TITE-gBOIN: Time-to-event Bayesian optimal interval design to accelerate dose-finding accounting for toxicity grades.

Abstract

The new therapeutic agents, such as molecular targeted agents and immuno-oncology therapies, appear more likely to induce multiple toxicities at different grades than dose-limiting toxicities defined in traditional dose-finding trials. In addition, it is often challenging to make adaptive decisions on dose escalation and de-escalation on time because of the fast accrual rate and/or the late-onset toxicity outcomes, causing the potential suspension of the enrollment and the delay of the trials. To address these issues, we propose a time-to-event Bayesian optimal interval design to accelerate the dose-finding process utilizing toxicity grades based on both cumulative and pending toxicity outcomes. The proposed design, named "TITE-gBOIN" design, is a nonparametric and model-assisted design and has the virtues of robustness, simplicity and straightforward to implement in actual oncology dose-finding trials. A simulation study shows that the TITE-gBOIN design has a higher probability of selecting the MTDs correctly and allocating more patients to the MTDs across various realistic settings while reducing the trial duration significantly, therefore can accelerate early-stage dose-finding trials.