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Abstract

This paper reviews Bayesian procedures for phase 1 dose-escalation studies and compares different dose schedules and cohort sizes. The methodology described is motivated by the situation of phase 1 dose-escalation studies in oncology, that is, a single dose administered to each patient, with a single binary response (“toxicity” or “no toxicity”) observed. It is likely that a wider range of applications of the methodology is possible. In this paper, results from 10000-fold simulation runs conducted using the software package Bayesian ADEPT are presented. Four designs were compared under six scenarios. The simulation results indicate that there are slight advantages of having more dose levels and smaller cohort sizes.

Keywords

Bayesian statistics Computer software Decision procedure Dose-escalation Phase 1 study

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References

O'Quigley

Pepe

Fisher

. Continual Reassessment Method: a practical design for phase 1 clinical trials in cancer. Biometrics. 1990;46: 33–48.

Carter

. Study design principles in the clinical evaluation of new drugs as developed by the chemotherapy programme of the National Cancer Institute. In: Staquet

, ed. The Design of Clinical Trials in Cancer Therapy. Brussels, Belgium: Editions Scientific Europe; 1973; 242–289.

Møller. An extension of the continual reassessment methods using a preliminary up-and-down design in a dose finding study in cancer patients, in order to investigate a greater range of doses. Stat Med. 1995;14:911–922.

Korn

Midthune

Chen

Rubinstein

Christian

Simon

. A comparison of two phase 1 designs. Stat Med. 1994;13: 1799–1806.

O'Quigley

Reiner

. A stopping rule for the continual reassessment method. Biometrika. 1998; 85:741–748.

Zohar

Chevret

. The continual reassessment method: comparison of Bayesian stopping rules for dose-ranging studies. Stat Med. 2001;20: 2827–2843.

Whitehead

Brunier

. Bayesian decision procedures for dose determining experiments. Stat Med. 1995;14:885–893.

Whitehead

Williamson

. An evaluation of Bayesian decision procedures for dose-finding studies. J Biopharma Stat. 1998;8:445–467.

Zhou

Whitehead

. Practical implementation of Bayesian dose-escalation procedures. Drug Inf J. 2003;37:45–59.

10.

Ferry

Smith

Malkhandi

Fyfe

de-Takats

Anderson

Baker

Kerr

. Phase 1 clinical trial of the flavonoid quercetin—pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996;2: 659–668.

11.

Zhou

Whitehead

. Bayesian ADEPT: Operating Manual. Reading, United Kingdom: The University of Reading; 2002.

12.

Patterson

Francis

Ireson

Webber

Whitehead

. A novel Bayesian decision procedure for early-phase dose finding studies. J Biopharma Stat. 1999;9:583–597.

13.

Whitehead

Zhou

Patterson

Webber

Francis

. Easy-to-implement Bayesian methods for dose-escalation studies in healthy volunteers. Biostatistics. 2001;2:47–61.

14.

O'Quigley

Hughes

Fenton

. Dose-finding designs for HIV studies. Biometrics. 2001;57:1018–1029.

15.

Braun

. The Bivariate CRM: Extending the CRM to phase I trials of two competing outcomes. Control Clin Trials. 2002;23:240–255.

16.

Whitehead

Zhou

Stevens

Blakey

Price

Leadbetter

. Bayesian decision procedures for dose-escalation based on evidence of undesirable events and therapeutic benefit. Stat Med. 2005;24. In press.

Choosing the Number of Doses and the Cohort Size for Phase 1 Dose-Escalation Studies

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