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

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. 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. 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/m 2 /day on Day 1, equivalent to 70% of the adult RP2D; temozolomide was given at the pediatric RP2D dose of 150 mg/m 2 /day. The cohort was enriched for patients with molecular alterations in cell cycle pathways. 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/m 2 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. 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 activity. ClinicalTrials.gov NCT2813135. Registered on: 24 June 2016.