A dose-schedule finding design for phase Ⅰ-Ⅱ clinical trials

摘要

Dose finding methods aiming at identifying an optimal dose of a treatment with a given schedule may be at a risk of misidentifying the best treatment for patients. We propose a phase Ⅰ-Ⅱ clinical trial design to find the optimal dose-schedule combination. We define schedule as the method and timing of administration of a given total dose in a treatment cycle. We propose a Bayesian dynamic model for the joint effects of dose and schedule. The model proposed allows us to borrow strength across dose-schedule combinations without making overly restrictive assumptions on the ordering pattern of the schedule effects. We develop a dose-schedule finding algorithm to allocate patients sequentially to a desirable dose-schedule combination, and to select an optimal combination at the end of the trial. We apply the proposed design to a phase Ⅰ-Ⅱ clinical trial of a 7-secretase inhibitor in patients with refractory metastatic or locally advanced solid tumours, and we examine the operating characteristics of the design through simulations.