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

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. 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 O 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. 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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Declaration of Competing Interest ELR has received a grant research from Bristol Meyer Squibb and honoraria for lectures or advisory board from Bayer, Janssen, Leo Pharma, Pierre Fabre, Servier and Seattle Genetics. JFu received honoraria for lectures and consultation from the following for-profit companies: Novartis, Seagen. FD received honoraria for advisory board and lectures from Novocure and Servier. PH has an advisory role at BMS, Glaxo Smith Kline, MSD, Novocure, is in the speakers bureau of Lilly, medac, Novocure, Seagen and has received travel grants from Lilly, medac, Novocure, Seagen. OLC received research support from Novocure and honoraria from BMS. MP has received research grants from Pfizer and Roche and honoraria for advisory boards from Bayer. PR has received honoraria for lectures or advisory board participation from Alexion, Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Merck Sharp and Dohme, Midatech Pharma, Novocure, QED, and Roche and research support from Merck Sharp and Dohme and Novocure. MvdB received honoraria for advisory boards from Genenta, Boehringer, Astra Zeneca, Chimerix, Roche, Fore Biotherapeutics and Servier. MW has received research grants from Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Merck (EMD), Novartis, Novocure, Orbus, Philogen, Roche and Sandoz. TG, JFe, JJ, CAM, DG, SC, MC and GR declare no conflict of interest.