Treatment of cancer has rapidly evolved over time in quite dramatic ways, for example from chemotherapies, targeted therapies to immunotherapies and chimeric antigen receptor T-cells. Nonetheless, the basic design of early phase I trials in oncology still follows pre-dominantly a dose-escalation design. These trials monitor safety over the first treatment cycle in order to escalate the dose of the investigated drug. However, over time studying additional factors such as drug combinations and/or variation in the timing of dosing became important as well. Existing designs were continuously enhanced and expanded to account for increased trial complexity. With toxicities occurring at later stages beyond the first cycle and the need to treat patients over multiple cycles, the focus on the first treatment cycle only is becoming a limitation in nowadays multi-cycle treatment therapies. Here we introduce a multi-cycle time-to-event model (TITE-CLRM: Time-Interval-To-Event Complementary-Loglog Regression Model) allowing guidance of dose-escalation trials studying multi-cycle therapies. The challenge lies in balancing the need to monitor safety of longer treatment periods with the need to continuously enroll patients safely. The proposed multi-cycle time to event model is formulated as an extension to established concepts like the escalation with over dose control principle. The model is motivated from a current drug development project and evaluated in a simulation study.

翻译：癌症治疗方式随时间推移已发生显著且快速的演变，例如从化疗、靶向治疗发展到免疫疗法及嵌合抗原受体T细胞疗法。然而，肿瘤学早期I期试验的基本设计仍主要遵循剂量递增模式。这类试验通过监测首个治疗周期的安全性来提升研究药物的剂量。但随着研究深入，药物组合和/或给药时机的变化等其他因素也变得至关重要。为应对日益增长的试验复杂性，现有设计不断得到改进与扩展。由于毒性反应可能出现在首个周期之后的后续阶段，且患者需要接受多周期治疗，仅关注首个治疗周期已成为当今多周期治疗方案中的局限。本文提出一种多周期时间-事件模型（TITE-CLRM：时间间隔-事件互补双对数回归模型），可为研究多周期疗法的剂量递增试验提供指导。核心挑战在于平衡长期治疗安全性监测与持续安全入组患者的需求。所提出的多周期时间-事件模型构建为对既定概念（如过量控制原则下的剂量递增）的扩展。该模型源自当前药物研发项目，并通过模拟研究进行了验证。