The Trial Development Group develops new innovative treatment concepts based on current research findings, including from the KiTZ preclinical program. A multidisciplinary team of specialized physicians and study managers from the Study Management Group collaborates closely with the Department of Biostatistics at DKFZ to develop novel international study protocols. The scope of activities includes Phase I to Phase III trials as well as registry studies at various locations across Europe and beyond. Key areas of focus include biomarker screening, biomarker-driven studies, as well as targeted therapies and immunotherapies with new drugs and innovative combination therapies. Collaborations with the pharmaceutical industry facilitate access to drugs still in development
The INFORM2 studies aim to identify molecular subgroups and new drug targets, the clinical relevance of which are further investigated in clinical studies. In addition, new mechanisms and vulnerabilities of pediatric tumors are identified in the preclinical research program, which are efficiently translated into Phase I/II studies. The Trial Development Group designs protocols that enable the conduct of biomarker-driven Phase I/II combination studies as a series of basket trials. National and international networks for conducting Phase I/II studies in pediatric oncology have been established to recruit molecularly defined subgroups efficiently.
The adjuvant standard therapy for pediatric low-grade glioma (pLGG) in children and adolescents has consisted of chemotherapy and radiotherapy for decades. KiTZ groups have found that pLGG is a disease of the MAPK signaling pathway, thus opening up new possibilities for targeted therapy. Whether these new treatment options represent an improvement in the therapy of pLGGs in terms of tumor control and clinical symptoms (visual function, motor functions, etc.) compared to standard chemotherapy is currently unclear. Additionally, many questions regarding the optimal combination therapy and duration of targeted therapies for pLGG remain unanswered.
The LOGGIC (Low Grade Glioma in Children) Program is a Europe-wide (SIOPE) study program aimed at improving the molecular understanding of pLGGs and developing new therapy standards. This includes, on one hand, establishing a European molecular platform, the LOGGIC Core BioClinical Data Bank, and, on the other hand, developing and conducting the randomized Phase III study LOGGIC/Firefly-2 with a RAF inhibitor in newly diagnosed pLGG patients. Additionally, new preclinical insights into the molecular pathogenesis of pLGG are being further developed in Phase I/II studies, including ERK and RAF inhibitors, for patients with recurrent disease.
The Trial Development Group, the Study Management Group, and patient representatives combine their expertise to overcome regulatory and bureaucratic barriers for early phase clinical studies in pediatric oncology. At the national level, there is intensive exchange with authorities and ministries within networks and working groups such as the German Consortium for Translational Cancer Research (DKTK) and the German Centers for Health Research (DZG). At the international level, this occurs through networks such as the ITCC network and the European Medicines Agency (EMA). Research projects are coordinated with various partners to identify barriers to clinical studies in children and adolescents and develop solutions.
van Tilburg CM, Kilburn LB, Perreault S, et al. LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration. BMC Cancer. 2024;24(1):147.
Heipertz AE, Pajtler KW, Pfaff E, … van Tilburg C.M. Outcome of Children and Adolescents With Relapsed/Refractory/Progressive Malignancies Treated With Molecularly Informed Targeted Drugs in the Pediatric Precision Oncology Registry INFORM. JCO Precis Oncol. 2023;7:e2300015.
Hardin EC, Schmid S, Sommerkamp A, … van Tilburg C.M. LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients. Neuro Oncol. 2023.
van Tilburg CM, Pfaff E, Pajtler KW, et al. The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets. Cancer Discov. 2021;11(11):2764-2779.
Beck L, Witt R, Nesper-Brock M, … van Tilburg C.M. A Study of Regulatory Challenges of Pediatric Oncology Phase I/II Trial Submissions and Guidance on Protocol Development. Clin Pharmacol Ther. 2021;110(4):1025-1037.
van Tilburg CM, Witt R, Heiss M, et al. INFORM2 NivEnt: The first trial of the INFORM2 biomarker driven phase I/II trial series: the combination of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies. BMC Cancer. 2020;20(1):523.
van Tilburg CM, Milde T, Witt R, et al. Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia. Clin Epigenetics. 2019;11(1):188.
