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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.

Trials

Authors: Thomas Zeyen, Anna-Laura Potthoff, Robert Nemeth, Dieter H Heiland, Michael C Burger, Joachim P Steinbach, Peter Hau, Ghazaleh Tabatabai, Martin Glas, Uwe Schlegel, Oliver Grauer, Dietmar Krex, Oliver Schnell, Roland Goldbrunner, Michael Sabel, Niklas Thon, Daniel Delev, Hans Clusmann, Clemens Seidel, Erdem Güresir, Matthias Schmid, Patrick Schuss, Frank A Giordano, Alexander Radbruch, Albert Becker, Johannes Weller, Christina Schaub, Hartmut Vatter, Judith Schilling, Frank Winkler, Ulrich Herrlinger, Matthias Schneider

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.

© 2022. The Author(s).

PMID: 35045869

Participating cluster members