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

Background: This first-in-human phase I/IIa study evaluated auceliciclib, a second-generation, highly selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor with potent antitumour activity, high brain penetration, and a wide preclinical therapeutic index. The trial assessed safety, tolerability, pharmacokinetics, and preliminary efficacy of auceliciclib as monotherapy in advanced solid tumours (phase I) and in combination with temozolomide for recurrent/relapsed high-grade glioma (phase IIa). Methods: This open-label study enrolled patients with advanced solid tumours or recurrent/relapsed high-grade glioma progressing after standard therapies. Dose escalation deployed accelerated titration followed by a 3 + 3 design. Phase I evaluated auceliciclib monotherapy (50-350 mg once daily; 175-500 mg twice daily). Phase IIa assessed auceliciclib (100-150 mg once daily; 100-500 mg twice daily) plus temozolomide (100 mg once daily). Regimens followed 21-day (once daily) or 28-day (twice daily) schedules per 28-day cycle. Results: Thirty-seven patients (20 in phase I; 17 in phase IIa) were treated. No dose-limiting toxicities were observed. Grade ≥3 auceliciclib-related TEAEs were infrequent (5.0% in phase I; 5.9% in phase IIa), with fatigue (40.5%), nausea (40.5%), vomiting (24.3%), and diarrhoea (21.6%) being the most common events. Pharmacokinetic analysis showed dose-dependent exposure, with twice-daily dosing yielding higher systemic levels, and a prolonged half-life at higher doses. Among 33 assessable patients, 14 achieved stable disease, including three high-grade glioma patients with disease control ≥24 weeks. Conclusions: Auceliciclib was well tolerated, and demonstrated dose-dependent pharmacokinetics and preliminary clinical activity in heavily pretreated patients. Recommended phase II doses are 500 mg twice daily (monotherapy) and 300 mg twice daily with 100 mg temozolomide once daily (combination therapy). These findings support further clinical development of auceliciclib for high-grade glioma and other malignancies.