The use of `backfilling', assigning additional patients to doses deemed safe, in phase I dose-escalation studies has been used in practice to collect additional information on the safety profile, pharmacokinetics and activity of a drug. These additional patients help ensure that the Maximum Tolerated Dose (MTD) is reliably estimated and give additional information in order to determine the recommended phase II dose (RP2D). In this paper, we study the effect of employing backfilling in a phase I trial on the estimation of the MTD and the duration of the study. We consider the situation where only one cycle of follow-up is used for escalation as well as the case where there may be delayed onset toxicities. We find that, over a range of scenarios, there is an increase in the proportion of correct selections and a notable reduction in the trial duration at the cost of more patients required in the study.
翻译:在第一阶段剂量降温研究中,使用`补足'法,将更多病人的剂量分配到认为安全的剂量,在实践中,已经利用了第一阶段剂量降幅研究,收集关于药物安全状况、药用动力学和活性的额外信息,这些新增病人帮助确保可靠地估计最大耐用剂量(MTD),并提供补充信息,以确定建议的第二阶段剂量(RP2D),在本文件中,我们研究了在第一阶段试验中使用补足法对估计MTD和研究持续时间的影响,我们考虑了只有一种周期的后续跟踪用于升级的情况,以及可能出现延迟发作毒性的情况,我们发现,在一系列情况下,正确选择的比例有所上升,试验时间明显缩短,以研究所需的更多病人为代价。