Yin Guosheng, Yang Zhao
Department of Statistics and Actuarial Science, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Contemp Clin Trials Commun. 2020 Aug 18;19:100650. doi: 10.1016/j.conctc.2020.100650. eCollection 2020 Sep.
Late-onset (LO) toxicities often arise in the new era of phase I oncology dose-finding trials with targeted agents or immunotherapies. The current LO toxicities modelling is often formulated in a weighted likelihood framework, where the time-to-event continual reassessment method (TITE-CRM) is commonly used. The TITE-CRM uses the patient exposure time as a weight for the censored observation, while there is large uncertainty on which weight function to be used. As an alternative, the fractional scheme formulates an efficient and robust paradigm to address LO toxicity issues in dose finding. We review the fractional continual reassessment method (fCRM) and compare its operating characteristics with those of the TITE-CRM as well as other competitive designs via extensive simulation studies based on both the fixed and randomly generated scenarios. The fCRM is shown to possess desirable operating characteristics in identifying the maximum tolerated dose (MTD) and deliver competitive performances in comparison with other designs. It provides an alternative efficient and robust paradigm for interpreting and addressing LO toxicities in the new era of phase I dose-finding trials in precision oncology. A real trial example is used to illustrate the practical use of the fCRM design.
迟发性（LO）毒性在使用靶向药物或免疫疗法的肿瘤学I期剂量探索试验的新时代中经常出现。当前的LO毒性建模通常在加权似然框架中制定，其中事件时间连续重新评估方法（TITE-CRM）被普遍使用。TITE-CRM使用患者暴露时间作为截尾观察的权重，而对于使用哪种权重函数存在很大的不确定性。作为一种替代方法，分数方案制定了一种有效且稳健的范式来解决剂量探索中的LO毒性问题。我们回顾了分数连续重新评估方法（fCRM），并通过基于固定和随机生成场景的广泛模拟研究，将其操作特性与TITE-CRM以及其他竞争性设计的操作特性进行比较。结果表明，fCRM在识别最大耐受剂量（MTD）方面具有理想的操作特性，并且与其他设计相比具有竞争力的性能。它为在精准肿瘤学I期剂量探索试验的新时代中解释和解决LO毒性提供了一种替代的有效且稳健的范式。一个实际试验示例用于说明fCRM设计的实际应用。
