Time-to-event Bayesian Optimal Interval Design to Accelerate Phase I Trials

Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients' toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose escalation/de-escalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target DLT rate and has higher accuracy to identify the MTD. Compared to the more complicated model-based time-to-event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD, but is simpler to implement with substantially better overdose control. As the TITE-CRM is more aggressive, it is less likely to underdose patients. A numerical study shows that the TITE-BOIN design supports continuous accrual, without sacrificing patient safety nor the accuracy of identifying the MTD, and therefore has great potential to accelerate early phase drug development.

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