A novel framework of Bayesian optimal interval design for phase I trials with late-onset toxicities.

Abstract As molecularly targeted agents (MTAs) and immunotherapies have widely demonstrated delayed toxicity profile after multiple treatment cycles, the traditional phase I dose-finding designs may not be appropriate anymore because they just account for the acute toxicities occurring in the early period of treatment. When the dose-limiting toxicity (DLT) assessment window is prolonged to account for late-onset DLTs, it will cause logistic issues if the enrollment is suspended until all the DLT information is collected. We propose a novel framework to estimate the toxicity probability in the scenarios where some patients' DLT information are not complete and then implement the Bayesian optimal interval (BOIN) design to make decisions on dose escalation/de-escalation. Our proposed approach maintains BOIN's transparency by simply comparing the estimated toxicity probability with the escalation/de-escalation boundaries to decide the next dose level. The numerical studies show that our proposed framework can achieve comparable operating characteristics as other dose-finding designs considering late-onset DLTs, thus providing an attractive option of phase I dose-finding clinical trials for MTAs and immunotherapies.