Efficacy of Mirdametinib Alone or Combination With Radiotherapy for Germline and Sporadic NF1-Altered High-Grade Glioma

Inclusion Criteria: * Tumor diagnosis: * Cohort 1 (applies to non-NF1 related GBM): GBM, IDH-wildtype grade 4 of brain or spinal cord by WHO 2021 central nervous system tumor diagnostic criteria52 that is recurrent after irradiation and first-line chemotherapy (if appropriate). Any number of prior recurrences is acceptable. Tumor Next Generation Sequencing (NGS) must demonstrate at least one pathogenic/likely pathogenic NF1 alteration (known or suspected to confer loss of function) at time of first or recurrent surgery that could putatively confer loss-of-function. * Cohort 2 (applies to participants with NF1): Pathology consistent with GBM, IDH-wildtype grade 4 by WHO 2021 CNS tumor diagnostic criteria or HGG with somatic TP53 mutation (brain or spinal cord). Participants may not have received any therapy beyond surgical resection for the target HGG. * Cohort 3 (applies to participants with NF1): HGAP (including low-grade glioma classified as HGAP by methylation profiling) or other HGG not meeting criteria for Cohort 2. Participants may not have received prior therapy for the HGG. * Neurofibromatosis 1: * Cohort 1: Participants may not have a diagnosis of NF1. * Cohort 2/3: All participants must have a diagnosis of NF1 based on the 2021 revised consensus criteria. * Age: Cohort 1: Participants must be ≥ 18 years of age at the time of enrollment. Cohorts 2/3: Participants must be ≥ 12 years of age at the time of enrollment. * Performance Level: Participants must …