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; Gueresir, Erdem; Schmid, Matthias; Schuss, Patrick; Giordano, Frank A.; Radbruch, Alexander; Becker, Albert; Weller, Johannes; Schaub, Christina; Vatter, Hartmut; Schilling, Judith; Winkler, Frank; Herrlinger, Ulrich und Schneider, Matthias (2022): Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial. In: Trials, Bd. 23, Nr. 1, 57

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch