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

The Continual Reassessment Method (CRM) was developed for Phase I trials to identify a maximum‐tolerated dose of an agent using a design in which each participant is treated with a single administration of the agent. We propose an extension of the CRM in which participants receive multiple administrations of an agent using a so‐called step‐up dosing procedure in which participants receive one or more administrations of lower doses of the agent before they receive their penultimate dose. We use methods developed for the CRM to model the probability of DLT for each administration, which leads to the use of conditional probability models to model the joint probability of DLT across multiple administrations. We compare our approach to two existing methods that use time‐to‐event modeling methods for modeling the probability of DLT. We demonstrate through simulations that our approach has operating characteristics similar to existing methods, but due to its foundations in the CRM, ours is simpler to implement than existing approaches and is therefore more likely to be adopted in practice.