Change-point joint model for identification of plateau of activity in early phase trials

This article presents a phase I/II trial design for targeted therapies and immunotherapies, with the objective of identifying the optimal dose (OD). We employ a joint modeling technique for discrete time-to-event toxicity data and repeated and continuous biomarker measurements. For the biomarker measurements, we implement a change point linear mixed effects skeleton model. This model can accommodate both plateauing and nonplateauing dose-activity relationships. For each new cohort of patients, we estimate the maximum tolerated dose (MTD) taking toxicity as a cumulative endpoint, over six treatment cycles. Then, we select the OD using two different criteria. The OD is a dose that is equally active to the MTD or a dose located on the beginning of the plateau of the dose-activity relationship. Joint modeling allows us to take into account informative censoring due to toxicities or lack of activity and we also consider consent withdrawal and intermittent missing responses. Model estimation relies on likelihood inference.