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BMC Medical Research Methodology

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Open Access 01-12-2017 | Research Article

Implementing the EffTox dose-finding design in the Matchpoint trial

Authors: Kristian Brock, Lucinda Billingham, Mhairi Copland, Shamyla Siddique, Mirjana Sirovica, Christina Yap

Published in: BMC Medical Research Methodology | Issue 1/2017

Abstract

Background

The Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial.

Methods

EffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes. We describe a nomenclature for succinctly describing outcomes in phase I/II dose-finding trials. We use dose-transition pathways, where doses are calculated for each feasible set of outcomes in future cohorts. We introduce the phenomenon of dose ambivalence, where EffTox can recommend different doses after observing the same outcomes. We also describe our experiences with outcome ambiguity, where the categorical evaluation of some primary outcomes is temporarily delayed.

Results

We arrived at an EffTox parameterisation that is simulated to perform well over a range of scenarios. In scenarios where dose ambivalence manifested, we were guided by the dose-transition pathways. This technique facilitates planning, and also helped us overcome short-term outcome ambiguity.

Conclusions

EffTox is an efficient and powerful design, but not without its challenges. Joint phase I/II clinical trial designs will likely become increasingly important in coming years as we further investigate non-cytotoxic treatments and streamline the drug approval process. We hope this account of the problems we faced and the solutions we used will help others implement this dose-finding clinical trial design.

Trial registration

Matchpoint was added to the European Clinical Trials Database (https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005629-65/GB) on 2013-12-30.

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Title: Implementing the EffTox dose-finding design in the Matchpoint trial
Authors: Kristian Brock
Lucinda Billingham
Mhairi Copland
Shamyla Siddique
Mirjana Sirovica
Christina Yap
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Medical Research Methodology / Issue 1/2017
Electronic ISSN: 1471-2288
DOI: https://doi.org/10.1186/s12874-017-0381-x

At a glance: The STEP trials

Springer Medicine

Implementing the EffTox dose-finding design in the Matchpoint trial

Abstract

Background

Methods

Results

Conclusions

Trial registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

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