2. Academic Validation
  3. Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial

  • Eur J Cancer. 2024 Feb:198:113475. doi: 10.1016/j.ejca.2023.113475.
Emilie Le Rhun 1,  Thierry Gorlia 2,  Jörg Felsberg 3,  Joost Jongen 4,  Claude-Alain Maurage 5,  François Ducray 6,  Dorothee Gramatzki 7,  Peter Hau 8,  Olivier L Chinot 9,  Matthias Preusser 10,  Stephanie Cartalat 6,  Patrick Roth 7,  Martin van den Bent 4,  Julia Furtner 11,  Maike Collienne 2,  Guido Reifenberger 3,  Michael Weller 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland; Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland; Neuro-Oncology, General and Stereotaxic Neurosurgery Service, University Hospital of Lille, Lille, France; University of Lille, Inserm, U-1192, Lille, France. Electronic address: emilie.lerhun@usz.ch.
  • 2 European Organization for Research and Treatment of Cancer, Brussels, Belgium.
  • 3 Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany.
  • 4 The Brain Tumour Center at the Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • 5 Univ. Lille, UFR3S - Laboratoire d'Histologie, Lille, France.
  • 6 CHU Lyon, Neuro-Oncology, Lyon, France.
  • 7 Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
  • 8 Department of Neurology - NeuroOncology and Wilhelm Sander Neuro-Oncology Unit, University Hospital Regensburg, Regensburg, Germany.
  • 9 Neuro-oncology, CHU Timone, Marseille, France.
  • 10 Division of Oncology, Department of Medicine 1, Medical University, Vienna, Austria.
  • 11 Department of Biomedical imaging and Image-guided Therapy, Medical University of Vienna, Austria; Research Center for Medical Image Analysis and Artificial Intelligence (MIAAI), Faculty of Medicine and Dentistry, Danube Private University, 3500 Krems, Austria.
PMID: 38159337 DOI: 10.1016/j.ejca.2023.113475
Abstract

Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit 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 in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA Methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor 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). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-Myc and Mcl-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of Mcl-1 were associated with inferior survival.

Conclusions: TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

Keywords

Astrocytoma; C-MYC; CDK; Chemotherapy; Survival proteins.

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