Sequential Designs for Phase I Clinical Trials with Late-Onset Toxicities

Authors

  • Ying Kuen Cheung,

    Corresponding author
    1. Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706, U.S.A.
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  • Rick Chappell

    1. Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706, U.S.A.
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*email:ken@stat.wisc.edu

Abstract

Summary. 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, Biometrics46, 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.

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