A Phase I Dose‐Finding Design Incorporating Intra‐Patient Dose Escalation

ABSTRACT Conventional Phase I trial designs assign a single dose to each patient, necessitating a minimum number of patients per dose to reliably identify the maximum tolerated dose (MTD). However, in many clinical trials, such as those involving pediatric patients or patients with rare cancers, recruiting an adequate number of patients can pose challenges, limiting the applicability of standard trial designs. To address this challenge, we propose a new Phase I dose‐finding design, denoted as IP‐CRM, that integrates intra‐patient dose escalation with the continual reassessment method (CRM). In the IP‐CRM design, intra‐patient dose escalation is allowed, guided by both individual patients' toxicity outcomes and accumulated data across patients, and the starting dose for each cohort of patients is adaptively updated. We further extend the IP‐CRM design to address carryover effects and/or intra‐patient correlations. Due to the potential for each patient to contribute multiple data points at varying doses owing to intra‐patient dose escalation, the IP‐CRM design offers the advantage of determining the MTD with a considerably reduced sample size compared to standard Phase I dose‐finding designs. Simulation studies show that our IP‐CRM design can efficiently reduce sample size while concurrently enhancing the probability of identifying the MTD when compared with standard CRM designs and the 3 + 3 design.