标题： 针对随机 II 期癌症试验的三结局时间至事件设计 显示英文标题

标题： A time-to-event three-outcome design for randomized phase II cancer trials

摘要： 肿瘤反应是一种二元变量，在许多癌症二期单臂试验中，历史上一直是衡量抗肿瘤活性的主要指标。西蒙两阶段设计经常被采用。Sargent等人在这一背景下提出了一种三结局试验设计，该设计需要更小的样本量。然而，对于许多新的分子靶向疗法而言，肿瘤反应可能并不是衡量抗肿瘤活性最可靠的终点。越来越多的情况下，时间至事件型终点，如无进展生存期（PFS），被用于二期试验中。当这些终点作为疗效的主要衡量标准时，通常需要随机对照研究设计。鉴于二期试验资源有限，这类研究往往功效不足，具有相对较大的I型和II型错误率，并且在二期试验后有时不可避免地会出现一个“灰色”决策区，在这个区域无法根据现有信息做出进一步开发行动的明确决定。与功效不足的标准两结局研究相比，三结局设计促使临床试验设计者在设计阶段考虑落入“灰色”区的可能性，并选择更合适的试验设计参数。我们提出了一种三结局设计，适用于在使用时间至事件型终点的随机比较二期试验中，无论是否有中期分析。 显示英文摘要

摘要： Tumor response, a binary variable, has historically been the main measure of antitumor activity for many cancer phase II single-arm trials. Simon two-stage designs are often used. Sargent et al. proposed a three-outcome trial design in this setting which requires smaller sample sizes. For many new, molecularly targeted therapies, however, tumor response may not be the most reliable endpoint for measuring anti-tumor activity. Increasingly, time-to-event endpoints, such as progression-free survival (PFS), are used in the phase II setting. When such endpoints are the primary measure of efficacy, a randomized concurrently controlled study design is usually required. Given limited resources for phase II, studies are often underpowered with relatively large type I and II error rates, and it is sometimes unavoidable to have a "gray" decision zone after phase II where a clear decision regarding further development actions cannot be made without additional information. Compared with an underpowered standard two-outcome study, a three-outcome design prompts clinical trialists to contemplate the likelihood of landing in the "gray" zone at the trial design stage and choose study design parameters more appropriately. We propose a three-outcome design, with or without interim analyses, for randomized comparative phase II trials when a time-to-event endpoint is used.