Pembrolizumab and Tazemetostat to Overcome Immune Tolerance Following ASCT or CAR T-cell Therapy in Patients With Aggressive B-Cell Non-Hodgkin's Lymphoma

Patients who are currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days prior to the first dose of study intervention Exception: Out of spec CAR-T products are permitted

Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) or prior exposure to EZH2 inhibitors

Patients who have received prior radiotherapy within 14 days of start of study intervention

* Note: Patients must have recovered from all radiation-related toxicities, not require corticosteroids; patients with radiation pneumonitis are excluded

* Note: A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease

Patients who have had major surgery within 4 weeks before the first planned dose of tazemetostat (i.e. cycle 2, day 1)

* Note: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to the first planned dose of tazemetostat

Patients with a known history of Human Immunodeficiency Virus (HIV) infection

Patients with a known history of chronic hepatitis B (HBV) infection

* Note: Patients who are hepatitis B surface antigen (HBsAg) positive, have received antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to registration are eligible. Patients should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention

Patients with any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN)

Patients with any prior history of T-cell lymphoblastic lymphoma (T-LBL)/ T cell acute lymphoblastic leukemia (T-ALL) or B cell acute lymphoblastic leukemia (B-ALL)

Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or tazemetostat

Patients receiving medications or substances that are inhibitors or inducers of CYP450 enzymes are eligible as long as they meet the criteria

Patients with a diagnosis of immunodeficiency or patients receiving chronic systemic glucocorticoids (in dosing exceeding 10 mg daily of prednisone equivalent) within 7 days prior to the first dose of study drug. Exceptions are:

* To modulate symptoms of an adverse events (AE) that is suspected to have an immunologic etiology or related to prior CAR T-cell therapy

* For the prevention of emesis

* To premedicate for IV contrast allergies

* To treat chronic obstructive pulmonary disease (COPD) exacerbations (only short-term oral or IV use in doses \>10 mg/day prednisone equivalent)

* For topical use or ocular use

* Intraarticular joint use

* For inhalation in the management of asthma or chronic obstructive pulmonary disease

Patients who have active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs)

* Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed

Patients who have received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention

* Note: Administration of killed vaccines is allowed

Patients who have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

* Note: Patients with radiation pneumonitis are excluded

Patients who have known additional malignancy that is progressing and/or receiving active therapy. Exceptions are patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin. Additionally carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are eligible

Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following:

* Hypertension that is not controlled on medication

* Ongoing or active infection requiring systemic treatment

* Active tuberculosis bacillus (TB) infection

* History of allogenic tissue/solid organ transplant

* Symptomatic congestive heart failure

* Unstable angina pectoris

* Cardiac arrhythmia

* Psychiatric illness/social situations that would limit compliance with study requirements

* Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints

Female patients who are pregnant or nursing

* Note: Pregnant women are excluded from this study because pembrolizumab is a Class D agent with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab and mother should abstain from breast feeding for 6 months. Tazemetostat should also not be used during pregnancy because there is potential risk for teratogenicity

Patients with known active CNS metastases and/or carcinomatous meningitis

Patients with severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients.

Patients with presence of any clinically significant toxicities related to prior anticancer treatment (i.e., chemotherapy, immunotherapy, and/or radiotherapy), excluding transplant or CAR-T planned for current protocol, unless they have either resolved to grade 1 per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 OR are clinically stable and no longer clinically significant at the time the patient provides voluntary written informed

Patients who have had an allogenic tissue/solid organ transplant

Patients with the 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 tazemetostat

Patients with a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator

What this study is about