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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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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. |
format | Online Article Text |
id | pubmed-8851091 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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