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Toxicity-dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials

Wheeler, Graham M., Sweeting, Michael J. and Mander, Adrian P. 2017. Toxicity-dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials. Statistics in Medicine 36 (16) , pp. 2499-2513. 10.1002/sim.7280

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Phase I trials of anti-cancer therapies aim to identify a maximum tolerated dose (MTD), defined as the dose that causes unacceptable toxicity in a target proportion of patients. Both rule-based and model-based methods have been proposed for MTD recommendation. The escalation with overdose control (EWOC) approach is a model-based design where the dose assigned to the next patient is one that, given all available data, has a posterior probability of exceeding the MTD equal to a pre-specified value known as the feasibility bound. The aim is to conservatively dose-escalate and approach the MTD, avoiding severe overdosing early on in a trial. The EWOC approach has been applied in practice with the feasibility bound either fixed or varying throughout a trial, yet some of the methods may recommend incoherent dose-escalation, that is, an increase in dose after observing severe toxicity at the current dose. We present examples where varying feasibility bounds have been used in practice, and propose a toxicity-dependent feasibility bound approach that guarantees coherent dose-escalation and incorporates the desirable features of other EWOC approaches. We show via detailed simulation studies that the toxicity-dependent feasibility bound approach provides improved MTD recommendation properties to the original EWOC approach for both discrete and continuous doses across most dose-toxicity scenarios, with comparable performance to other approaches without recommending incoherent dose escalation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Centre for Trials Research (CNTRR)
Publisher: Wiley
ISSN: 0277-6715
Date of First Compliant Deposit: 13 June 2019
Date of Acceptance: 18 February 2017
Last Modified: 16 Jul 2019 13:55

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