ABSTRACT

In traditional dose-finding studies, dose-limiting toxicity (DLT) is determined within a fixed time observation window where DLT is often defined as a binary outcome. In the setting of oncology dose-finding trials, often patients in advanced stage of diseases are enrolled. Therefore, disease progression may occur within the DLT observation window leading to treatment discontinuation and rendering the patient unevaluable for DLT assessment. As a result, additional patients have to be enrolled, increasing the sample size. We propose and compare several practical approaches for handling disease progression which occurs within the DLT observation window, while in the framework of the time-to-event continual reassessment method (TITE-CRM) which allows using partial observations. The approaches differ on the way they define an evaluable patient and in the way incomplete observations are included. The practical approaches, which we call strategies A, B and C, are illustrated and contrasted in the context of a single simulated trial, and compared via simulations under various scenarios of dose-progression relationship, in the setting of advanced soft-tissue sarcoma.

 抽象的

在传统的剂量探索研究中，剂量限制毒性（DLT）是在固定时间观察窗口内确定的，其中 DLT 通常被定义为二元结果。在肿瘤学剂量探索试验中，通常会招募处于疾病晚期的患者。因此，疾病进展可能发生在 DLT 观察窗口内，导致治疗停止并使患者无法进行 DLT 评估。因此，必须招募更多患者，从而增加样本量。我们提出并比较了几种处理 DLT 观察窗口内发生的疾病进展的实用方法，同时在允许使用部分观察的事件时间持续重新评估方法 (TITE-CRM) 的框架内。这些方法的不同之处在于定义可评估患者的方式以及包含不完整观察的方式。我们将这些实用方法称为策略 A、B 和 C，在单个模拟试验的背景下进行说明和对比，并通过在晚期软组织肉瘤的情况下剂量进展关系的各种场景下的模拟进行比较。