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).

Cohorts 1 and 2: Eligible participants will receive radiotherapy concurrently with twice daily mirdametinib. Mirdametinib will continue after completion of radiation in continuous 28-day cycles with treatment lasting up to 24 cycles. MR imaging to assess response will be performed 4 weeks after completion of radiation therapy, and every 2 months thereafter using Response Assessment in Neuro-Oncology (RANO) 2.0 enhancing criteria.

Cohort 3: Eligible participants will receive twice-daily mirdametinib in 28-day cycles for 6 cycles. MR imaging to assess response by Response Assessment in Neuro-Oncology (RANO) 2.0 non-enhancing criteria will be performed every 3 months thereafter to determine radiographic response. Participants with ongoing benefit may remain on therapy for up to 24 cycles following evaluation of the primary endpoint as determined by the treating physician.

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 have performance status of >= 60 using Karnofsky for participants aged >= 16 years, and Lansky for participants < 16 years of age.

• Cohort 3: Participants must have measurable disease by RANO 2.0 HGG or LGG criteria on baseline MRI.

• Participants must have available archival tissue from the HGG or GBM of interest. Tissue blocks strongly preferred and will be returned to sending site at end of study. Exceptions may be made following discussion with study team if tissue has been exhausted and methylation profiling already performed.

• Organ Function Requirements:

  • Adequate bone marrow function defined as:

    • Absolute neutrophil count > 1,000/mcL
    • Platelets > 100,000/mcL
    • Hemoglobin > 9 g/dL

  • Adequate renal function defined as:

    • Creatinine ≤ 1.5x institutional upper limit of normal based on age/gender OR
    • Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

  • Adequate liver function defined as:

    • Total bilirubin (sum of conjugated + unconjugated) <=1.5x upper limit of normal (ULN) for age (for participants with Gilbert's disease ≤3x ULN), and
    • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) < 2.5x the upper limit of normal (ULN).
    • PT/INR and partial thromboplastin time (PTT) test < 1.5x the laboratory ULN

  • CPK level ≤ 1.5x institutional ULN

  • Blood pressure within upper limit of normal as defined below. Antihypertensives are permissible to achieve blood pressure within ULN, however must be on stable antihypertensive regimen with no adjustments within 30 days of enrollment.

    • In adolescents, a blood pressure (BP) ≤ 90th percentile for age, height, and sex.
    • In adults (>=18 years of age), a systolic blood pressure consistently ≤150 mmHg and a diastolic pressure consistently ≤ 100 mmHg.

• The following intervals from previous treatments are required to be eligible for all cohorts:

  • 12 weeks from an anti-VEGF therapy
  • 4 weeks from a nitrosourea chemotherapy
  • 3 weeks from a non-nitrosourea chemotherapy
  • 2 weeks or 5 half-lives from any investigational (not FDA-approved) agents
  • 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)

• The following intervals from previous radiation are required to be eligible for each cohort:

  • Cohort 1: 24 weeks from prior radiation for the same tumor.
  • Cohort 2: 24 weeks from prior radiation for any other tumor. Note: Participants who received prior radiation for which the expected new prescription isodose field will overlap with the high dose field will be excluded.
  • Cohort 3: 12 weeks from any radiation therapy.

• Written informed consent must be obtained from all participants (>18 years of age) or their legal guardians (if the participant is <18 years of age).

• Participants must be maintained on a stable or decreasing dose of systemic corticosteroid regimen (no increase for 5 days) prior to baseline MRI. Topical and inhaled steroid treatment is allowed.

• Sexually active fertile participants and their partners must agree to use highly effective methods of contraception e.g., hormonal oral contraception, injectables, intrauterine device, surgical sterilization including vasectomy, or hormonal implant with barrier methods (male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 6 weeks after the last dose of study treatment. Barrier methods alone are insufficient. True sexual abstinence is an acceptable method of birth control for both men and women. Persons of childbearing potential will be given a pregnancy test within 72 hours prior to the first dose of study treatment and must have a negative urine or serum pregnancy test.

• Female participants must agree not to harvest or donate eggs (ova, oocytes) and male participants must agree to not harvest or donate sperm for the purpose of reproduction during the treatment period and for at least 6 months after the last dose of study treatment. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.

Exclusion Criteria:

• 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.

• Prior MEK inhibitor therapy:

  • 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).
  • Topical MEK inhibitor within 12 months is not an exclusion but cannot be continued while on study.

• Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, any of the following:

  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) ≤ 180 days prior to start date;
  • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
  • Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or ECHO;
  • Baseline QTc interval > 450 msec;
  • History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia).

• Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (≤ 90 days) history of a partial or complete bowel obstruction, or other conditions that will interfere significantly with the absorption of oral drugs.

• History of recent (≤ 90 days) thromboembolic or cerebrovascular event such as transient ischemic attack, cerebrovascular accident, or hemodynamically significant (massive or sub-massive) deep vein thrombosis or pulmonary emboli (DVT/PE). Note: Participants with DVT/PE that does not result in hemodynamic instability may enroll as long as they are anticoagulated for at least 4 weeks.

• Other Malignancies:

  • Cohort 1: Participants must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Participants with other malignancies must be disease-free for > 2 years.
  • Cohorts 2/3: Participants must have no current or prior diagnosis of malignant peripheral nerve sheath tumor or other malignancy requiring treatment in the last 2 years. A stable or previously treated LGG is acceptable.

• Ophthalmologic conditions:

  • Current or history of central serous retinopathy.
  • Current or history of retinal vein occlusion.
  • Known intraocular pressure (IOP) >21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP). Participants with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair. Participants with orbital plexiform neurofibromas should have IOP measured prior to enrollment.
  • Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study.
  • Note: Mild and controlled/stable age-related macular degeneration or non-proliferative diabetic retinopathy may be acceptable at the investigator's discretion after consultation with the ophthalmologist.
  • Participants with any other significant abnormality on ophthalmic examination should be discussed with the Study Chair for potential eligibility.

• Other clinically significant disorders that would preclude safe study participation, including:

  • Active infection,
  • Poorly controlled HIV. HIV testing will not be required as part of this trial, unless HIV is clinically suspected,
  • Poorly controlled Hepatitis B or Hepatitis C

• Pregnant or lactating women.

• Previously identified allergy or hypersensitivity to components of the study treatment formulations.

• Current use of a prohibited medication (including herbal medications, supplements, or foods), or use of a prohibited medication ≤ 7 days prior to the start of study treatment.

• Use of any medications or substances that are strong inhibitors of breast cancer resistance protein (BCRP) < 14 days prior to the study treatment initiation.

• Participants who have other medical, social or concurrent challenges that are likely to negatively impact their ability to meet all of the trial obligations and therefore may increase the risk of safe participation in the study.