Extending the Continual Reassessment Method to accommodate step-up dosing in Phase I trials

Area of Science:

• Clinical Trials
• Biostatistics
• Pharmacology

Background:

• Phase I clinical trials aim to find the maximum-tolerated dose (MTD) of new agents.
• The Continual Reassessment Method (CRM) is a common design for single-agent administration in Phase I trials.
• Existing methods for multiple administrations can be complex to implement.

Purpose of the Study:

• To extend the CRM for Phase I trials involving multiple administrations of an agent.
• To develop a simpler, CRM-based approach for dose-finding with step-up dosing procedures.
• To compare the proposed method with existing time-to-event modeling approaches.

Main Methods:

• Utilized CRM principles to model the probability of dose-limiting toxicity (DLT) for each administration.
• Employed conditional probability models to capture the joint probability of DLT across multiple administrations.
• Compared the new method against two established time-to-event modeling techniques via simulations.

Main Results:

• The proposed CRM extension demonstrated operating characteristics comparable to existing methods.
• Simulations indicated the new approach is simpler to implement than current alternatives.
• The method effectively models DLT probabilities in multi-dose settings.

Conclusions:

• The extended CRM offers a more practical and implementable solution for Phase I trials with step-up dosing.
• This simplified approach is expected to increase adoption in clinical practice.
• The method provides a robust framework for identifying MTD with complex dosing regimens.