Sequential designs for phase I clinical trials with late-onset toxicities

被引:367
作者
Cheung, YK [1 ]
Chappell, R
机构
[1] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA
[2] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA
关键词
continual reassessment method; dose limiting; late-onset toxicities; likelihood-based design; phase I trial; time-to-event;
D O I
10.1111/j.0006-341X.2000.01177.x
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Traditional designs for phase I clinical trials require each patient (or small group of patients) to be completely followed before the next patient or group is assigned. In situations such as when evaluating late-onset effects of radiation or toxicities from chemopreventive agents, this may result in trials of impractically long duration. We propose a new method, called the time-to-event continual reassessment method (TITE-CRM), that allows patients to be entered in a staggered fashion. It is an extension of the continual reassessment method (CRM; O'Quigley, Pepe, and Fisher, 1990, Biometrics 46, 33-48). We also note that this time-to-toxicity approach can be applied to extend other designs for studies of short-term toxicities. We prove that the recommended dose given by the TITE-CRM converges to the correct level under certain conditions. A simulation study shows our method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2-4 years by our method.
引用
收藏
页码:1177 / 1182
页数:6
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