Multi-stage dose expansion cohort (MSDEC) design with Bayesian stopping rule

Area of Science:

• Clinical Trial Design
• Biostatistics
• Pharmacology

Background:

• Phase I trials commonly use algorithm-based (e.g., 3+3) or model-based (e.g., CRM) designs to find the maximum tolerated dose (MTD).
• The traditional 3+3 design is widely used for its simplicity, but it may lack accuracy in MTD determination, especially with limited patient numbers.
• Dose-expansion cohorts (DEC) are increasingly employed to better define toxicity profiles of novel agents.

Purpose of the Study:

• To propose a novel multi-stage dose-expansion cohort (MSDEC) hybrid frequentist-Bayesian design for Phase I clinical trials.
• To enhance the safety and accuracy of MTD determination in early-phase drug development.
• To integrate historical data effectively using a power prior within a Bayesian framework.

Main Methods:

• The MSDEC design combines a power prior for modeling historical dose-escalation data with a sequential conditional probability ratio test for safety monitoring.
• A Bayesian stopping rule is developed for safety monitoring.
• Maximum sample size is determined using a fixed-sample-size test with exact binomial computation.

Main Results:

• Simulation studies indicate that the MSDEC design effectively reduces the probability of patients receiving toxic doses.
• The power prior allows objective weighting of historical data, reducing reliance on subjective expert opinion for Bayesian model parameterization.
• The hybrid approach balances the strengths of frequentist and Bayesian methodologies for robust dose-finding.

Conclusions:

• The proposed MSDEC design offers a safer and potentially more accurate approach to MTD determination in Phase I trials compared to traditional methods.
• The use of power prior in a Bayesian context provides a data-driven and flexible way to incorporate historical information.
• This hybrid design represents a significant advancement in optimizing early-phase clinical trial methodology for novel therapeutics.