文的补充材料可在线获取。