The Joint i3+3 (Ji3+3) design for phase I/II adoptive cell therapy clinical trials

Abstract

ABSTRACT Adoptive cell therapy (ACT), such as chimeric antigen receptor (CAR) T-cell therapy, has demonstrated promising therapeutic effects with potentially non-monotonic dose–response curves. Building upon the i3 + 3 design for cytotoxic agents [1], we propose a new method – joint i3 + 3 (Ji3 + 3) that takes into account of both safety and efficacy outcomes in making dosing recommendations. This allows for efficient dose escalation and identification of biological optimal dose of ACTs which may not be cytotoxic. The Ji3 + 3 design is rule based, easy to understand for clinicians, and is simple to implement. Simulation results show that Ji3 + 3 outperforms existing designs when monotonic dose–response assumption is violated, and still achieves comparable performance when the assumption holds. The simplicity and superior operating characteristics make Ji3 + 3 a good candidate for phase I/II ACT dose-finding trials in the clinical community when toxicity and efficacy are both considered as binary endpoints.