Department of Biostatistics, CB #7420, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Stat Med. 2021 Apr 15;40(8):2073-2082. doi: 10.1002/sim.8892. Epub 2021 Feb 15.
The continual reassessment method (CRM) is a well-known design for dose-finding trials with the goal of estimating the maximum tolerated dose (MTD), the dose with a given probability of toxicity. The standard assumption is that the probability of toxicity monotonically increases with dose. We show that the CRM can still be consistent and correctly identify the MTD even when the dose-toxicity curve is not monotone as long as there is monotonicity of the true toxicity probabilities right below and right above the true MTD. In the case of multiple therapies, where it is unclear how to order combinations of dose levels of multiple therapies, our findings provide insight into the performance of the partial order CRM (POCRM). To select the correct dose combination at the end of a trial, the POCRM does not have to select a monotone ordering of drug combinations. We illustrate the connection between our results for the CRM with a nonmonotone dose-toxicity curve and the POCRM via simulations.
持续评估法（CRM）是一种著名的剂量探索试验设计，旨在估计最大耐受剂量（MTD），即具有给定毒性概率的剂量。标准假设是毒性概率随剂量单调增加。我们表明，只要真实毒性概率在真实 MTD 下方和上方具有单调性，即使剂量-毒性曲线不单调，CRM 仍然可以保持一致性并正确识别 MTD。在多种疗法的情况下，不清楚如何对多种疗法的剂量水平组合进行排序，我们的发现为部分有序 CRM（POCRM）的性能提供了深入了解。为了在试验结束时选择正确的剂量组合，POCRM 不必选择药物组合的单调排序。我们通过模拟说明了 CRM 与非单调剂量-毒性曲线和 POCRM 之间的联系。
