Epcoritamab and Tazemetostat for the Treatment of Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Assent, when appropriate, will be obtained per institutional guidelines
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies

  * If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Age: ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) ≤ 2
* Histologically confirmed follicular lymphoma, grades 1-3A
* Relapsed/ refractory disease after at least one line of prior lymphoma therapy
* Radiologically measurable lymphadenopathy (≥ 1.5 cm) or ≥ 1 measurable extranodal lesion (long axis \> 1.0 cm) on CT scan or magnetic resonance imaging (MRI)
* Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
* WITHOUT BONE MARROW INVOLVEMENT: Absolute neutrophil count (ANC) ≥ 1,000/mm\^3 (NOTE: Growth factor use is allowed to reach ANC)
* WITH BONE MARROW INVOLVEMENT: ANC ≥ 500/mm\^3 (NOTE: Growth factor use is allowed to reach ANC)
* WITHOUT BONE MARROW INVOLVEMENT: Platelets ≥ 50,000/mm\^3 (NOTE: Platelet transfusions are within 14 days of platelet assessment if thrombocytopenia is secondary to disease involvement)
* WITH BONE MARROW INVOLVEMENT: Platelets ≥ 25,000/mm\^3 (NOTE: Platelet transfusions are within 14 days of platelet assessment if thrombocytopenia is secondary to disease involvement)
* Total bilirubin ≤ 2 x upper limit of normal (ULN) (unless has Gilbert's disease or secondary to disease)
* Aspartate aminotransferase (AST) ≤ 2.5 x ULN
* Alanine aminotransferase (ALT) ≤ 2.5 x ULN
* Creatinine clearance of ≥ 45 mL/min per 24 hour urine test or the Cockcroft-Gault formula
* If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN; If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
* If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN; If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
* Fridericia's formula-corrected QT interval (QTcF) ≤ 480 ms (Note: To be performed within 28 days prior to day 1 of protocol therapy)
* If seropositive for HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), nucleic acid quantitation must be performed. Viral load must be undetectable. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* Meets other institutional and federal requirements for infectious disease titer requirements (Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy)
* Women of childbearing potential (WOCBP): negative serum pregnancy test
* Agreement by females of childbearing potential must agree to either abstain from heterosexual intercourse or to use two effective methods of birth control simultaneously (effective methods described below). The time period for effective contraceptive requirements begins ≥ 28 days prior to initiating tazemetostat and for the course of the study treatment period through at least 6 months after the last dose of tazemetostat, 4 months after the last dose of epcoritamab, or 4 months after the last dose of tocilizumab (if applicable), whichever is longer. Childbearing potential is defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only). Two effective methods includes one highly effective method and one barrier method.

  * Highly effective methods:

    * Intrauterine device (IUD)
    * Intrauterine hormone-releasing system (IUS)
    * Hormonal (stopping ovulation with two drugs \[estrogen and progesterone\]: oral, within the vagina, or on/under the skin; stopping ovulation with one drug progesterone-only: oral, injected, or on/under the skin). NOTE: Due to the potential of tazemetostat interference with hormonal contraception methods, use of these method requires that you add a barrier method of contraception (preferably male condom)
    * Bilateral tubal ligation
    * Partner's vasectomy (if medically confirmed there are no live sperm and sole sexual partner)
  * Barrier methods:

    * Male latex or synthetic condom
    * Diaphragm
    * Cervical cap
* Agreement by males to either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual contact with a female of childbearing potential from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation. NOTE: Male subjects must not donate semen or sperm from first dose of tazemetostat, during study treatment (including during dose interruptions), and for 3 months after discontinuation of tazemetostat

Exclusion Criteria:

* Concurrent enrollment in another therapeutic investigational study
* Prior bispecific antibodies or tazemetostat
* Autologous stem cell transplant within 30 days prior to day 1 of protocol therapy
* Allogeneic stem cell transplant if complicated by active graft versus host disease (GVHD) or if on immunosuppressive agents
* Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days or five half-lives (whichever is shorter for non-radiation therapy) prior to day 1 of protocol therapy
* Immunosuppressive agents other than prednisolone 20 mg daily or equivalent
* Major surgery within 4 weeks of first dose of study drug
* Vaccination with live vaccines within 4 weeks of the first dose of study drug
* Strong and moderate CYP3A4 inducers/ inhibitors within 14 days prior to day 1 of protocol therapy
* Current evidence of central nervous system involvement by the lymphoma
* Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia, or NYHA (New York Heart Association) heart failure class III-IV, or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months of screening
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
* History of active human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV)

  * Participants who are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded
* Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

  * If a patient has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection, the patient must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection

    * Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/recommendations
  * Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:

    * No signs/symptoms suggestive of active SARS-CoV-2 infection
    * Negative molecular (e.g., PCR) result or 2 negative antigen test results at least 24 hours apart
    * SARS-CoV-2 testing is only required if a patient has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection. Patients who fit this description must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection
* Clinically significant uncontrolled illness
* Uncontrolled active systemic infection
* Any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN) or any prior history of T lymphoblastic leukemia (T-LBL)/T acute lymphoblastic leukemia (T-ALL) or B acute lymphoblastic leukemia (B-ALL)
* Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Exceptions are:

  * Malignancy treated with curative intent and no known active disease present for ≥ 3 years prior to initiation of therapy on current study
  * Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease
  * Adequately treated in situ carcinomas (e.g., breast, cervical, esophageal, etc.) without evidence of disease
  * Asymptomatic prostate cancer managed with "watch and wait" strategy or hormonal therapy
* Inability to take oral medication or have malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat
* Females only: Pregnant or breastfeeding
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)