Sequential designs for phase I clinical trials with late-onset toxicities.
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.
Cheung
Y K
YK
Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706, USA. ken@stat.wisc.edu
Chappell
R
R
D016588:Anticarcinogenic Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000517:prevention & control / Q000532:radiotherapy; D011878:Radiotherapy / Q000009:adverse effects; D015203:Reproducibility of Results; D012107:Research Design; D012449:Safety; D013997:Time Factors; D017211:Treatment Failure
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents