A Study of Mirdametinib for the Treatment of People with Central Nervous System Tumors

Inclusion Criteria

• Be >= 18 years of age
• Have Karnofsky performance status (KPS) of >= 70% or Eastern Cooperative Oncology Group (ECOG) performance status of =< 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
• Absolute neutrophil count (ANC) > 1,500/mm^3
• Platelet count > 100,000 mm³
• Hemoglobin > 9.0 mg/dL
• Total bilirubin =< 1.5 x upper limit of normal (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
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN if baseline was normal or =< 3.0 x baseline if baseline was abnormal
• Creatinine clearance (CrCL) of >= 50 mL/min by the Cockcroft-Gault formula
• Left ventricular ejection fraction > 50% as assessed by multi-gated acquisition or ultrasound or echocardiography
• Corrected QT interval (QTc) < 480 ms according to the Fridericia method (QTcF)
• Women of childbearing potential must have a negative serum pregnancy test before the start of therapy
• 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
• 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
• COHORT A: 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
• COHORT A: 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. As a result, histiocytic neoplasms are not exclusively pathologic diagnoses—rather, they are interpretations of histologic findings in a clinical and radiologic context
• COHORT A: 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 Logarithm of the Minimum Angle of Resolution [LogMAR]) or worse in either eye ** Diminished visual field, defined as 20% or higher deficit in Humphrey Visual Field 24-2 pattern deviation
• COHORT B: Have: somatic NF1 mutation as per next-generation sequencing (such as MSK Impact) --or- germline NF1 as per National Institutes of Health (NIH) clinical criteria
• COHORT B: Have a histologically confirmed glioma (per the 2021 World Health Organization [WHO] Classification of Tumors of the central nervous system)
• COHORT B: Have measurable, MRI-evaluable, unequivocal contrast enhancing disease as determined by radiologist on T1 post-contrast weighted images. Per Response Assessment in Neuro-Oncology (RANO) criteria, measurable lesion is defined as at least 1 enhancing lesion measuring > 1 cm x > 1 cm
• COHORT B: Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both
• COHORT B: 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)
• COHORT B: Have expected survival of >= 3 months

Exclusion Criteria

• Is pregnant or nursing
• Is participating in another interventional study at the same time; participation in non-therapeutic registries is allowed
• 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
• Concomitant use of medications that strongly induce CYP3A
• 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)
• Evidence of serious active infections. Patients are allowed to enroll if they have been fever free for at least 48 hours
• Uncontrolled or severe intercurrent medical condition
• 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
• Have significant active ophthalmologic disease within 6 months before the start of treatment, including central retinal vein occlusion
• 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
• COHORT A: 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 kinases