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Description
ABSTRACT-ACNS1833
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, orallyavailable, 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.
Status | Active |
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Effective start/end date | 7/1/22 → 7/1/25 |
Funding
- Public Health Institute: $2.00
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