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

TLDR

Traditional phase I designs require complete follow‑up of each patient before enrolling the next, which makes trials of late‑onset toxicities like radiation or chemopreventive agents impractically long. The authors propose the time‑to‑event continual reassessment method (TITE‑CRM) to allow staggered patient entry and to extend other short‑term toxicity designs. TITE‑CRM extends the conventional CRM by incorporating time‑to‑toxicity data, enabling dose‑escalation decisions while patients remain under observation. The method converges to the correct dose, and simulations show comparable accuracy and safety to CRM while shortening trial duration from up to 12 years to 2–4 years.

Abstract

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.