This is a phase 2, open label, parallel multi-arm study of mirdametinib in combination with radiation in participants with recurrent sporadic glioblastoma (GBM) harboring NF1 alterations (Cohort 1); participants with NF1 with a newly diagnosed GBM (Cohort 2); mirdametinib alone in other NF1-associated High-Grade Gliomas (Cohort 3).
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.
Cohort 1: Participants may not have a diagnosis of NF1.
Tumor positive for pathogenic IDH-mutation, H3.1 or H3.3 mutation, or BRAF alteration.
Participant has not recovered to ≤ Grade 1 non-hematologic toxic effects of prior therapy before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and may enroll.
Cohort 1: Prior MEK inhibitor therapy contraindicated
Cohorts 2/3: Prior MEK inhibitor therapy to target glioma contraindicated (even if the target tumor was previously suspected or biopsy-proven low-grade glioma). No oral MEK inhibitor therapy in the past 12 months for other manifestations of NF1 (including non-target glioma).
Parallel
mirdametinib with radiation
Combination productParticipants in Cohorts 1 and 2 will receive mirdametinib in combination with radiation therapy followed by mirdametinib alone.
mirdametinib
DrugParticipants in Cohort 3 will receive mirdametinib alone.
Cohort 1
Estimate overall survival at 12 months in participants with recurrent sporadic GBM harboring an NF1 alteration treated with repeat irradiation in combination with mirdametinib.
Cohort 2
Estimate overall survival at 18 months in participants with a newly-diagnosed NF1-associated GBM treated with irradiation in combination with mirdametinib in Cohort 2.
Cohort 3
Estimate response rate at six months in participants with germline NF1 and HGAP or a non-GBM high grade glioma. Tumor response is based on MRI imaging per RANO 2.0 guidelines.
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University of Alabama at Birmingham
Lead sponsor
Children's Hospital of Philadelphia
Collaborator
Congressionally Directed Medical Research Programs
Collaborator
This trial is not recruiting at the moment. You can still explore other options:
