The purpose of this study to find out whether mirdametinib is a safe and effective treatment for Central Nervous System/CNS tumors (glioma and neurohistiocytosis).

Inclusion criteria - Cohorts A and B

Demographic Characteristics

a. Be > 18 years of age

General Criteria

1. Have Karnofsky Performance Status (KPS) of ≥ 70% or ECOG Performance Status of ≤ 2
2. Is able to understand and provide written informed consent for the trial prior to any study-specific procedures and is willing to comply with scheduled visits, treatment plans, procedures and laboratory tests. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to and approved by the institutional review board.

Medical and Therapeutic Criteria

1. Have adequate bone marrow function, as determined by:

   • Absolute neutrophil count (ANC) >1,500/mm3
   • Platelet count >100,000 mm³
   • Hemoglobin >9.0 mg/dL

2. Have adequate hepatic function, as determined by:

   • Total bilirubin ≤1.5 x ULN if baseline was normal or ≤1.5 x baseline if baseline was abnormal. Patients with previously documented Gilbert's Syndrome may have total bilirubin ≤3 x ULN.
   • AST and ALT ≤3.0 x ULN if baseline was normal or ≤3.0 x baseline if baseline was abnormal

3. Have adequate renal function, as determined by:

   o Creatinine clearance (CrCL) of ≥50 mL/min by the Cockcroft-Gault formula

   CrCl (mL/min) = [140 - age (years)] x weight (kg) x 0.85 for female patients 72 creatinine (mg / dL)

4. Adequate cardiac function defined as follows

   • Left ventricular ejection fraction >50% as assessed by multi-gated acquisition or ultrasound or echocardiography and
   • Corrected QT interval (QTc) <480 ms according to the Fridericia method (QTcF)

5. Women of childbearing potential must have a negative serum pregnancy test before the start of therapy.

6. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

7. Patients previously treated with radiotherapy must have recovered from acute toxicities associated with such treatment. Toxicities of investigational therapies should have recovered to grade 1 or less before start of the trial medication.

Additional cohort specific inclusion criteria - Neurohistiocytosis Cohort A

Subjects must meet all of the following criteria to be enrolled in the Neurohistiocytosis cohort of this study:

1. Have documented MAPK pathway mutation, or mutation not identified by tumor sequencing.: Patients with completed but negative tumor sequencing, or patients without sequencing performed but without safe disease sites for biopsy, are eligible for this study owing to the high likelihood of MAPK pathway mutation.

2. Have documentation of disease: Patients must have a histologically confirmed histiocytic neoplasm or a constellation of histologic, radiologic, clinical, and/or molecular findings consistent with histiocytic neoplasm. This qualification is made because it is well known that biopsies of histiocytic neoplasms are variable and do not always demonstrate "typical" morphologic appearance with all of the classically described elements.[54] As a result, histiocytic neoplasms are not exclusively pathologic diagnoses-rather, they are interpretations of histologic findings in a clinical and radiologic context.

3. Have measurable neurohistiocytic disease: Patients must have measurable radiologic or functional neurologic disease as defined by any of the following below. The presence of systemic disease is allowed however there must be at least one eligible manifestation of neurologic disease as defined below:

   • Measurable disease according to modified PERCIST (mPERCIST) involving neurologic structures, i.e. meninges, brain or spinal cord parenchyma, or ocular structures (see sections below for these criteria) OR

   • Measurable disease according to RECIST 1.1 involving neurologic structures OR

   • Any of the below neurologic deficits referable to neurohistiocytosis amenable to longitudinal quantified assessment. The following are the allowable deficits, deemed referable to disease, with their corresponding assessments and minimum required abnormalities:

     • Dysarthria as defined Speech Intelligibility of B or worse as measured by the Frenchay Dysarthria Scale
     • Ataxia as defined by a score of 3 or higher on the Scale for assessment and rating of ataxia (SARA)
     • Diplopia as defined by Prism Diopter of 5 or higher
     • Loss of visual acuity defined as best corrected visual acuity (BCVA) 20/40 (0.3 LogMAR) or worse in either eye
     • Diminished visual field, defined as 20% or higher deficit in Humphrey Visual Field 24-2 pattern deviation.

Additional cohort specific inclusion criteria - Glioma Cohort B

Subjects must meet all of the following criteria to be enrolled in the glioma cohort of this study:

1. Have: somatic NF1 mutation as per next-generation sequencing (such as MSK Impact) --or- germline NF1 as per NIH clinical criteria
2. Have a histologically confirmed glioma (per the 2021 WHO Classification of Tumors of the central nervous system)
3. Have measurable, MRI-evaluable, unequivocal contrast enhancing disease as determined by radiologist on T1 post-contrast weighted images. Per RANO criteria, measurable lesion is defined as at least 1 enhancing lesion measuring > 1 cm x > 1 cm
4. Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both
5. Surgical resection is indicated for treatment, but surgery is not urgently indicated (e.g. for whom surgery within the next 4-6 weeks is appropriate)
6. Have expected survival of > 3 months

Exclusion Criteria:

Subjects who meet any of the following criteria will not be enrolled in the study:

General criteria

1. Is pregnant or nursing

2. Is participating in another interventional study at the same time; participation in non-therapeutic registries is allowed

   Medical and Therapeutic criteria

3. Receipt of tumor directed therapy (chemotherapy, targeted therapy, biologic, investigational) within 28 days or 5 half-lives (whichever is shorter) before the first dose of mirdametinib.

4. Concomitant use of medications that strongly induce CYP3A

5. History of allergic reaction to the study agent(s), compounds of similar chemical or biologic composition to the study agent (s) (or any of its excipients).

6. Evidence of serious active infections. Patients are allowed to enroll if they have been fever free for at least 48 hours

7. Uncontrolled or severe intercurrent medical condition

8. Have significant active cardiac disease within 6 months before the start of treatment, including New York Heart Association Class III or IV congestive heart failure, atrial fibrillation, myocardial infarction, unstable angina and/or stroke.

9. Have significant active ophthalmologic disease within 6 months before the start of treatment, including central retinal vein occlusion

10. Has a history of or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator

11. Cohort A only: Patients with documented driver mutations outside of the MAPK pathway are not eligible for this study. These are uncommon and include mutations in ALK, RET, CSF1R, NTRK, and other kinases20 .

On Study Guidelines:

Physicians should consider the following when evaluating if the patient is appropriate for this study:

• Cohorts A and B: Patients with cytopenias, renal impairment or hepatic impairment deemed the direct result of disease and therefore amenable to improvement with mirdametinib treatment may be enrolled at the discretion of the treating investigator
• Cohort A: There is no prior therapy requirement given the poor CNS efficacy of standard therapies, morbidity of neurohistiocytosis, and the available data about safety and efficacy in nine patients treated with mirdametinib.
• The effects of mirdametinib on the developing human fetus are unknown. For this reason, female participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 6 weeks following the completion of study therapy. Male participants with female partners of reproductive potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 3 months following the completion of study therapy. Should a participant become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made following one year after publication and for up to 36 months later. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.