<scp>PKBOIN</scp>‐12: A Bayesian Optimal Interval Phase I/<scp>II</scp> Design Incorporating Pharmacokinetics Outcomes to Find the Optimal Biological Dose

Immunotherapies and targeted therapies have gained popularity due to their promising therapeutic effects across multiple treatment areas. The focus of early phase dose-finding clinical trials has shifted from finding the maximum tolerated dose (MTD) to identifying the optimal biological dose (OBD), which aims to balance the toxicity and efficacy outcomes, thus optimizing the risk-benefit trade-off. These trials often collect multiple pharmacokinetics (PK) outcomes to assess drug exposure, which has shown correlations with toxicity and efficacy outcomes but has not been utilized in the current dose-finding designs for OBD selection. Moreover, PK outcomes are usually available within days after initial treatment, much faster than toxicity and efficacy outcomes. To bridge this gap, we introduce the innovative model-assisted PKBOIN-12 design, which enhances BOIN12 by integrating PK information into both the dose-finding algorithm and the final OBD determination process. We further extend PKBOIN-12 to TITE-PKBOIN-12 to address the challenges of late-onset toxicity and efficacy outcomes. Simulation results demonstrate that PKBOIN-12 more effectively identifies the OBD and allocates a greater number of patients to it than BOIN12. Additionally, PKBOIN-12 decreases the probability of selecting inefficacious doses as the OBD by excluding those with low drug exposure. Comprehensive simulation studies and sensitivity analysis confirm the robustness of both PKBOIN-12 and TITE-PKBOIN-12 in various scenarios.