Tazemetostat in Malignant Peripheral Nerve Sheath Tumors

Inclusion Criteria: * A histologic confirmation of recurrent/refractory and/or metastatic malignant peripheral nerve sheath tumor with Response Evaluation Criteria in Solid Tumors (RECIST) measurable disease * Patients ≥ 12 years of age at the time of enrollment * Performance status: 12-15 years old: Lansky \> 50; 16-17 years old: Karnofsky \> 50; ≥ 18 years old: Eastern Cooperative Group (ECOG) score 0-2 * Subjects must have adequately recovered from the acute toxic effects of all prior anti-cancer therapy per enrolling physician and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. * Anti-cancer agents known to be Myelosuppressive: ≥ 28 days after the last dose of agent. * Anti-cancer agents not known to be myelosuppressive: \> 7 days after the last dose of agent. * Antibodies: \> 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to Grade \< 1. * Systemic Corticosteroids: if related to prior therapy \> 14 days must have elapsed, or on stable dose for treatment of CNS disease. * Hematopoietic growth factors: \> 14 days after the last dose of a long-acting growth factor. * Interleukins, Interferons, and Cytokines (other than hematopoietic growth factors): \> 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors). * Radiation therapy (XRT)/External Beam Irradiation including Protons: \> 14 days after local XRT; \> 150 days after traumatic brain injury, craniospinal XRT or if radiation to \> 50% of the pelvis; \> 42 days if other substantial bone marow radiation. * Radiopharmaceutical therapy: \> 42 days after systemically administered radiopharmaceutical therapy. * Major surgery \> 14 days prior, with evidence of wound healing and no active surgical complications * Subjects must not have had prior exposure to Tazemetostat or other inhibitor(s) of EZH2 * Adequate laboratory values of organ function, defined as: * Peripheral absolute neutrophil count (ANC) \> 1000/mm3. * Platelet count \> 100,000/mm2 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). * Hemoglobin \> 8.0 g/dL at baseline (may receive RBC transfusions). * Creatinine clearance or radioisotope GFR \> 70 ml/min/1.73 m2, or serum creatinine based on age/gender * Total bilirubin \< 1.5 ULN or direct bilirubin \< 1 x ULN. * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5 x ULN; if liver metastases present, then AST and ALT must be \< 5 x ULN. * Serum albumin \> 2 g/dL. * Coagulation INR \< 1.5, while on anti-coagulation INR \< 2.5. * Nervous system disorders (CTCAE v5.0) resulting from prior therapy must be \< Grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible. * Subjects must not have more than one active malignancy at the time of enrollment * Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures. All subjects and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional standard practice. * Use of contraception: * Women of childbearing potential (WOCBP) who are heterosexually active must be using two highly effective methods of contraception to avoid pregnancy throughout the study and for at least 6 months after the last dose of study drug to minimize the risk of pregnancy as Tazemetostat might counteract the effects of hormonal contraceptives. Birth control methods that can be used while in this study include: established use of oral, injected or implanted hormonal birth control or placement of an intrauterine device \[IUD\] or intrauterine system \[IUS\]. They or their partner must also use a second method, (e.g., condom with spermicidal foam/gel/film/cream/suppository or occlusive cap \[diaphragm or cervical/vault caps\] with spermicidal foam/gel/film/cream/suppository. If their male partner is vasectomized, they do not need to use any of the birth control methods listed above. The type of birth control they use must be discussed with the study doctor before beginning the study. The study doctor must approve the method you use before they can enter the study. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. * Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms,vasectomy) throughout the study and should avoid donating sperm, for 90 days following the last dose of study drug. Exclusion Criteria: * Subjects who are currently taking the following concomitant medications: * Anti-cancer Agents: Subjects who are currently receiving other anti-cancer agents are not eligible. * CYP3A4 Agents: Subjects who are currently receiving drugs that are strong inducers or strong inhibitors of CYP3A4 are not eligible. Strong inducers or inhibitors of CYP3A4 are prohibited from 14 days prior to the first dose of Tazemetostat to the end of the study. Note: Dexamethasone for CNS tumors or metastases, on a stable dose, is allowed. * Grapefruit, grapefruit juice, Seville oranges and food/drinks containing them should be avoided one week before the first dose of the study intervention * Subjects who are acutely ill with an uncontrolled active infection on systemic anti-infective agents are not eligible. * Subjects with a prior history of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL) or other myeloproliferative neoplasm (MPN). * Subjects who have any of the following underlying major cardiac issues or conditions: * Known QTc prolongation or documentation * Documented New York Heart Association (NYHA) Class III or IV congestive heart failure. * Myocardial infarction within 6 months prior to registration. * Unstable angina within 6 months prior to registration. * Symptomatic arrhythmia. * Subjects who in the opinion of the investigator may be high risk for treatment complications or unable to comply with the safety monitoring requirements of the study * Heterosexually active males or females of reproductive potential may not participate unless they have agreed to use two highly effective contraceptive methods for the duration of study treatment as Tazemetostat might counteract the effects of hormonal contraceptives. Female subjects of childbearing potential should agree to remain abstinent or use adequate contraceptive methods for 6 months after the last dose of Tazemetostat. Male subjects should agree to remain abstinent or use adequate contraceptive methods, and agree to refrain from donating sperm, and for 90 days after the last dose of Tazemetostat. * Females who are pregnant or breastfeeding will not be entered on this study because there is currently no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. * Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose. Non-live versions of the COVID-19 vaccine are allowed. * Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness. * Known hypersensitivity to tazmetostat or any component of the formulation of tazemetostat * Inability to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of tazmetostat