A Bayesian time-to-event pharmacokinetic model for phase I dose-escalation trials with multiple schedules

• and T Friede  |  BK Günhan  |  S Weber

• https://arxiv.org/pdf/2002.06204v1.pdf

Phase I dose-escalation trials must be guided by a safety model in order to avoid exposing patients to unacceptably high risk of toxicities. Traditionally, these trials are based on one type of schedule. In more recent practice, however, there is often a need to consider more than one schedule, which means that in addition to the dose itself, the schedule needs to be varied in the trial. Hence, the aim is finding an acceptable dose-schedule combination. However, most established methods for dose-escalation trials are designed to escalate the dose only and ad-hoc choices must be made to adapt these to the more complicated setting of finding an acceptable dose-schedule combination. The model uses a time-varying exposure measure to account for the risk of a dose-limiting toxicity over time. The dose-schedule decisions are informed by an escalation with overdose control criterion. The model is formulated using interpretable parameters which facilitates the specification of priors. In a simulation study, they compared the proposed method with an existing method. The simulation study demonstrates that the proposed method yields similar or better results compared to an existing method in terms of recommending acceptable dose-schedule combinations, yet reduces the number of patients enrolled in most of scenarios.

Input variables : dose-schedule combination within a phase I trial as in Wages et al.(Wages NA, O’Quigley J, Conaway MR. Phase I design for completely or partially ordered treatment schedules. Stat Med. 2014;33(4):569–579.)
Output Variables : maximum tolerated dose-schedule combination (MTC) in the targeted toxicity interval compared to the partial order continual reassessment method (POCRM)

Visit Model : arxiv.org

Additional links : arxiv.org | github.com