EPILOGUE

Progressive, relapsed and refractory pediatric low-grade glioma (pLGG) is a serious and potentially fatal disease for which there is currently no standard of care (SOC) after systemic frontline SOC treatments. pLGG is considered a chronic disease and patients with pLGG can suffer from significant damage to vital functions and long-lasting side effects throughout their lives. Genetically, pLGG is a single pathway disease driven by alterations in the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. In addition to activated MAPK signaling, the role of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP) has recently been highlighted as playing a major role in pLGG. This protected senescent state of the tumor cell is triggered by MAPK alterations, maintained by the SASP, and characterized by cell cycle arrest and resistance to conventional chemotherapy. Ongoing studies of various MAPK pathway inhibitors in pLGG illustrate the potential of these targeted drugs, but also show that responses are often only durable for as long as treatment is being administered. This exploratory, multicenter, international, open label, combination phase I/II umbrella trial applies an intra-individual dose escalation concept to achieve the optimal tolerable dose for each patient for different (combination) treatment arms. The primary objectives are to determine safe starting doses in an intra-individual dose escalation regimen and to evaluate activity and safety of the treatment arms. Pediatric patients aged 6-21 years with refractory, relapsed, or progressive pLGG with the presence of a genetic activating RAF alteration assessed by molecular analysis are eligible for this trial. Patients will be randomized to three treatment arms: Arm 1 (Single agent Extracellular Signal-Regulated Kinases (ERK) inhibitor ulixertinib), Arm 2 (Combination ulixertinib + type II Rapidly Accelerated Fibrosarcoma Gene (RAF) inhibitor tovorafenib) or Arm 3 (Combination ulixertinib + vinblastine). Activity and safety of the treatment arms will be evaluated. The duration of treatment will be maximum 12 cycles (1 cycle = 28 days), with a re-challenge option in case of rebound tumor growth. Per treatment arm, 22 patients will be included. The EPILOGUE App will be used by children and legal guardians to complete short health questionnaires (called PROMIS) during the study. These questionnaires help doctors understand how the child participating in the EPILOGUE study is feeling and how the treatment is affecting daily life. This application is not a certified medical device under the EU Medical Device Regulation (MDR). The EPILOGUE App is designed exclusively for use within the scope of the EPILOGUE research project. It is not intended for commercial or general medical use. It is not intended for emergency care and does not replace medical consultation, diagnosis, or treatment.