Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor, including CDK-9, that inhibits tumor growth down-stream via depletion of survival proteins such as MCL-1 and MYC. MCL-1 and MYC are frequently overexpressed in glioblastoma. Methods: The EORTC 1608 (NCT03224104) (STEAM) phase 1b trial had a three parallel group (A,B,C) open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of zotiraciclib in elderly patients (more than 65 years) with IDH1^R132H-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 zotiraciclib in IDH1^R132H-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. Results: The MTD was 150 mg in combination with radiotherapy alone (group A, n=12) or temozolomide alone (group B, n=9) 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, gastro-intestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C (n=50) was 6.7%. Conclusions: Zotiraciclib exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials may be required to explore activity in combination with radiotherapy or temozolomide. Clinical trial information: NCT03224104.