Dose expansion cohorts in Phase I trials

Area of Science:

• Clinical Trials Methodology
• Pharmacometrics
• Oncology Drug Development

Background:

• Phase I clinical trials increasingly use dose expansion cohorts (DEC) to better define toxicity and study specific patient groups.
• Standard 3+3 designs often lack clear protocols for updating the maximum tolerated dose (MTD) with DEC data.
• DEC provide valuable safety and efficacy information beyond the initial dose-escalation phase.

Purpose of the Study:

• To propose and evaluate methods for re-evaluating the MTD using data from DEC.
• To refine MTD estimation by incorporating new safety and efficacy data collected during the expansion phase.
• To provide a framework for monitoring safety and efficacy in DEC, particularly around the estimated MTD.

Main Methods:

• Developing methods to continuously monitor safety and re-estimate the MTD within the DEC.
• Utilizing auxiliary data, including toxicity, pharmacokinetics, and efficacy, to refine MTD estimates.
• Comparing proposed methods through simulations, focusing on efficacy alone or combined with safety endpoints.

Main Results:

• The proposed methods allow for the refinement of MTD estimates by leveraging data from DEC.
• Continuous monitoring enables adaptive adjustments to the MTD based on accumulating evidence.
• Simulation results demonstrate the utility of the proposed approaches for evaluating efficacy and safety in DEC.

Conclusions:

• Re-evaluating the MTD using DEC data enhances the precision of dose selection in early-phase oncology trials.
• The proposed methods offer a structured way to integrate DEC findings into MTD determination.
• This adaptive approach improves the characterization of experimental agents' safety and efficacy profiles.