Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017;27(6):1028-1042.
doi: 10.1080/10543406.2017.1293076. Epub 2017 Mar 25.

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM

Joseph S Koopmeiners  1   2 , Andrew Wey  3
Affiliations

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM

Joseph S Koopmeiners et al. J Biopharm Stat. 2017.

Abstract

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 well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable tradeoff with respect to the average number treated at the MTD.

Keywords: Continual reassessment method; Phase I clinical trial; dose finding; long-memory property.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Dose-toxicity relationship for the six scenarios considered in our simulation study
Figure 2
Figure 2
Histogram of the number of cohorts treated at the MTD for Scenarios 1 through 3 and a maximum sample size of N = 21 for each of the six dose-finding algorithms. Also presented are the mean and standard deviation of the number of cohorts treated at the MTD.
Figure 3
Figure 3
Histogram of the number of cohorts treated at the MTD for Scenarios 4 through 6 and a maximum sample size of N = 21 for each of the six dose-finding algorithms. Also presented are the mean and standard deviation of the number of cohorts treated at the MTD.
See this image and copyright information in PMC

References

    1. Babb J, Rogatko A, Rogatko A, Zacks S. Cancer phase I clinical trials: Efficient dose escalation with overdose control. Statistics in Medicine. 1998;17:1103–1120. - PubMed
    1. Braun TM. The bivariate continual reassessment method: extending the CRM to phase I trials of two competing outcomes. Controlled Clinical Trials. 2002;23:240–256. - PubMed
    1. Carlin BP, Zhong W, Koopmeiners JS. Discussion of ’small-sample behavior of novel phase I cancer trial designs’ by Assaf P Oron and Peter D Hoff. Clin Trials. 2013;10:81–85. - PMC - PubMed
    1. Cheung YK. Commentary on ’Small-sample behavior of novel phase I cancer trial designs’. Clin Trials. 2013;10:86–87. - PubMed
    1. Gasparini M, Eisele J. A curve-free method for phase i clinical trials. Biometrics. 2000;56:609–615. - PubMed

MeSH terms

LinkOut - more resources