Le Rhun, Emilie and Gorlia, Thierry and Felsberg, Joerg and Jongen, Joost and Maurage, Claude-Alain and Ducray, Francois and Gramatzki, Dorothee and Hau, Peter and Chinot, Olivier L. and Preusser, Matthias and Cartalat, Stephanie and Roth, Patrick and van den Bent, Martin and Furtner, Julia and Collienne, Maike and Reifenberger, Guido and Weller, Michael (2024) Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial. EUROPEAN JOURNAL OF CANCER, 198: 113475. ISSN 0959-8049, 1879-0852
Full text not available from this repository. (Request a copy)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, nonrandomized, 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-methyl guanine 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FAMILY PROTEIN EXPRESSION; TEMOZOLOMIDE; RADIOTHERAPY; MODULATION; Astrocytoma; CDK; C-MYC; Chemotherapy; Survival proteins |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Apr 2024 08:53 |
| Last Modified: | 04 Mar 2025 09:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/62728 |
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