Article Dans Une Revue European Journal of Cancer Année : 2024

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

T. Gorlia
  • Fonction : Auteur
J. Felsberg
  • Fonction : Auteur
J. Jongen
  • Fonction : Auteur
F. Ducray
  • Fonction : Auteur
D. Gramatzki
  • Fonction : Auteur
P. Hau
  • Fonction : Auteur
O. L. Chinot
  • Fonction : Auteur
M. Preusser
  • Fonction : Auteur
S. Cartalat
  • Fonction : Auteur
P. Roth
  • Fonction : Auteur
M. van den Bent
  • Fonction : Auteur
J. Furtner
  • Fonction : Auteur
M. Collienne
  • Fonction : Auteur
G. Reifenberger
  • Fonction : Auteur

Résumé

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.
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hal-04818120 , version 1 (04-12-2024)

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Emilie Le Rhun, T. Gorlia, J. Felsberg, J. Jongen, Claude-Alain Maurage, et al.. Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial.. European Journal of Cancer, 2024, European Journal of Cancer, 198, pp.113475. ⟨10.1016/j.ejca.2023.113475⟩. ⟨hal-04818120⟩

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