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Clinical trials: Non-immunologic

Session: Poster Session

CTNI-34 - Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: final results of the EORTC 1608 STEAM trial

Friday, November 17, 2023
7:30 PM – 9:30 PM PT
Location: Exhibit Hall A/B
Non-CME

    Poster Presenter(s)

  • Emilie Le Rhun

    Departments of Neurosurgery and Neurology, University Hospital and University of Zurich
    Zurich, Zurich, Switzerland

    • Author(s)

  • TG

    Thierry Gorlia

    EORTC headquarter
    Brussels, Belgium

  • JF

    Jörg Felsberg

    Heinrich Heine University and University Hospital Düsseldorf
    Düsseldorf, Germany

  • JF

    Julia Furtner

    Medical University of Vienna
    Vienna, Austria

  • JJ

    Joost LM Jongen

    Erasmus MC Cancer Institute
    Rotterdam, Netherlands

  • CM

    Claude-Alain Maurage

    University of Lille
    Lille, France

  • Francois Ducray

    Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon
    Lyon, France

  • Patrick Roth

    Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
    Zurich, Zurich, Switzerland

  • PH

    Peter Hau

    Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg
    Regensburg, Bayern, United States

  • OC

    Olivier Chinot

    University Hospital Timone
    Marseille, France

  • Matthias Preusser

    Medical University of Vienna
    Vienna, Austria

  • SC

    Stephanie Cartalat

    Neurological Hospital
    Lyon, France

  • Martin J. van den Bent

    Erasmus MC Cancer Institute
    Rotterdam, Netherlands

  • MC

    Maike Collienne

    EORTC headquarter
    Brussels, Belgium

  • Guido Reifenberger

    Institute of Neuropathology, Heinrich Heine University Medical Faculty and University Hospital Düsseldorf
    Düsseldorf, Germany

  • Michael Weller

    Department of Neurology and Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
    Zurich, Zurich, Switzerland

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.MethodsEORTC 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.ResultsThe 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.ConclusionTG02 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.