Brain-Penetrant CDK4/6 Inhibitor Auceliciclib Shows Early Clinical Activity in Recurrent High-Grade Glioma

Clinical Summary:

• Design/Population: This first-in-human phase 1/2a study evaluated auceliciclib, a highly selective, brain-penetrant CDK4/6 inhibitor, as monotherapy in patients with advanced solid tumors and in combination with temozolomide in patients with recurrent or relapsed high-grade glioma.

• Key Outcomes: Auceliciclib demonstrated a favorable safety profile with no dose-limiting toxicities or maximum tolerated dose reached. Dose-dependent pharmacokinetics and preliminary disease stabilization were observed, particularly among patients with recurrent high-grade glioma, while hematologic toxicity remained infrequent.

• Clinical Relevance: These findings support continued development of auceliciclib as a brain-penetrant CDK4/6 inhibitor and establish recommended phase 2 doses for future biomarker-guided studies in high-grade glioma and other advanced malignancies.

Results from a first-in-human phase 1/2a study demonstrated that auceliciclib, a second-generation, brain-penetrant CDK4/6 inhibitor, was well tolerated and showed preliminary evidence of clinical activity in patients with advanced solid tumors and recurrent or relapsed high-grade glioma.

"Glioblastoma, the most prevalent and aggressive high-grade malignant primary brain tumour, remains associated with a median survival of ∼15 months despite [standard of care] comprising maximal resection, radiotherapy, and temozolomide," stated Theo Teo, MD, Aucentra Therapeutics, Adelaide, Australia, and coauthors. "Following progression on [standard of care], most patients develop recurrent [glioblastoma], for which no universally accepted [standard of care] exists." 

In this open-label study, 37 heavily pretreated patients received auceliciclib either as monotherapy for advanced solid tumors (phase 1; n = 20) or in combination with temozolomide for recurrent or relapsed high-grade glioma (phase 2a; n = 17). Dose escalation evaluated once-daily and twice-daily auceliciclib schedules, with primary objectives including safety, tolerability, pharmacokinetics, and preliminary antitumor activity.

No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. Grade ≥3 auceliciclib-related treatment-emergent adverse events occurred in 5% of patients receiving monotherapy and 5.9% of patients receiving combination therapy. The most frequently reported treatment-related adverse events included fatigue (40.5%), nausea (40.5%), vomiting (24.3%), and diarrhea (21.6%). Hematologic toxicity was uncommon, and no treatment-related deaths occurred.

Pharmacokinetic analyses demonstrated dose-dependent systemic exposure, with twice-daily dosing producing higher plasma concentrations than once-daily administration. Based on the overall safety, pharmacokinetic, and preliminary efficacy findings, the recommended phase 2 doses were established as 500 mg twice daily for auceliciclib monotherapy and 300 mg twice daily in combination with 100 mg of once-daily temozolomide.

Among 33 evaluable patients, stable disease was achieved in 38.9% of patients receiving auceliciclib monotherapy and 46.7% of patients treated with auceliciclib plus temozolomide. Median progression-free survival was 7.6 weeks and 10 weeks, respectively. Three patients with high-grade glioma maintained disease control for at least 24 weeks, providing preliminary evidence of durable clinical benefit in this population.

The investigators also noted that auceliciclib demonstrated substantially lower hematologic toxicity than currently approved CDK4/6 inhibitors, a finding they attributed to its preferential inhibition of CDK4 over CDK6. They concluded that future studies incorporating pharmacodynamic and biomarker-driven patient selection may help identify patients most likely to benefit from treatment. 

“These findings suggest that auceliciclib may not only improve therapeutic outcomes but also broaden the therapeutic indications for CDK4/6 inhibition by minimising toxicity across a wide therapeutic index," concldued Dr Teo et al. “Further clinical investigation is warranted, ideally incorporating pharmacodynamic and biomarker-driven patient selection to define populations most likely to benefit.”

Source:

Teo T, Karanjia J, Wabnitz P, et al. A phase I/IIa study of auceliciclib in patients with advanced solid tumours and in combination with temozolomide in patients with recurrent/relapsed high-grade glioma. ESMO Open. Published online: February 2026. doi: 10.1016/j.esmoop.2025.106035