Perlmutter Cancer Center

Low-grade gliomas (LGG) are the most common central nervous system tumor among children, accounting for approximately one-third of pediatric brain tumors. These tumors include a heterogeneous group of astrocytic, oligodendroglial and mixed glial-neuronal histologies that can occur anywhere in the brain or spinal cord. Although complete surgical resection is the mainstay of therapy whenever feasible, tumors that are unresectable often require additional therapy. Radiation therapy is an effective treatment option for pediatric LGG, but it may result in significant morbidities, including cognitive decline, endocrine deficiencies, secondary malignancies, vascular damage, or growth abnormalities. Since the 1980s, chemotherapy has been used to delay or obviate the need for radiation therapy and reduce the overall therapy-associated morbidity in pediatric LGG. Two commonly used chemotherapy regimens (carboplatin and vincristine [CV] and a combination of thioguanine, procarbazine, lomustine and vincristine [TPCV]) were directly compared in the CCG trial A9952 among children with LGG not associated with neurofibromatosis type 1. CV resulted in a slightly lower 5-year event free survival than TPCV; however, CV avoids the risks of secondary malignancy and infertility posed by the TPCV regimen and remains the most popular chemotherapy regimen with the most robust historical data for children with LGG. Recent advances in our understanding of the biology of pediatric LGG have identified the critical role of activation of 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). This discovery has paved the way for the development of drugs that target the MAPK pathway. Selumetinib (AZD6244; ARRY-142886) is a potent, selective, orally-available, non-ATP competitive small molecule inhibitor of MEK-1/2 that lies downstream of BRAF. Phase 1 and phase 2 selumetinib trial data have shown excellent responses and activity in children with multiply recurrent LGG with and without the most common BRAF aberrations. As an alternative to CV, selumetinib may offer reduced cytotoxicity, easier administration (oral) and improved quality of life with the potential for similar or improved efficacy. ACNS1833 is a prospective randomized phase 3 study comparing selumetinib to CV in previously untreated LGG not associated with neurofibromatosis or BRAFV600E. This non-inferiority study will compare event- free survival, functional/behavioral outcomes and quality of life measures for patients treated with CV versus selumetinib.