CTNI-34. ZOTIRACICLIB (TG02) FOR NEWLY DIAGNOSED GLIOBLASTOMA IN THE ELDERLY OR FOR RECURRENT GLIOBLASTOMA: FINAL RESULTS OF THE EORTC 1608 STEAM TRIAL

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2023-11, Vol.25 (Supplement_5), p.v81-v82
• Main Authors: Rhun, Emilie Le, Gorlia, Thierry, Felsberg, Jörg, Furtner, Julia, Jongen, Joost, Maurage, Claude-Alain, Ducray, Francois, Roth, Patrick, Hau, Peter, Chinot, Olivier, Preusser, Matthias, Cartalat, Stephanie, van den Bent, Martin, Collienne, Maike, Reifenberger, Guido, Weller, Michael
• Format: Article
• Language: English
• Subjects: Clinical Trials: Non-Immunologic
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noad179.0316

Abstract BACKGROUND Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor that is supposed to suppress tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. METHODS EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 in IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months. Secondary objectives included efficacy, quality of life, and safety. Expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. RESULTS The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B) in elderly patients. Two dose-limiting toxicities were observed at 150 mg, one in group A (grade 3 seizure) and one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C was 6.7%. CDK9 and its indirect targets, c-MYC and MCL-1, were confirmed to be expressed and their expression was correlated, supporting a regulatory role for CDK-9. The protein levels of CDK-9 and MCL-1 correlated with overall survival. CONCLUSION TG02 exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials are required to explore activity in combination with RT or TMZ. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.