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Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials
Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this revi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357685/ https://www.ncbi.nlm.nih.gov/pubmed/30734002 http://dx.doi.org/10.1016/j.ctro.2019.01.005 |
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author | Spiegelberg, Linda Houben, Ruud Niemans, Raymon de Ruysscher, Dirk Yaromina, Ala Theys, Jan Guise, Christopher P. Smaill, Jeffrey B. Patterson, Adam V. Lambin, Philippe Dubois, Ludwig J. |
author_facet | Spiegelberg, Linda Houben, Ruud Niemans, Raymon de Ruysscher, Dirk Yaromina, Ala Theys, Jan Guise, Christopher P. Smaill, Jeffrey B. Patterson, Adam V. Lambin, Philippe Dubois, Ludwig J. |
author_sort | Spiegelberg, Linda |
collection | PubMed |
description | Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this review, the implementation of hypoxia-activated prodrugs in the clinic has, so far, not been successful. The lack of stratification of patients based on tumor hypoxia status, which can vary widely, is sufficient to account for the failure of phase III trials. To fully exploit the potential of hypoxia-activated prodrugs, hypoxia stratification of patients is needed. Here, we propose a biomarker-stratified enriched Phase III study design in which only biomarker-positive (i.e. hypoxia-positive) patients are randomized between standard treatment and the combination of standard treatment with a hypoxia-activated prodrug. This implies the necessity of a Phase II study in which the biomarker or a combination of biomarkers will be evaluated. The total number of patients needed for both clinical studies will be far lower than in currently used randomize-all designs. In addition, we elaborate on the improvements in HAP design that are feasible to increase the treatment success rates. |
format | Online Article Text |
id | pubmed-6357685 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-63576852019-02-07 Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials Spiegelberg, Linda Houben, Ruud Niemans, Raymon de Ruysscher, Dirk Yaromina, Ala Theys, Jan Guise, Christopher P. Smaill, Jeffrey B. Patterson, Adam V. Lambin, Philippe Dubois, Ludwig J. Clin Transl Radiat Oncol Article Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this review, the implementation of hypoxia-activated prodrugs in the clinic has, so far, not been successful. The lack of stratification of patients based on tumor hypoxia status, which can vary widely, is sufficient to account for the failure of phase III trials. To fully exploit the potential of hypoxia-activated prodrugs, hypoxia stratification of patients is needed. Here, we propose a biomarker-stratified enriched Phase III study design in which only biomarker-positive (i.e. hypoxia-positive) patients are randomized between standard treatment and the combination of standard treatment with a hypoxia-activated prodrug. This implies the necessity of a Phase II study in which the biomarker or a combination of biomarkers will be evaluated. The total number of patients needed for both clinical studies will be far lower than in currently used randomize-all designs. In addition, we elaborate on the improvements in HAP design that are feasible to increase the treatment success rates. Elsevier 2019-01-18 /pmc/articles/PMC6357685/ /pubmed/30734002 http://dx.doi.org/10.1016/j.ctro.2019.01.005 Text en © 2019 The Authors http://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 Spiegelberg, Linda Houben, Ruud Niemans, Raymon de Ruysscher, Dirk Yaromina, Ala Theys, Jan Guise, Christopher P. Smaill, Jeffrey B. Patterson, Adam V. Lambin, Philippe Dubois, Ludwig J. Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials |
title | Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials |
title_full | Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials |
title_fullStr | Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials |
title_full_unstemmed | Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials |
title_short | Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials |
title_sort | hypoxia-activated prodrugs and (lack of) clinical progress: the need for hypoxia-based biomarker patient selection in phase iii clinical trials |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357685/ https://www.ncbi.nlm.nih.gov/pubmed/30734002 http://dx.doi.org/10.1016/j.ctro.2019.01.005 |
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