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Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation

Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be...

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Autores principales: Langenhorst, Jurgen B., Dorlo, Thomas P.C., van Kesteren, Charlotte, van Maarseveen, Erik M., Nierkens, Stefan, de Witte, Moniek A., Boelens, Jaap Jan, Huitema, Alwin D.R.
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/PMC7239337/
https://www.ncbi.nlm.nih.gov/pubmed/31957334
http://dx.doi.org/10.1002/psp4.12486
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author Langenhorst, Jurgen B.
Dorlo, Thomas P.C.
van Kesteren, Charlotte
van Maarseveen, Erik M.
Nierkens, Stefan
de Witte, Moniek A.
Boelens, Jaap Jan
Huitema, Alwin D.R.
author_facet Langenhorst, Jurgen B.
Dorlo, Thomas P.C.
van Kesteren, Charlotte
van Maarseveen, Erik M.
Nierkens, Stefan
de Witte, Moniek A.
Boelens, Jaap Jan
Huitema, Alwin D.R.
author_sort Langenhorst, Jurgen B.
collection PubMed
description Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m(2)) to either covariate‐based or therapeutic drug monitoring (TDM)‐guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of end points and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM‐guided dosing to current practice with NRM as primary outcome (n = 70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible.
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spelling pubmed-72393372020-05-21 Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation Langenhorst, Jurgen B. Dorlo, Thomas P.C. van Kesteren, Charlotte van Maarseveen, Erik M. Nierkens, Stefan de Witte, Moniek A. Boelens, Jaap Jan Huitema, Alwin D.R. CPT Pharmacometrics Syst Pharmacol Research Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m(2)) to either covariate‐based or therapeutic drug monitoring (TDM)‐guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of end points and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM‐guided dosing to current practice with NRM as primary outcome (n = 70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible. John Wiley and Sons Inc. 2020-04-21 2020-05 /pmc/articles/PMC7239337/ /pubmed/31957334 http://dx.doi.org/10.1002/psp4.12486 Text en © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. 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/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Langenhorst, Jurgen B.
Dorlo, Thomas P.C.
van Kesteren, Charlotte
van Maarseveen, Erik M.
Nierkens, Stefan
de Witte, Moniek A.
Boelens, Jaap Jan
Huitema, Alwin D.R.
Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation
title Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation
title_full Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation
title_fullStr Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation
title_full_unstemmed Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation
title_short Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation
title_sort clinical trial simulation to optimize trial design for fludarabine dosing strategies in allogeneic hematopoietic cell transplantation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239337/
https://www.ncbi.nlm.nih.gov/pubmed/31957334
http://dx.doi.org/10.1002/psp4.12486
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