Probability-of-decision interval 3+3 (POD-i3+3) design for phase I dose finding trials with late-onset toxicity.

Late-onset toxicities often occur in phase I trials investigating novel immunotherapy and molecular targeted therapies. For trials with cohort based designs (such as modified toxicity probability interval, Bayesian optimal interval, and i3+3), patients are often turned away since the current cohort are still being followed without definite dose-limiting toxicities, which results in prolonged trial duration and waste of patient resources. In this paper, we incorporate a probability-of-decision framework into the i3+3 design and allow real-time dosing inference when the next patient becomes available. Both follow-up time for the pending patients and time to dose-limiting toxicities for the observed patients are used in calculating the posterior probability of each possible dosing decision. An intensive simulation study is conducted to evaluate the operating characteristics of the newly proposed probability-of-decision-i3+3 design under various dosing scenarios and patient accrual settings. Results show that the probability-of-decision-i3+3 design achieves comparable safety and reliability performances but much shorter trial duration compared to the complete designs.