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Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial

BACKGROUND: Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGM...

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Autores principales: Zeyen, Thomas, Potthoff, Anna-Laura, Nemeth, Robert, Heiland, Dieter H., Burger, Michael C., Steinbach, Joachim P., Hau, Peter, Tabatabai, Ghazaleh, Glas, Martin, Schlegel, Uwe, Grauer, Oliver, Krex, Dietmar, Schnell, Oliver, Goldbrunner, Roland, Sabel, Michael, Thon, Niklas, Delev, Daniel, Clusmann, Hans, Seidel, Clemens, Güresir, Erdem, Schmid, Matthias, Schuss, Patrick, Giordano, Frank A., Radbruch, Alexander, Becker, Albert, Weller, Johannes, Schaub, Christina, Vatter, Hartmut, Schilling, Judith, Winkler, Frank, Herrlinger, Ulrich, Schneider, Matthias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767701/
https://www.ncbi.nlm.nih.gov/pubmed/35045869
http://dx.doi.org/10.1186/s13063-021-05977-0
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author Zeyen, Thomas
Potthoff, Anna-Laura
Nemeth, Robert
Heiland, Dieter H.
Burger, Michael C.
Steinbach, Joachim P.
Hau, Peter
Tabatabai, Ghazaleh
Glas, Martin
Schlegel, Uwe
Grauer, Oliver
Krex, Dietmar
Schnell, Oliver
Goldbrunner, Roland
Sabel, Michael
Thon, Niklas
Delev, Daniel
Clusmann, Hans
Seidel, Clemens
Güresir, Erdem
Schmid, Matthias
Schuss, Patrick
Giordano, Frank A.
Radbruch, Alexander
Becker, Albert
Weller, Johannes
Schaub, Christina
Vatter, Hartmut
Schilling, Judith
Winkler, Frank
Herrlinger, Ulrich
Schneider, Matthias
author_facet Zeyen, Thomas
Potthoff, Anna-Laura
Nemeth, Robert
Heiland, Dieter H.
Burger, Michael C.
Steinbach, Joachim P.
Hau, Peter
Tabatabai, Ghazaleh
Glas, Martin
Schlegel, Uwe
Grauer, Oliver
Krex, Dietmar
Schnell, Oliver
Goldbrunner, Roland
Sabel, Michael
Thon, Niklas
Delev, Daniel
Clusmann, Hans
Seidel, Clemens
Güresir, Erdem
Schmid, Matthias
Schuss, Patrick
Giordano, Frank A.
Radbruch, Alexander
Becker, Albert
Weller, Johannes
Schaub, Christina
Vatter, Hartmut
Schilling, Judith
Winkler, Frank
Herrlinger, Ulrich
Schneider, Matthias
author_sort Zeyen, Thomas
collection PubMed
description BACKGROUND: Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGMT-methylated glioblastoma is not standardized and may consist of re-resection, re-irradiation, and chemotherapy with temozolomide (TMZ), lomustine (CCNU), or a combination thereof. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID) and registered in the USA, sensitizes glioblastoma cells to temozolomide-induced toxicity via inhibition of gap junction-mediated intercellular cytosolic traffic and demolishment of tumor microtube (TM)-based network morphology. METHODS: In this study, combined MFA/TMZ therapy will be administered (orally) in patients with first relapse of MGMT-methylated glioblastoma. A phase I component (6–12 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II component (2 × 30 patients) with progression-free survival as the primary endpoint. DISCUSSION: This study is set up to assess toxicity and first indications of efficacy of MFA repurposed in the setting of a very difficult-to-treat recurrent tumor. The trial is a logical next step after the identification of the role of resistance-providing TMs in glioblastoma, and results will be crucial for further trials targeting TMs. In case of favorable results, MFA may constitute the first clinically feasible TM-targeted drug and therefore might bridge the idea of a TM-targeted therapeutic approach from basic insights into clinical reality. TRIAL REGISTRATION: EudraCT 2021-000708-39. Registered on 08 February 2021
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spelling pubmed-87677012022-01-19 Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial Zeyen, Thomas Potthoff, Anna-Laura Nemeth, Robert Heiland, Dieter H. Burger, Michael C. Steinbach, Joachim P. Hau, Peter Tabatabai, Ghazaleh Glas, Martin Schlegel, Uwe Grauer, Oliver Krex, Dietmar Schnell, Oliver Goldbrunner, Roland Sabel, Michael Thon, Niklas Delev, Daniel Clusmann, Hans Seidel, Clemens Güresir, Erdem Schmid, Matthias Schuss, Patrick Giordano, Frank A. Radbruch, Alexander Becker, Albert Weller, Johannes Schaub, Christina Vatter, Hartmut Schilling, Judith Winkler, Frank Herrlinger, Ulrich Schneider, Matthias Trials Study Protocol BACKGROUND: Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGMT-methylated glioblastoma is not standardized and may consist of re-resection, re-irradiation, and chemotherapy with temozolomide (TMZ), lomustine (CCNU), or a combination thereof. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID) and registered in the USA, sensitizes glioblastoma cells to temozolomide-induced toxicity via inhibition of gap junction-mediated intercellular cytosolic traffic and demolishment of tumor microtube (TM)-based network morphology. METHODS: In this study, combined MFA/TMZ therapy will be administered (orally) in patients with first relapse of MGMT-methylated glioblastoma. A phase I component (6–12 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II component (2 × 30 patients) with progression-free survival as the primary endpoint. DISCUSSION: This study is set up to assess toxicity and first indications of efficacy of MFA repurposed in the setting of a very difficult-to-treat recurrent tumor. The trial is a logical next step after the identification of the role of resistance-providing TMs in glioblastoma, and results will be crucial for further trials targeting TMs. In case of favorable results, MFA may constitute the first clinically feasible TM-targeted drug and therefore might bridge the idea of a TM-targeted therapeutic approach from basic insights into clinical reality. TRIAL REGISTRATION: EudraCT 2021-000708-39. Registered on 08 February 2021 BioMed Central 2022-01-19 /pmc/articles/PMC8767701/ /pubmed/35045869 http://dx.doi.org/10.1186/s13063-021-05977-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Study Protocol
Zeyen, Thomas
Potthoff, Anna-Laura
Nemeth, Robert
Heiland, Dieter H.
Burger, Michael C.
Steinbach, Joachim P.
Hau, Peter
Tabatabai, Ghazaleh
Glas, Martin
Schlegel, Uwe
Grauer, Oliver
Krex, Dietmar
Schnell, Oliver
Goldbrunner, Roland
Sabel, Michael
Thon, Niklas
Delev, Daniel
Clusmann, Hans
Seidel, Clemens
Güresir, Erdem
Schmid, Matthias
Schuss, Patrick
Giordano, Frank A.
Radbruch, Alexander
Becker, Albert
Weller, Johannes
Schaub, Christina
Vatter, Hartmut
Schilling, Judith
Winkler, Frank
Herrlinger, Ulrich
Schneider, Matthias
Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
title Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
title_full Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
title_fullStr Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
title_full_unstemmed Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
title_short Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
title_sort phase i/ii trial of meclofenamate in progressive mgmt-methylated glioblastoma under temozolomide second-line therapy—the mecmeth/noa-24 trial
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767701/
https://www.ncbi.nlm.nih.gov/pubmed/35045869
http://dx.doi.org/10.1186/s13063-021-05977-0
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