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EPILOGUE Clinical Trial

Head: Prof. Cornelis van Tilburg, PhD

Postal address:

Im Neuenheimer Feld 430
69120 Heidelberg

Targeted therapy alone or in combination with conventional chemotherapy for children and adolescents with progressive/relapsed/refractory pediatric low-grade glioma (pLGG) – EPILOGUE

Formal title: “EPILOGUE – phase I/II combination umbrella trial in progressive/relapsed/refractory pediatric low-grade glioma (pLGG)”.

Progressive/relapsed/refractory pLGG is a serious disease with a significant impact on quality of life and disease burden. Although it is a MAPK-driven single-pathway disease, targeted treatments have so far been associated with limited durability of response and rebound growth after treatment withdrawal. Our preclinical data demonstrate synergistic activity of dual targeting of the MAPK pathway at the level of RAF and ERK, as well as in combination with chemotherapy. These data provide a strong in vitro and in vivo rationale to evaluate ulixertinib in pLGG as single agent as well as in combination with tovorafenib and conventional chemotherapy (vinblastine).

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 and the presence of a genetic activating RAF alteration, as assessed by molecular analysis, are eligible for this trial. Patients are randomized to three treatment arms: 

  • Arm 1: single-agent ERK inhibitor ulixertinib
  • Arm 2: combination of ulixertinib and the type II RAF inhibitor tovorafenib
  • Arm 3: combination of ulixertinib and vinblastine.

The maximum treatment duration is 12 cycles (1 cycle = 28 days), with the option for re-challenge in case of tumor rebound. 
 

 

 

  • Children and adolescents with progressive/relapsed/refractory pLGG after first- or maximum second-line therapy
  • Histopathological diagnosis of glioma or glioneuronal tumor and DNA methylation classification consistent with pLGG diagnosis
  • Presence of a genetic activating RAF alteration
  • Molecular analysis for biomarker identification, e.g. via the LOGGIC Core BioClinical Databank or an equivalent platform
  • Age at the time of informed consent ≥ 6 to ≤ 21 years
  • Disease that is measurable as defined by RAPNO-LGG criteria. 
     

Full eligibility criteria can be found here.

Coordinating Investigator: Prof. Cornelis van Tilburg, MD, PhD

Project Management: Melanie Heiss

Participating sites and recruitment status: A full list of participating sites and their recruitment status can be found here.

Financing:

  • The trial is funded by the Dietmar Hopp Foundation (Project number: 1DH2211236) and Everest startup funding provided by The Brain Tumor Charity (Grant number: GN-000707)
  • Study medication will be supplied by Day One Biopharmaceuticals, Inc. (tovorafenib) and BioMed Valley Discoveries, Inc. (ulixertinib). In addition, both companies support the trial financially.

International monitoring is conducted by ECRIN.

For more information, see CTIS.

EU CT Number.: 2024-516896-34-00 .