Mirdametinib and Vorinostat for the Treatment of Neurofibromatosis Type 1 and Histone H3 Lysine 27 Trimethylation-Negative Malignant Peripheral Nerve Sheath Tumors

Inclusion Criteria

• Known neurofibromatosis type 1 (NF-1) syndrome based on current diagnostic criteria
• Diagnosis of suspected primary malignant peripheral nerve sheath tumor (MPNST) by PET or MRI imaging
• Confirmation of histone H3 lysine 27 trimethylation-negative MPNST by immunohistochemistry
• Twelve years of age or older
• Complete blood count (CBC), platelet, liver and kidney function within institutional normal limits performed within 14 days of 1st dose of study drugs
• Must be able to swallow capsules
• Females of childbearing potential must use highly effective contraception (intrauterine device, surgical sterilization, hormonal contraception, contraceptive rod, abstinence) from the time of study enrollment through 6 months after the last dose of vorinostat and mirdametinib * Barrier methods such as condoms (male or female) or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream or vaginal suppository must be used in addition to hormonal contraception * Examples of highly effective birth control methods include the following: ** Using twice the normal protection of birth control (i.e., double-barrier) by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier method (e.g., condom or diaphragm). *** Oral contraceptive pills *** Depot or injectable birth control *** Intrauterine device (IUD) *** Transdermal contraceptive patch *** Vaginal contraceptive ring * Note: The rhythm method or abstinence alone are not considered adequate methods of contraception. * Males with partners of childbearing potential must use highly effective contraception from the time of study enrollment through 3 months after the last dose of vorinostat and mirdametinib
• Provides voluntary written consent prior to any study related activities, with parental/guardian consent and assent for those 12 to 17 years of age at enrollment

Exclusion Criteria

• Pregnant or breastfeeding – females of childbearing potential must have a negative pregnancy test (serum and urine) within 7 days prior to the 1st dose of the study drugs
• Significant cardiac disease * Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented * Patients who have a Bazett's formula corrected QT interval (QTcB) ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 50% are not eligible for enrollment * Symptomatic heart failure * New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy * Severe valvular heart disease * History of atrial fibrillation
• Ophthalmologic conditions: * Current or past history of central serous retinopathy * Current or past history of retinal vein occlusion (RVO) or retinal detachment * Uncontrolled glaucoma - If checking pressure is clinically indicated, patients with intraocular pressure (IOP) > 22 mmHg or upper limit of normal (ULN) adjusted by age are not eligible * Comorbidities that put undue risk of RVO such as uncontrolled hypertension (HTN) (chronic systolic blood pressures > 160 mm Hg) and/or uncontrolled diabetes mellitus type 2 (DM II) (chronic clinical signs/symptoms of hyperglycemia and/or an glycosylated hemoglobin [A1c] value > 9%)
• Radiation therapy or chemotherapy in the past year
• Participants receiving systemic or ocular glucocorticoid therapy (with the exception of participants with endocrine deficiencies who are allowed to receive physiologic or stress doses of steroids, if necessary) within 14 days prior to the first dose of study treatment
• Suspected primary malignant peripheral nerve sheath tumor in proximity to any vital neurovascular structures that would be considered a high risk during a needle biopsy procedure
• Participants receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible. Lists including medications and substances known or with the potential to interact with the CYP3A4 isoenzymes, including but not limited to * Strong Inducers (e.g, rifampin, rifabutin, etc.) * Strong Inhibitors (ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin, grapefruit juice) * Moderate Inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifapentine, St. John’s Wort) * Moderate Inhibitors (e.g., bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, ritonavir, indinavir, broceprevir, telaprevir, metoclopramide, nicardipine, troleandomycin, verapamil, grapefruit juice)
• During eligibility screening, potential patients will be screened for hepatitis B, per national guidelines. Patients found to have hepatitis B will be excluded