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Sequential or combined designs for Phase I/II clinical trials? A simulation study.

Authors
  • Rossoni, Caroline1, 2
  • Bardet, Aurélie1, 2
  • Geoerger, Birgit3
  • Paoletti, Xavier1, 2
  • 1 Biostatistics and Epidemiology Department, Gustave Roussy, Villejuif, France. , (France)
  • 2 INSERM U1018, CESP OncoStat, Université Paris-Saclay, UVSQ, Villejuif, France. , (France)
  • 3 Department of Pediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France. , (France)
Type
Published Article
Journal
Clinical trials (London, England)
Publication Date
Dec 01, 2019
Volume
16
Issue
6
Pages
635–644
Identifiers
DOI: 10.1177/1740774519872702
PMID: 31538815
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Both phases are increasingly combined. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling to identify the best trade-off between toxicity and activity (efficacy-toxicity). We explore this question in the context of a paediatric Phase I/II platform trial. In series of simulations, we assessed the operating characteristics of dose-escalation followed by an expansion cohort (DE-EC) designs without and with reassessment of the maximum tolerated dose during the expansion cohort (DE-ECext) and of the efficacy-toxicity (EffTox) design. We investigated the probability to identify an active and tolerable agent, that is, the percentage of correct decision, for various dose-toxicity activity scenarios. For a large therapeutic index, the percentage of correct decision reached 96.0% for efficacy-toxicity versus 76.1% for dose-escalation followed by an expansion cohort versus 79.6% for DE-ECext. Conversely, when all doses were deemed not active, the percentage of correct decision was 47% versus 55.9% versus 69.2%, respectively, for efficacy-toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Finally, in the case of a narrow therapeutic index, the percentage of correct decision was 48.0% versus 64.3% versus 67.2%, respectively, efficacy-toxicity, dose-escalation followed by an expansion cohort and DE-ECext. As narrow indexes are common in oncology, according to the present results, the sequential dose-escalation followed by an expansion cohort is recommended. The importance to re-estimate the maximum tolerated dose during the expansion cohort is confirmed. However, despite their theoretical advantages, Phase I/II designs are challenged by the variations in populations between the Phase I and the Phase II parts and by the lagtime in the evaluation of toxicity and activity.

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