University of Leicester
Browse

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

Download (1.2 MB)
journal contribution
posted on 2018-05-04, 14:00 authored by Graham M. Wheeler, Michael J. Sweeting, Adrian P. Mander
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.

History

Citation

Statistics in Medicine, 2017, 36 (16), pp. 2499-2513

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

Statistics in Medicine

Publisher

Wiley

issn

0277-6715

eissn

1097-0258

Acceptance date

2017-02-18

Copyright date

2017

Available date

2018-05-04

Publisher version

https://onlinelibrary.wiley.com/doi/abs/10.1002/sim.7280

Language

en