Auceliciclib Demonstrates Favorable Safety and Preliminary Activity in Advanced Solid Tumors and Recurrent High-Grade Glioma

Key Clinical Summary:

• Design/Population: A phase 1/2a open-label study evaluated auceliciclib, a highly selective, brain-penetrant CDK4/6 inhibitor, in 37 heavily pretreated patients: 20 with advanced solid tumors (phase 1 monotherapy) and 17 with recurrent/relapsed high-grade glioma (phase 2a, combined with temozolomide).
• Key Outcomes: No dose-limiting toxicities were observed, and grade ≥ 3 treatment-related adverse events were uncommon. Common adverse events included nausea, fatigue, vomiting, and diarrhea. In phase 1, median PFS was 7.6 weeks with 38.9% stable disease; in phase 2a, median PFS was 10 weeks with 46.7% stable disease. Pharmacokinetics showed dose-dependent exposure, with higher levels achieved using twice-daily dosing. Recommended phase 2 doses were 500 mg BID (monotherapy) and 300 mg BID with temozolomide.
• Clinical Relevance: Auceliciclib demonstrated acceptable tolerability and early disease stabilization signals, particularly in recurrent high-grade glioma, supporting further investigation of this brain-penetrant CDK4/6 inhibitor with potential biomarker-guided development to optimize patient selection and therapeutic impact.

Auceliciclib, a second-generation, highly selective CDK4/6 inhibitor with high brain penetration, showed acceptable tolerability and early signals of clinical activity in patients with advanced solid tumors and recurrent or relapsed high-grade glioma, according to results from a phase 1/aa study.

Glioblastoma is the most common and aggressive high-grade primary brain tumor and carries a median survival of approximately 15 months despite standard-of-care treatment with maximal resection, radiotherapy, and temozolomide. Following progression, recurrent disease lacks a universally accepted standard therapy, with salvage approaches producing limited benefit and median overall survival (OS) generally ranging from 2.9 to 18.3 months and progression-free survival (PFS) less than 6 months. 

Researchers conducted an open-label study to determine the safety, tolerability, pharmacokinetics, and efficacy of auceliciclib among heavily pretreated patients. Phase I evaluated auceliciclib monotherapy across escalating dose levels (50 to 350 mg once daily and 175 to 500 mg twice daily) among patients with locally advanced or metastatic solid tumors. Phase IIa assessed auceliciclib (100 to 150 mg once daily; 100 to 500 mg twice daily) in combination with temozolomide 100 mg once daily in patients with recurrent or relapsed high-grade glioma. Treatment cycles were administered on 21-day (once daily dosing) or 28-day (twice daily dosing) schedules within 28-day cycles. 

Overall, 37 patients, 20 with advanced solid tumors in the phase 1 monotherapy cohort and 17 with high-grade glioma in the phase 2a combination cohort. The median age among patients was 62.5 (range, 27 to 82) and 58.0 (range, 38 to 70), respectively. All included patients received at least 1 prior line of therapy. 

In terms of safety, 131 treatment-emergent adverse events were reported among 95% of patients in phase 1 and 139 events among all patients in phase 2. No dose limiting toxicities were observed. Grade 3 or higher auceliciclib-related treatment-emergent adverse events were uncommon. The most frequently reported adverse events were in phase 1 were nausea (30.0%), diarrhea (25.0%), vomiting (15.0%), fatigue (15.0%), and headache (15.0%). The most common adverse events in phase 2a were fatigue (70.6%), nausea (52.9%), vomiting (35.5%), and diarrhea (17.6%). 

Pharmacokinetic analyses demonstrated dose-dependent systemic exposure, with higher exposure observed with twice-daily dosing and a prolonged half-life at higher dose levels. Among 33 evaluable patients, the median PFS was 7.57 weeks (95% confidence interval [CI], 6.29 to 11) and 38.9% of patients achieved stable disease in phase 1. In phase 2a, the median PFS was 10 weeks (95% CI, 7.14 to 43.43) and 46.7% of patients achieved stable disease. 

Based on safety, pharmacokinetic, and preliminary efficacy findings, the recommended phase II doses were established at 500 mg twice daily for monotherapy and 300 mg twice daily in combination with temozolomide 100 mg once daily.

The researchers concluded, “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.”

They added, “Given its promising safety and pharmacologic profile, 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