(BIQSFP for ACNS1831) A Phase 3 Randomized Study of Selumetinib (IND # 77782) versus Carboplatin/Vincristine in Newly Diagnosed or Previously Untreated Neurofibromatosis Type 1 (NF1) Associated Low-Grade Glioma (LGG)

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Low-grade gliomas (LGG) are the most common central nervous system (CNS) tumors in the pediatric population. Although the etiology of most childhood LGG is unknown, 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 has proven effective in the treatment of LGG, however, toxicity from radiation is significant, especially in children with NF1 where the risk of a radiation-induced secondary malignancy and vascular disease is increased. Therefore, most experts agree that the first line standard of care in treating NF1-associated LGG is chemotherapy. 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 differs from patients without NF1, where tumor growth is typically the primary characteristic utilized in making treatment decisions. In the CCG A9952 trial, children with NF1- associated LGG were non-randomly assigned to the carboplatin and vincristine (CV) arm given the potential risk of secondary malignancy with the alkylating-containing regimen (thioguanine, procarbazine, CCNU, and vincristine). The 5-year event-free survival rate was 69% ± 4% for the NF1 group and 39% ± 4% for patients without NF1 who were randomly assigned to CV (P < 0.001). Most experts would agree that CV is considered the standard of care in patients with NF1-associated LGG that require treatment. Recently, major advancements in the understanding of the molecular pathways implicated in pediatric LGG have been made. The most frequent genetic aberrations involve the mitogen-activated protein kinase (MAPK) pathway, most commonly due to activation of BRAF through a tandem duplication that results in the KIAA1549-BRAF fusion or an activating BRAF point mutation (BRAFV600E). NF1 also activates the same RAS/RAF/MAPK cascade, suggesting a common pathway in the majority of LGG. Novel drug development has now allowed for the manipulation and targeting of the MAPK pathway in the treatment of LGG. Selumetinib (AZD6244/ ARRY-142886) is a potent, selective, orally-available, non-ATP competitive small molecule inhibitor of MEK-1/2 which lies downstream of BRAF. The Pediatric Brain Tumor 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. These data led to the development of this study, which is a prospective randomized phase 3 study comparing selumetinib to CV in previously untreated NF1-associated LGG. This study will compare both the event-free survival (EFS) and visual functional outcomes (primarily assessed by Teller Acuity Cards) between the two randomized arms.
Effective start/end date3/1/232/28/25


  • Public Health Institute: $2.00


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