Rubio-San-Simón A, Marshall LV, Karamouza E, André N, Abbou S, Rubino J, Nebchi S, Aerts I, Thebaud E, Brisset C, Ducassou S, Le Teuff G, Geoerger B.
Target Oncol. 2026 Mar 16. doi: 10.1007/s11523-026-01208-1. Online ahead of print.PMID: 41838385
Phase I/II Study of the CDK2/9 Inhibitor Fadraciclib in Combination with Chemotherapy in Children with Advanced Malignancies: Arm K of the AcSé-ESMART Trial.
Background: Cyclin-dependent kinase (CDK) dysregulation is common in pediatric cancers. The dual CDK2/9 inhibitor fadraciclib has shown preclinical antitumor activity, alone and in combination, supporting clinical evaluation in children.
Objective: Arm K of the AcSé-ESMART proof-of-concept phase I/II platform trial aimed to define the recommended phase II dose (RP2D), pharmacokinetics, antitumor activity and predictive biomarker(s) of fadraciclib in combination with temozolomide in pediatric patients with recurrent/refractory solid malignancies.
Patients and methods: Fadraciclib was administered intravenously once on Day 1 ± Day 15, and temozolomide orally on Days 1-5. Dose escalation of fadraciclib followed the continuous reassessment method starting at 135 mg/m2/day on Day 1, equivalent to 70% of the adult RP2D; temozolomide was given at the pediatric RP2D dose of 150 mg/m2/day. The cohort was enriched for patients with molecular alterations in cell cycle pathways.
Results: Twelve patients were enrolled and treated (median age: 12.1 years, range 4.0-17.9). Main diagnoses were sarcoma and central nervous system tumors. Dose-limiting toxicities and main treatment-related adverse events were hematologic. The final tolerated intravenous fadraciclib dose could be estimated at 135 mg/m2 on Day 1 or Day 1 and 15 as the trial was closed prematurely following emerging adult data and the company’s shift from an intravenous to a new oral formulation. No objective response was observed; two patients with ependymoma and extra-cerebral malignant rhabdoid tumor had stable disease for 6 and 9 cycles, respectively.
Conclusions: This pediatric study was the first to explore the CDK2/9 inhibitor fadraciclib. Fadraciclib combined with temozolomide showed a manageable safety profile with limited clinical