• Histologically confirmed peripheral T-cell lymphomas (PTCL) with allowed subtypes listed below as per the revised World Health Organization 2022 classification \[6\]:

• PTCL subtypes allowed

‣ PTCL-not otherwise specified (NOS)

‣ Nodal T-follicular helper cell lymphoma - angioimmunoblastic type, follicular type, or NOS

‣ Anaplastic Large Cell Lymphoma (ALK+)

‣ Enteropathy-associated T-cell lymphoma

‣ Monomorphic epitheliotropic intestinal T-cell lymphoma

‣ Hepatosplenic T-cell lymphoma

‣ Subcutaneous panniculitis-like T-cell lymphoma

‣ Adult T-cell leukemia / lymphoma - lymphomatous, acute, or unfavorable chronic subtypes

• Patients must have relapsed or refractory disease.

∙ Relapsed disease is defined when a patient progressed (\>3 months) after achieving CR with a previous treatment

‣ Refractory disease is defined when a patient failed to achieve a CR or PR after a previous treatment

• Patients received at least 1 prior therapy for PTCL.

• At least one bi-dimensionally measurable nodal lesion, defined as ≥ 1.5 cm in its longest dimension, or one bi-dimensionally measurable extranodal lesion, defined as ≥ 1.0 cm in its longest diameter on fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan as defined by response criteria for PTCL

• Age ≥ 18.

• Patients with Hepatitis C can be included if they have completed therapy for hepatitis C with undetectable viral load.

• Patients with Hepatitis B can be included if they are on suppressive therapy for hepatitis B infection and with no detectable viral load.

• Patients with HIV can be included if they are on appropriate antiretroviral therapy, there is no interaction with the study drug, a CD4+ T-cell counts ≥ 350 cells/µL and no detectable viral load.

• Adequate organ function as defined below unless attributed to disease involvement (Note: transfusions and growth factors allowed during screening; however, transfusion-dependency defined as requiring blood products ≥once per week not allowed):

• i. Liver function: No more than moderate hepatic impairment per NCI ODWG criteria - Total bilirubin ≤ 3X upper limit of normal (ULN), AST ≤ ULN (unless attributed to fatty liver or disease involvement).

• ii. Kidney function: CrCl \> 30ml/min using Cockroft-Gault, based on actual weight.

• iii. ANC ≥ 1,000/µL, Platelet Count ≥ 75,000/ µL, Hemoglobin ≥ 8.0 g/dl.

⁃ Left ventricular ejection fraction (LVEF) defined by multiple-gated acquisition (MUGA) scan or echocardiogram within the institutional limits of normal.

⁃ Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2.

⁃ A negative urine or serum pregnancy test is required for all women of childbearing potential within 1 week prior to enrolling on this trial and within 3 days of first dose of study drug. Note: Urine pregnancy tests that cannot be confirmed as negative require a confirmatory negative serum pregnancy test.

⁃ Non-childbearing potential is defined as:

‣ Postmenopausal: Defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, FSH measurements indicating post-menopausal status must be documented in patient's medical history.

‣ Permanently sterile: Documented permanent sterilization e.g., hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

⁃ If female of childbearing potential, subject must not be pregnant or be breastfeeding and is required to have a negative urine or serum pregnancy test within 3 days prior to the first dose of study drug. In addition, females of childbearing potential must either practice complete abstinence or agree to use two effective methods of contraception simultaneously, beginning ≥ 28 days prior to start of tazemetostat, during tazemetostat treatment, and for at least 6 months after final dose of tazemetostat. See Appendix E regarding contraception guidelines.

⁃ Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom during any sexual contact with a female of childbearing potential, from first dose of tazemetostat, during study treatment including dose interruptions, and for 3 months after last dose of tazemetostat. This applies even to males who have undergone successful vasectomy with medically confirmed azoospermia.

⁃ Willing and able to participate in all required evaluations and procedures in this study protocol including receiving intravenous administration of investigational product and being admitted, when required, for at least 24 hours during investigational product administration.