ACNS1931: A Phase 3 Study of Selumetinib

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ABSTRACT Low-grade gliomas (LGGs) are the most common pediatric central nervous system tumor, accounting for approximately one-third of pediatric brain tumors. LGGs are a heterogeneous group of astrocytic, oligodendroglial and mixed glial-neuronal histologies that can occur anywhere in the brain or spinal cord. The most appropriate therapy for LGGs that recur after initial therapy is uncertain. At many centers, vinblastine is often used for children with recurrent LGGs. Radiation therapy is an effective treatment option for LGG, but it may result in significant morbidities, including cognitive decline, endocrine deficiencies, secondary malignancies, vascular damage, or growth abnormalities. Recently, the mitogen-activated protein kinase (MAPK) pathway has been demonstrated to be activated in pediatric LGGs of nearly all histological subtypes, most commonly through activation of BRAF (KIAA1549-BRAF fusion or BRAFV600E). MEK1/2 antagonists inhibit the MAPK pathway and have demonstrated anti-tumor activity against progressive pediatric LGGs. Selumetinib is a potent, selective, orally-available, non-ATP competitive, small molecule antagonist of MEK1/2. Selumetinib clinical trial data (both phase 1 and 2) have shown tumor responses and anti-tumor activity in children with multiply recurrent LGGs, regardless of the specific molecular aberration present. ACNS1931 is a prospective, randomized, phase 3 study comparing selumetinib to selumetinib + vinblastine in children with progressive LGG not associated with neurofibromatosis, tuberous sclerosis, BRAFV600E mutations, or IDH1 mutations. The study will begin with a brief feasibility (dose-finding) phase to establish the maximum tolerated/recommended phase 2 dose of selumetinib + vinblastine prior to initiation of the efficacy phase. The efficacy phase will compare event-free survival, tumor response, vision, and quality of life for patients treated with selumetinib versus selumetinib + vinblastine. It will also examine the impact of BRAF rearrangement on event-free survival and tumor response following treatment with both selumetinib-containing arms. Version Date: 09/16/2022 Page 8
Effective start/end date3/1/212/28/25


  • Public Health Institute: $2.00


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