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 ORCID: 0009-0000-1485-7820, Thon, Niklas, Delev, Daniel, Clusmann, Hans, Seidel, Clemens, Gueresir, Erdem, Schmid, Matthias ORCID: 0000-0002-0788-0317, Schuss, Patrick ORCID: 0000-0002-5806-2576, Giordano, Frank A., Radbruch, Alexander, Becker, Albert, Weller, Johannes, Schaub, Christina, Vatter, Hartmut, Schilling, Judith, Winkler, Frank ORCID: 0000-0003-4892-6104, Herrlinger, Ulrich and Schneider, Matthias (2022). Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial. Trials, 23 (1). LONDON: BMC. ISSN 1745-6215

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Abstract

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 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Zeyen, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Potthoff, Anna-LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemeth, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heiland, Dieter H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burger, Michael C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinbach, Joachim P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hau, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tabatabai, GhazalehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glas, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlegel, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grauer, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krex, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnell, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldbrunner, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sabel, MichaelUNSPECIFIEDorcid.org/0009-0000-1485-7820UNSPECIFIED
Thon, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delev, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clusmann, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, ClemensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gueresir, ErdemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmid, MatthiasUNSPECIFIEDorcid.org/0000-0002-0788-0317UNSPECIFIED
Schuss, PatrickUNSPECIFIEDorcid.org/0000-0002-5806-2576UNSPECIFIED
Giordano, Frank A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radbruch, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weller, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaub, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vatter, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schilling, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winkler, FrankUNSPECIFIEDorcid.org/0000-0003-4892-6104UNSPECIFIED
Herrlinger, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-695842
DOI: 10.1186/s13063-021-05977-0
Journal or Publication Title: Trials
Volume: 23
Number: 1
Date: 2022
Publisher: BMC
Place of Publication: LONDON
ISSN: 1745-6215
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COMBINATION; CELLS; LIFEMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69584

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