Mirdametinib in Histiocytic Disorders

Inclusion Criteria:

1. Subjects must be ≥ 2 years of age AND have a diagnosis of a histiocytic disorderthat requires systemic therapy

• If patient has had a diagnostic biopsy, biopsy must be reviewed and confirmedby CCHMC pathologist as feasible

• If patient has had a biopsy but has not had molecular testing done, must havetissue available for mutational analysis

• If patient has isolated pituitary/CNS disease or situations where biopsy is notfeasible, positive ddPCR blood test for mutation associated with histiocyticneoplasm with clinical features of histiocytosis is sufficient

2. Must have measurable disease on PET scan or brain MRI

3. Subjects must demonstrate adequate organ function as defined:

• Renal: maximum serum creatinine 2x the upper limit of normal (ULN) OR acreatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2

• Liver: ALT ≤ 3x ULN AND normal INR (≤ 1.5)

• Hematologic: Hematology: Albumin ≥ 2.8 g/dL; Absolute neutrophil count ≥ 1.5 x 109/L; Platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0 g/dL

• Patients with organ function abnormalities outside of these thresholds deemedto be the result of histiocytic disease will be considered eligible

Exclusion Criteria:

1. Prior therapy with stipulations as described:

• Myelosuppressive Chemotherapy: Must not have received any cytotoxicchemotherapy which impacts the growth and development of cells in the bonemarrow within 14 days of enrollment onto this study (i.e. cytarabine,cladribine, clofarabine, mercaptopurine, methotrexate, vinblastine)

• MEK Inhibitors: Must not have received a MEK inhibitor within 30 days (or 5half-lives, whichever is longer) of enrollment, NOR have had diseaseprogression on MEK inhibitor

• Steroids: Due to the increased risk of an ocular event, the use of systemicoral, inhaled, or ocular glucocorticoid therapy is prohibited within 14 daysprior to first dose of mirdametinib. Throughout the treatment period, shortterm glucocorticoid treatment (30 days or less) is permitted. Any patientsrequiring long-term steroid use (more than 30 consecutive days) are noteligible. The exception to this rule is subjects with endocrine deficiencieswho require physiologic steroids

• Radiation: Must not have received radiation within 14 days of study enrollmentor have received radiation to the orbit at any time

2. Risk factors for retinal vein occlusion (RVO) are listed. Exclusion should beconsidered by clinical discretion if they have any of the following risk factors forRVO at screening:

• Intraocular pressure (IOP) > 21 mmHg; if IOP is unable to be obtained (eg age,cooperation, tolerability), ophthalmologist's exam findings and overallassessment will be utilized. If in the ophthalmologist's assessment there areno signs of raised IOP, the subject will be considered eligible for thisparameter

• Glaucoma or any significant abnormality (≥ grade 2) on ophthalmologic exam thatis uncontrolled with intervention

• Serum cholesterol > 300 mg/dL

• Serum triglycerides > 300 mg/dL

• Hyperglycemia (either fasting blood glucose > 125 mg/dL OR random blood glucose > 200 mg/dL)

• Uncontrolled hypertension (participants ≤ 12 years of age with a blood pressure ≥ 95th percentile for age + 12 mmHg; participants ≥ 13 years of age with ablood pressure ≥ 140/90 mm Hg) unresolved on repeat measurement

3. LVEF < 55% at screening OR history of clinically significant cardiac disease, unlessdeemed to be the direct result of disease

4. Subjects who are pregnant or breastfeeding, or are at risk of pregnancy or fatheringa baby and are unable to use acceptable methods of birth control during the lengthof the study