A phase II study to evaluate the use of the MEK inhibitor mirdametinib to reduce the size of Large/Giant congenital melanocytic nevi in children, adolescents and young adults

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

* INCLUSION CRITERIA: * Participants must have a clinical diagnosis of a large and giant congenital melanocytic nevi (LGCMN). * Participants must have a documented history of somatic pathogenic or likely pathogenic variation in NRAS or BRAF, or a pathogenic fusion in which one of the fusion partners is ALK, NTRK1, BRAF, or RAF1. Participants who do not have documented history will be tested by NSR device (via next-generation sequencing panel TruSight(TM) Oncology 500) * Participants must have: at least one nevus \> 20 cm OR at least one nevus with a projected adult diameter \> 20 cm (participants \< 18 years old). Note: Participants who have had prior surgical treatment of their LGCMN, but the remaining nevus has a diameter \> 20 cm, are eligible for enrollment. * Age \>= 3 years and \<= 40 years old. * Participants must have a Body Surface Area (BSA) \>= 0.4 m\^2. * Clinical performance status: Karnofsky \>= 70% (\>= 16 years); Lansky scale \>=70% (\< 16 years). * Participants must have adequate organ and marrow function as defined below: * Hemoglobin \>= 11 g/dL * Absolute neutrophil count \>= 1,000/mcL * Platelets \>= 100,000/mcL * Total bilirubin \<= 1.5 X institutional upper limit of normal (ULN) for age. Note: 3 X ULN for age for participants with Gilbert syndrome * Aspartate Aminotransferase (AST) \<= 3 X institutional ULN * Alanine Aminotransferase (ALT) \<= 3 X institutional ULN * Estimated creatinine clearance \>= 30 mL/min/1.73 m\^2 as calculated per the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (\>= 18 years old) or Chronic Kidney Disease in Children Under 25 (CKiD U25) in (\< 18 years old) * Cardiac function: Normal ejection fraction (echocardiogram \[ECHO\] or cardiac MRI), defined as ejection fraction (EF) \>= 53%; normal QTc interval, defined as QTcF \<= 450 msec * Blood pressure (BP): Adults (\>= 18 years old): BP \<= 130 systolic and \<= 80 diastolic Children (\< 18 years old): BP \<= the 95th percentile for age, height, and sex Adequate blood pressure can be achieved using medication for the treatment of hypertension. --Serum creatine phosphokinase (CPK) \<= 2.5 X institutional ULN * Participants with neurocutaneous melanocytosis must be asymptomatic and have nonprogressive disease. * Participants with seizure disorder may be enrolled if on anticonvulsants, and there has been no change to their anticonvulsant medication in the 4 weeks prior to the study treatment initiation, and the participant has been seizure-free during that time. * Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy must have an undetectable viral load. * Participants with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load and be on suppressive therapy, if indicated. * Participants with evidence of hepatitis C virus (HCV) infection must have an undetectable HCV viral load and be cured or on suppressive therapy, if indicated. * Women who are nursing or plan to nurse a child must agree to discontinue/postpone nursing while taking mirdametinib and until 1 week after the administration of the last dose of mirdametinib. * Women of child-bearing potential (WOCBP) must agree to use an effective contraception (barrier, hormonal, intrauterine device, surgical sterilization, continuous abstinence) while taking mirdametinib and until 6 weeks after administration of the last dose of mirdametinib. A participant may request a male partner to use an effective form of contraception to fulfill this requirement. Note: WOCBP defined as: * biologically female sex with a uterus and at least one ovary who is at least Tanner Stage 3, AND * entered puberty and has not completed menopause AND * does not meet the definition of female participant who cannot get pregnant as follows: * has undergone a hysterectomy OR * has undergone a bilateral oophorectomy OR * has completed menopause defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/ml or 6 weeks postsurgical OR * has not gone through menarche or reached Tanner Stage 3 Men (biologically male sex) must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) while taking mirdametinib and until 3 months after administration of the last dose of mirdametinib. A participant may request a female partner to use an effective form of contraception to fulfill this requirement. Men must not freeze or donate sperm within the same period. -Ability of participant or parent/guardian to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: * Participants who are receiving any investigational agents within the 30 days prior to the study treatment initiation. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to mirdametinib. * Prior treatment with mirdametinib or another specific MEK1/2 inhibitor. * 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). * Ophthalmologic findings secondary to long-standing optic pathway glioma or NCM (such as visual loss, optic nerve pallor, or strabismus) will NOT be considered a significant abnormality for the purposes of the study. * Cardiac conditions: * Heart failure (any New York Heart Association \[NYHA\] class) * Myocardial infarction, severe/unstable angina, coronary or peripheral artery bypass graft placement, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism within 6 months prior to starting study treatment. * Refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption of mirdametinib. * Any unresolved chronic toxicity grade \>= 2 per CTCAE from previous therapy, except for alopecia. * History of renal transplant. * Major surgery within 4 weeks prior to starting study treatment. * Prior history of melanoma or other malignancy. * Active infection (currently on treatment with anti-microbials). * Positive serum or urine beta-human chorionic gonadotropin (beta-HCG) pregnancy test performed at screening. * Uncontrolled, symptomatic intercurrent illness evaluated by medical history, physical exam, lab evaluations that would unacceptably increase risk for the participant or impair the ability to evaluate the endpoints of the study.