Novel bayesian adaptive early phase designs to accelerate the development of CAR T-cell therapy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment, particularly for hematopoietic malignancies. CAR T-cell therapy is a living drug with fundamentally different characteristics from those of other therapies. For example, CAR T-cell therapy efficacy may not increase with dose, and dose-limiting toxicity is rarely observed in the therapeutic dose range. Consequently, the conventional trial design paradigm is not suitable for the development of CAR T-cell therapy. Here, we review and introduce the phase I-II trial design paradigm to optimize the dose of CAR T-cell therapy on the basis of both toxicity and efficacy. We describe several novel Bayesian model-assisted designs, including BOIN12 and U-BOIN, which are simple to implement and have excellent operating characteristics for identifying the optimal biological dose for CAR T-cell therapy. Examples and software are provided to facilitate the use of these novel designs to accelerate the development of CAR T-cell therapy.