Division of Translational Research and Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, U.S.A.
Stat Med. 2013 Jan 15;32(1):131-41. doi: 10.1002/sim.5491. Epub 2012 Jul 17.
The time-to-event continual reassessment method (TITE-CRM) was proposed to handle the problem of long trial duration in Phase 1 trials as a result of late-onset toxicities. Here, we implement the TITE-CRM in dose-finding trials of combinations of agents. When studying multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. Therefore, the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. A CRM design for partially ordered trials (PO-CRM) was recently proposed. Simulation studies show that extending the TITE-CRM to the partial order setting produces results similar to those of the PO-CRM in terms of maximum tolerated dose recommendation yet reduces the duration of the trial.
时间事件连续再评估方法（TITE-CRM）被提出，以处理由于迟发性毒性而导致的 1 期试验中试验持续时间过长的问题。在这里，我们将 TITE-CRM 应用于联合用药的剂量发现试验中。当研究多种药物时，剂量-毒性曲线的单调性没有明确定义。因此，毒性概率遵循偏序，这意味着存在一些治疗组，在试验开始时，它们的毒性概率排序是未知的。最近提出了一种用于偏序试验的 CRM 设计（PO-CRM）。仿真研究表明，将 TITE-CRM 扩展到偏序设置中，在推荐最大耐受剂量方面的结果与 PO-CRM 相似，但可以缩短试验的持续时间。
