EPILOGUE

EPILOGUE - Phase I/II combination umbrella trial in relapsed paediatric 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. Paediatric 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 randomised 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 tumour rebound.

Population: Paediatric | Intervention type: Interventional