This is a single center Phase 0 "window of opportunity" trial for the treatment of newly diagnosed, PRC2 deficient, primary malignant peripheral nerve sheath tumors (MPNSTs) with a short course of the combination of mirdametinib and vorinostat prior to the most appropriate standard of care treatment for their specific tumor (typically localized radiation followed by surgical resection). Four to eight patients, 12 years of age or older and meeting the study's biomarker inclusion criteria, would be enrolled onto this trial. After voluntary written consent (assent with parent consent for minors) the patient undergoes MRI and PET imaging of the tumor and a needle biopsy to collect tumor is performed. Patients with histone H3K27 trimethylation deficient MPNST, as confirmed by immunohistochemistry, receive a single 28-day course of mirdametinib and vorinostat at standard oral dosing for each. At day 26, 27, or 28 the patient returns to clinic for a research visit repeating the baseline MRI and PET imaging and the needle biopsy for tumor tissue.

This ends direct study participation. The patient goes on to the most appropriate standard of care treatment for their MPNST. Information about the subsequent standard of care treatment is collected for the purposes of this study.

Inclusion Criteria:

• Known Neurofibromatosis type 1 (NF-1) syndrome based on current diagnostic criteria.
• Diagnosis of suspected MPNST by PET or MRI imaging
• Confirmation of histone H3 lysine 27 trimethylation-negative MPSNT 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 1 st dose of study drug.
• Must be able to swallow capsules.
• Females of childbearing potential must use highly effective contraception (see inclusion criteria section) from the time of study enrollment through 6 months after the last dose of vorinostat and mirdametinib. 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.
• 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 or urine) within 7 days prior to the 1 st dose of the study drugs.
• Significant cardiac disease
• Significant eye disease
• Radiation therapy or chemotherapy in the past year.