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Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations

There is still a lack of efficient designs for identifying the dose response in oncology combination therapies in early clinical trials. The concentration response relationship can be identified using the early tumor shrinkage time course, which has been shown to be a good early response marker of c...

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Autores principales: Seurat, Jérémy, Girard, Pascal, Goteti, Kosalaram, Mentré, France
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762808/
https://www.ncbi.nlm.nih.gov/pubmed/33080100
http://dx.doi.org/10.1002/psp4.12564
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author Seurat, Jérémy
Girard, Pascal
Goteti, Kosalaram
Mentré, France
author_facet Seurat, Jérémy
Girard, Pascal
Goteti, Kosalaram
Mentré, France
author_sort Seurat, Jérémy
collection PubMed
description There is still a lack of efficient designs for identifying the dose response in oncology combination therapies in early clinical trials. The concentration response relationship can be identified using the early tumor shrinkage time course, which has been shown to be a good early response marker of clinical efficacy. The performance of various designs using an exposure–tumor growth inhibition model was explored using simulations. Different combination effects of new drug M and cetuximab (reference therapy) were explored first assuming no effect of M on cetuximab (to investigate the type I error (α)), and subsequently assuming additivity or synergy between cetuximab and M. One‐arm, two‐arm, and four‐arm designs were evaluated. In the one‐arm design, 60 patients received cetuximab + M. In the two‐arm design, 30 patients received cetuximab and 30 received cetuximab + M. In the four‐arm design, in addition to cetuximab and cetuximab + M as standard doses, combination arms with lower doses of cetuximab were evaluated (15 patients/arm). Model‐based predictions or “simulated observations” of early tumor shrinkage at week 8 (ETS8) were compared between the different arms. With the same number of individuals, the one‐arm design showed better statistical power than other designs but led to strong inflation of α in case of misestimated reference for ETS8 value. The two‐arm design protected against this misestimation and, with the same total number of subjects, would provide higher statistical power than a four‐arm design. However, a four‐arm design would be helpful for exploring more doses of cetuximab in combination with M to better understand the interaction.
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spelling pubmed-77628082020-12-28 Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations Seurat, Jérémy Girard, Pascal Goteti, Kosalaram Mentré, France CPT Pharmacometrics Syst Pharmacol Research There is still a lack of efficient designs for identifying the dose response in oncology combination therapies in early clinical trials. The concentration response relationship can be identified using the early tumor shrinkage time course, which has been shown to be a good early response marker of clinical efficacy. The performance of various designs using an exposure–tumor growth inhibition model was explored using simulations. Different combination effects of new drug M and cetuximab (reference therapy) were explored first assuming no effect of M on cetuximab (to investigate the type I error (α)), and subsequently assuming additivity or synergy between cetuximab and M. One‐arm, two‐arm, and four‐arm designs were evaluated. In the one‐arm design, 60 patients received cetuximab + M. In the two‐arm design, 30 patients received cetuximab and 30 received cetuximab + M. In the four‐arm design, in addition to cetuximab and cetuximab + M as standard doses, combination arms with lower doses of cetuximab were evaluated (15 patients/arm). Model‐based predictions or “simulated observations” of early tumor shrinkage at week 8 (ETS8) were compared between the different arms. With the same number of individuals, the one‐arm design showed better statistical power than other designs but led to strong inflation of α in case of misestimated reference for ETS8 value. The two‐arm design protected against this misestimation and, with the same total number of subjects, would provide higher statistical power than a four‐arm design. However, a four‐arm design would be helpful for exploring more doses of cetuximab in combination with M to better understand the interaction. John Wiley and Sons Inc. 2020-11-05 2020-12 /pmc/articles/PMC7762808/ /pubmed/33080100 http://dx.doi.org/10.1002/psp4.12564 Text en © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research
Seurat, Jérémy
Girard, Pascal
Goteti, Kosalaram
Mentré, France
Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations
title Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations
title_full Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations
title_fullStr Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations
title_full_unstemmed Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations
title_short Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations
title_sort comparison of various phase i combination therapy designs in oncology for evaluation of early tumor shrinkage using simulations
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762808/
https://www.ncbi.nlm.nih.gov/pubmed/33080100
http://dx.doi.org/10.1002/psp4.12564
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