Modelling semi‐attributable toxicity in dual‐agent phase I trials with non‐concurrent drug administration
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Published version
Author(s)
Wheeler, Graham M
Sweeting, Michael J
Mander, Adrian P
Lee, Shing M
Cheung, Ying Kuen K
Type
Journal Article
Abstract
In oncology, combinations of drugs are often used to improve treatment efficacy and/or reduce harmful side effects. Dual‐agent phase I clinical trials assess drug safety and aim to discover a maximum tolerated dose combination via dose‐escalation; cohorts of patients are given set doses of both drugs and monitored to see if toxic reactions occur. Dose‐escalation decisions for subsequent cohorts are based on the number and severity of observed toxic reactions, and an escalation rule. In a combination trial, drugs may be administered concurrently or non‐concurrently over a treatment cycle. For two drugs given non‐concurrently with overlapping toxicities, toxicities occurring after administration of the first drug yet before administration of the second may be attributed directly to the first drug, whereas toxicities occurring after both drugs have been given some present ambiguity; toxicities may be attributable to the first drug only, the second drug only or the synergistic combination of both. We call this mixture of attributable and non‐attributable toxicity semi‐attributable toxicity. Most published methods assume drugs are given concurrently, which may not be reflective of trials with non‐concurrent drug administration. We incorporate semi‐attributable toxicity into Bayesian modelling for dual‐agent phase I trials with non‐concurrent drug administration and compare the operating characteristics to an approach where this detail is not considered. Simulations based on a trial for non‐concurrent administration of intravesical Cabazitaxel and Cisplatin in early‐stage bladder cancer patients are presented for several scenarios and show that including semi‐attributable toxicity data reduces the number of patients given overly toxic combinations. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
Date Issued
2017-01-30
Date Acceptance
2016-01-27
Citation
Statistics in Medicine, 2017, 36 (2), pp.225-241
ISSN
0277-6715
Publisher
Wiley
Start Page
225
End Page
241
Journal / Book Title
Statistics in Medicine
Volume
36
Issue
2
Copyright Statement
© 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Medical Research Council
Identifier
https://onlinelibrary.wiley.com/doi/10.1002/sim.6912
Grant Number
G0800860
Subjects
0104 Statistics
1117 Public Health and Health Services
Statistics & Probability
Publication Status
Published
Date Publish Online
2016-02-19