Implementing the EffTox dose-finding design in the Matchpoint trial

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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. 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. 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. 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.

BioMed Central: Medical Research Methodology

About this publication

This was my first first-author publication and a chapter in my PhD thesis. Working with EffTox was great, but challenging at times. The seamless phase I/II approach to dose-finding, where efficacy and toxicity outcomes guide dose selection, has never been more important in this era of targeted therapies in oncology. However, the EffTox design and the suite of phase I/II methods in general have been relatively underutilised. We hope this paper demonstrating our experiences with EffTox will inspire early phase trialists to look further than the 3+3.

Kristian Brock
Principal Biostatistician

I am an academic early phase clincial trial statistician.