  The primary object of a phase I clinical trial is to determine the maximum
tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation
study, where initial subjects are treated at the lowest dose level and
subsequent subjects are treated at progressively higher dose levels until the
MTD is identified. The continual reassessment method (CRM) is a popular
model-based dose-escalation design, which utilizes a formal model for the
relationship between dose and toxicity to guide dose-finding. Recently, it was
shown that the CRM has a tendency to get "stuck" on a dose-level, with little
escalation or de-escalation in the late stages of the trial, due to the
long-memory property of the CRM. We propose the randomized CRM (rCRM), which
introduces random escalation and de-escalation into the standard CRM
dose-finding algorithm, as an approach to overcoming the long-memory property
of the CRM. We discuss two approaches to random escalation and de-escalation
and compare the operating characteristics of the rCRM to the standard CRM by
simulation. Our simulation results show that the rCRM identifies the true MTD
at a similar rate and results in a similar number of DLTs compared to the
standard CRM, while reducing the trial-to-trial variability in the number of
cohorts treated at the true MTD.
