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Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial

BACKGROUND: Escalation With Overdose Control (EWOC) designs are increasingly used to ensure dose-toxicity curve of investigational oncology drugs is efficiently characterized during dose escalation steps. We propose a novel EWOC-based method that integrates the longitudinal pharmacokinetic (PK) data...

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Autores principales: Micallef, Sandrine, Sostelly, Alexandre, Zhu, Jiawen, Baverel, Paul G., Mercier, Francois
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851091/
https://www.ncbi.nlm.nih.gov/pubmed/35198796
http://dx.doi.org/10.1016/j.conctc.2022.100901
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author Micallef, Sandrine
Sostelly, Alexandre
Zhu, Jiawen
Baverel, Paul G.
Mercier, Francois
author_facet Micallef, Sandrine
Sostelly, Alexandre
Zhu, Jiawen
Baverel, Paul G.
Mercier, Francois
author_sort Micallef, Sandrine
collection PubMed
description BACKGROUND: Escalation With Overdose Control (EWOC) designs are increasingly used to ensure dose-toxicity curve of investigational oncology drugs is efficiently characterized during dose escalation steps. We propose a novel EWOC-based method that integrates the longitudinal pharmacokinetic (PK) data of individual patients in a Bayesian forecasting exposure-safety framework. METHODS: The method, called exposure-driven EWOC (ED-EWOC), relies on a population PK model coupled with a Bayesian logistic regression model to make dose recommendation for the next cohort of patients. RESULTS: We applied ED-EWOC to a real oncology clinical trial in parallel to a traditional EWOC approach. We found that for comparable priors, ED-EWOC dose recommendations were equivalent to the one suggested by EWOC when PK is dose proportional with low inter-individual variability. CONCLUSION: This case example demonstrates that ED-EWOC is logistically feasible during a trial conduct when PK bioanalysis can be expedited in the dose escalation phase. Overall, we anticipate that exposure-guided Bayesian designs could benefit patients and drug developers to identify the optimal dose steps of novel compounds entering the clinic with suspected liability in PK or that exhibit large inter-individual variability.
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spelling pubmed-88510912022-02-22 Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial Micallef, Sandrine Sostelly, Alexandre Zhu, Jiawen Baverel, Paul G. Mercier, Francois Contemp Clin Trials Commun Article BACKGROUND: Escalation With Overdose Control (EWOC) designs are increasingly used to ensure dose-toxicity curve of investigational oncology drugs is efficiently characterized during dose escalation steps. We propose a novel EWOC-based method that integrates the longitudinal pharmacokinetic (PK) data of individual patients in a Bayesian forecasting exposure-safety framework. METHODS: The method, called exposure-driven EWOC (ED-EWOC), relies on a population PK model coupled with a Bayesian logistic regression model to make dose recommendation for the next cohort of patients. RESULTS: We applied ED-EWOC to a real oncology clinical trial in parallel to a traditional EWOC approach. We found that for comparable priors, ED-EWOC dose recommendations were equivalent to the one suggested by EWOC when PK is dose proportional with low inter-individual variability. CONCLUSION: This case example demonstrates that ED-EWOC is logistically feasible during a trial conduct when PK bioanalysis can be expedited in the dose escalation phase. Overall, we anticipate that exposure-guided Bayesian designs could benefit patients and drug developers to identify the optimal dose steps of novel compounds entering the clinic with suspected liability in PK or that exhibit large inter-individual variability. Elsevier 2022-02-05 /pmc/articles/PMC8851091/ /pubmed/35198796 http://dx.doi.org/10.1016/j.conctc.2022.100901 Text en © 2022 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Micallef, Sandrine
Sostelly, Alexandre
Zhu, Jiawen
Baverel, Paul G.
Mercier, Francois
Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial
title Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial
title_full Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial
title_fullStr Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial
title_full_unstemmed Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial
title_short Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial
title_sort exposure driven dose escalation design with overdose control: concept and first real life experience in an oncology phase i trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851091/
https://www.ncbi.nlm.nih.gov/pubmed/35198796
http://dx.doi.org/10.1016/j.conctc.2022.100901
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