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

Zeyen T, Potthoff AL, Nemeth R, Heiland DH, Burger MC, Steinbach JP, Hau P, Tabatabai G, Glas M, Schlegel U, Grauer O, Krex D, Schnell O, Goldbrunner R, Sabel M, Thon N, Delev D, Clusmann H, Seidel C, Güresir E, Schmid M, Schuss P, Giordano FA, Radbruch A, Becker A, Weller J, Schaub C, Vatter H, Schilling J, Winkler F, Herrlinger U, Schneider M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 23

Article Number: 57

Journal Issue: 1

DOI: 10.1186/s13063-021-05977-0

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 × 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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Freiburg Germany (DE) Universitätsklinikum Bonn Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Universitätsklinikum Regensburg Germany (DE) Technische Universität Dresden Germany (DE) Universität zu Köln Germany (DE) Heinrich-Heine-Universität Düsseldorf Germany (DE) Ludwig-Maximilians-Universität (LMU) Germany (DE) Universitätsklinikum Aachen (UKA) Germany (DE) Universität Leipzig Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Universitätsklinikum Essen Germany (DE) Universitätsklinikum Knappschaftskrankenhaus Bochum Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE)

How to cite

APA:

Zeyen, T., Potthoff, A.L., Nemeth, R., Heiland, D.H., Burger, M.C., Steinbach, J.P.,... Schneider, M. (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). https://doi.org/10.1186/s13063-021-05977-0

MLA:

Zeyen, Thomas, et al. "Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial." Trials 23.1 (2022).

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