ACNS1831 COG SIOPE NF1 (NF1) A Phase 3 Randomized Study of Selumetinib (IND # TBD) versus Carboplatin/Vincristine in Newly Diagnosed or Previously Untreated Neurofibromatosis Type 1 (NF1) associated Low-Grade Glioma (LGG)

Background: Low-grade gliomas (LGG) are the most paediatric common central nervous system (CNS) tumours.

Children with the genetic disorder Neurofibromatosis type 1 (NF1) are at increased risk of developing LGG, most commonly within the optic pathway. This sensitive location makes surgical resection difficult and fraught with morbidities.

Radiation therapy is effective in the treatment of LGG, but toxicity is significant, especially in children with NF1 where the risk of a radiation-induced secondary malignancy and vascular disease is increased.

Since the vast majority of patients will not succumb to their disease, treatment is often focused on preserving or improving functional outcomes, particularly visual acuity.

This trial will include measures of visual acuity and adaptive behaviours as primary outcomes, thereby evaluating the impact of any therapeutic approach upon the natural history of the disease.

First line standard of care in treating NF1-associated LGG is chemotherapy, the most common regimen is carboplatin and vincristine (CV) and the the 5-year event-free survival rate in a previous study was 69% ± 4% for the NF1 LGG.

Recently, major advancements in the understanding of the molecular pathways implicated in paediatric LGG with a common pathway of activation of the RAS/RAF/MAPK pathway in both NF1 and sporadic LGG. This has led to early phase trials targeting the MAPK pathway in the treatment of LGG.

Selumetinib (AZD6244) is a potent, selective, orally-available, non-ATP competitive small molecule inhibitor of MEK-1/2 which lies downstream of BRAF.

The US Paediatric Brain Tumour Consortium (PBTC) phase 1 and phase 2 selumetinib trial data showed unprecedented responses and activity in children with multiply recurrent LGG, particularly in NF1-associated LGG and led to the development of this phase 3 study, ACNS1831.

Methods: ACNS1831 is an international randomised phase 3 study, comparing the efficacy of standard care (carboplatin and vincristine (CV)) to selumetinib treatment in previously untreated Neurofibromatosis (NF1)-associated low-grade glioma (LGG). Primary Aims: 1.

To determine whether the efficacy of treatment with selumetinib as measured by event-free survival (EFS) is non-inferior to treatment with carboplatin/vincristine (CV) in previously untreated NF1 LGG. 2.

To determine whether visual acuity (VA) in patients with NF1-associated LGG within the optic pathway, is better in those treated with selumetinib compared to CV.

How the results of this research will be used: The outcomes of this study will be used to inform the future treatment of children with NF1 associated LGG.