Paediatric strategy forum for medicinal product development of cyclin-dependent kinase inhibitors in children and adolescents ACCELERATE in collaboration with the European Medicines Agency With participation of the Food and Drug Administration

The twelfth multi-stakeholder Paediatric Strategy focused on cyclin-dependent kinase (CDK) inhibitors. Genetic aberrations in paediatric tumours increase CDK4/6 activity, thus the pathway is a therapeutic target. As a result, CDK4/6 inhibitors have been evaluated in clinical trials for children and young adults with different malignancies, both as single agents and in combination, including molecular enrichment in ESMART. In some instances, trials of different agents within this same class are very similar in design or target population, leading to duplication. Consistent with preclinical data with CDK4/6 inhibitors which mostly demonstrate cytostasis, but not tumour regression, objective responses are rare, although there may be slowing of tumour growth. Similar to adults, no predictive biomarkers have been identified and an integrated comprehensive clinical development strategy of this class of agents is lacking. Patient advocates believe that the many trials of CDK4/6 inhibitors, which have enrolled many children and young people, have not been matched by sufficient gains in knowledge. CDK9, CDK12 and CDK13 inhibitors, based on exploitation of transcriptional vulnerabilities, have shown promise in preclinical models of MYCN-driven neuroblastoma, osteosarcoma and translocation fusion-driven malignancies. The development of these inhibitors should be sequential, iterative and coordinated, including early engagement with regulators. In conclusion, there needs to be prioritisation and coordination of any further development of CDK4/6 inhibitors in paediatric malignancies. Definite tumour regression in preclinical models, not just cytostasis, should be taken as the go/no go decision point to progress such agents to clinical studies. Based on limited single agent activity in preclinical models, trials of new inhibitors should avoid unnecessary exposure of patients to monotherapy and rapidly progress to combination strategies, while retaining designs that allow early evaluation of activity. A framework to support integrated development strategies of new products across sponsors would be very beneficial.