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

*(English)*Zbl 1060.62547Summary: 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) [J. O’Quigley, M. Pepe, and L. Fisher, Biometrics 46, No. 1, 33–48 (1990; Zbl 0715.62242)]. 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.

##### MSC:

62L05 | Sequential statistical design |

62P10 | Applications of statistics to biology and medical sciences; meta analysis |

##### Keywords:

continual reassessment method; dose limiting; late-onset toxicities; likelihood-based design; phase I trial; time-to-event
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\textit{Y. K. Cheung} and \textit{R. Chappell}, Biometrics 56, No. 4, 1177--1182 (2000; Zbl 1060.62547)

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