Tazemetostat Plus CHOP in 1L T-cell Lymphoma

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed peripheral T celllymphoma of one of the following subtypes: PTCL-NOS, Follicular helper T-celllymphoma (ICC 2022) or Nodal T-follicular helper (TFH) cell lymphoma by (WHO 2022)which includes follicular helper T-cell lymphoma, AITL and follicular helper T celllymphoma, follicular type, EATL, MEITL. All pathology will be reviewed at BWH. BWHreview is not required prior to enrollment and patients may be enrolled based uponlocal pathology analysis. Ten blank slides will be required from outside tumorbiopsy for correlative studies.

• No prior treatment for T NHL with the exception of one cycle of CHOP or CHOEP or 7days of corticosteroids at a dose of up to prednisone 60 mg or equivalent forpalliation of disease related symptoms so long as the corticosteroids arediscontinued prior to tazemetostat prephase or cycle 1 of treatment if not receivingthe prephase.

• At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longestdimension as measured by CT.

• Age ≥18 years.

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).

• Participants must have adequate organ and marrow function as defined below:

• absolute neutrophil count ≥1,000/mcL (750 mcl if bone marrow involvement withlymphoma)

• platelets ≥75,000/mcL (25,000 if bone marrow involvement with lymphoma)

• total bilirubin ≤ institutional upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN

• creatinine ≤ 1.5 x institutional ULN OR

• glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2

• Because the effects of tazemetostat on human immunodeficiency virus (HIV)-infectedparticipants and anti-retroviral therapy is unknown, patients with known HIVinfection are not eligible for this trial.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. Participants with HCV infection who are currently on treatment,are not eligible.

• Left ventricular ejection fraction of > 50% as assessed by echocardiography ormulti-gate acquisition (MUGA) scan.

• The effects of tazemetostat on the developing human fetus are unknown. For thisreason and because other therapeutic agents used in this trial are known to beteratogenic, women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. For women ofchildbearing potential, a negative serum pregnancy test result within 7 days priorto commencement of dosing. Women who are considered not to be of childbearingpotential are not required to have a pregnancy test.

• Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 3months after completion of tazemetostat administration.Women should use effectivecontraceptive methods beginning ≥28 days prior to initiating, during tazemetostattreatment, and for at least 6 months after the final dose of tazemetostat

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Participants who have had chemotherapy for T cell lymphoma prior to entering thestudy (except 1 cycle of CHOP/CHOEP as noted above). Prior radiotherapy may beallowed after discussion with the sponsor-investigator so long as the area radiatedwas not the only measurable site of disease.

• Participants who are receiving any other investigational agents.

• Patients with known central nervous system involvement with lymphoma

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to tazemetostat or other agents used in study.

• Prior organ transplantation.

• Current motor or peripheral neuropathy with grade >1.

• History of other malignancy that could affect compliance with the protocol orinterpretation of results. Exceptions include:

• Patients with a history of curatively treated basal or squamous cell carcinomaor melanoma of the skin or in situ carcinoma of the cervix at any time prior tothe study are eligible.

• Patients with any malignancy appropriately treated with curative intent and themalignancy has been in remission without treatment for > 2 years prior toenrollment are eligible.

• Patients with low-grade, early-stage prostate cancer (Gleason score 6, Stage 1or 2) with no requirement for therapy at any time prior to study are eligible.

• Uncontrolled intercurrent illness.

• Pregnant women and women intending to become pregnant are excluded from this studybecause chemotherapeutic agents used in this study have the potential forteratogenic or abortifacient effects. Because there is an unknown but potential riskfor adverse events in nursing infants secondary to treatment of the mother withtazemetostat, breastfeeding should be discontinued if the mother is treated withtazemetostat.

• Evidence of significant, uncontrolled, concomitant diseases that could affectcompliance with the protocol or interpretation of results, including significantcardiovascular disease (such as New York Heart Association Class III or IV cardiacdisease, myocardial infarction within the last 6 months, unstable arrhythmias, orunstable angina)

• Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than fordiagnosis

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or significantinfections within 2 weeks before the start of Cycle 1.

• Inability to swallow pills.

• Because no dosing or adverse event data are currently available on the use oftazemetostat in combination with CHOP in participants <18 years of age, children areexcluded from this study, but will be eligible for future pediatric trials.