From Dose-Finding to Dose-Optimization in Early-Phase oncology clinical trials

Abstract

Dose optimization in Phase I oncology trials balances therapeutic efficacy and patient safety. Traditional dose-escalation methods, such as the 3 + 3 design, primarily focus on safety, often resulting in prolonged exposure to subtherapeutic or excessively toxic doses. Additionally, these methods may fail to account for modern therapies' complex pharmacokinetics and pharmacodynamics, including targeted agents and immunotherapies. Contemporary approaches address these gaps by incorporating biomarkers, pharmacokinetic profiling, and patient-reported outcomes to guide personalized dosing strategies. Such methods improve the precision of dose selection and promote individualized cancer care. This review underscores the importance of distinguishing between dose-finding and dose optimization, advocating for designs that integrate patient perspectives and pharmacologic insights from early-phase trials. Additionally, we highlight the challenges of traditional methodologies and the importance of simplifying complex designs without compromising their scientific rigor. By embracing innovative approaches and patient-centered metrics, Phase I trials can evolve beyond safety assessments to expedite the delivery of effective and tailored cancer therapies.

Keywords: Dose finding; Dose optimization; Early-phase clinical trials; New drug development; Patient-centric outcomes.