Pharmacological Phase I Clinical Trials in Pediatric Brain Tumors (1990–2024): A Historical Perspective

Central nervous system (CNS) tumors are the most common solid tumors in pediatric patients and the leading cause of childhood cancer-related mortality. Their rarity compared to adult cancers has made enrolling sufficient cases for clinical trials challenging. Consequently, pediatric CNS tumors were long treated with adult protocols despite distinct biological and clinical characteristics. This review examines key aspects of phase I pediatric oncology trials, including study design, primary outcomes, and pharmacological approaches, along with secondary considerations like clinical responses and ethical aspects. Firstly, we evaluated all phase I trial protocols focusing on pediatric CNS tumors with accessible results published in scientific databases (Pubmed, Scopus, Embase, Web of Science, and Google Scholar) from 1990 to November 2024. Secondly, we searched EudraCT and ClinicalTrials.gov on 30 November 2024 for ongoing trials. Our search yielded 60 completed phase I studies and 15 trials in progress. Dividing them by chronological order revealed that study designs and the response assessments evolved as the understanding of CNS tumor biology increased. Despite advancements improving diagnosis, management, and prognostication, mortality remains high, and morbidity persists. Notably, pediatric pharmacokinetics and pharmacodynamics differ from adults, complicating trial comparisons and dosage optimization. Future efforts should focus on large-scale clinical data collection to enhance trial efficiency.