Outpatient Epcoritamab in Large B-cell Lymphoma

Inclusion Criteria: First Line Cohort * No prior systemic antineoplastic therapy for large B-cell lymphoma. * Score of "frail" or "unfit" on Fondazione Italiana Linfomi simplified Geriatric Assessment (FIL sGA) (Appendix E). Second Line Cohort * Relapsed or refractory disease treated with 1 prior systemic antineoplastic line of therapy that includes an anti-CD20 monoclonal antibody plus an anthracycline and/or an alkylating agent. Patients who have received more than 1 prior systemic antineoplastic line of therapy are not eligible. * Not a candidate for high dose chemotherapy and autologous stem cell transplant per the treating investigator, or patient refusal of high dose chemotherapy and autologous transplant. Both Cohorts * Participants must have large B-cell lymphoma of one of the following histologic subtypes by WHO criteria: * Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) * High grade B-cell lymphoma (HGBCL) with rearrangements of MYC and BCL2 and/or BCL6 * HGBCL NOS * EBV+ DLBCL * Primary mediastinal B-cell lymphoma * T-cell/histiocyte rich LBCL * Grade 3B follicular lymphoma * Large B-cell lymphoma transformed from underlying indolent NHL * PET measurable disease per Lugano criteria (Section 10). * Age ≥18 years. * ECOG performance status 0-2 (Appendix A) * Participants must meet the following organ and marrow function as defined below: * absolute neutrophil count ≥1,000/mcL (Growth factor support as clinically indicated is permitted) * platelets ≥75,000/mcL (\>50,000 in the presence of bone marrow involvement or splenomegaly; platelet transfusions as clinically indicated are permitted) * Hemoglobin ≥8 g/dL (\>7 g/dL in the presence of bone marrow involvement; blood transfusions as clinically indicated are permitted) * Participants must have adequate organ function as defined below (unless abnormalities are considered related to target organ involvement or compression by lymphoma): * total bilirubin ≤ 1.5x institutional upper limit of normal (ULN) (Isolated bilirubin ≤3.0x ULN is acceptable if considered secondary to Gilbert's syndrome) * AST(SGOT) and ALT(SGPT) ≤3.0x institutional ULN * Creatinine clearance ≥40 mL/min eGFR (Cockcroft-Gault or MDRD equation) * PT within institutional normal range (unless on anticoagulation expected to affect PT, in which case PT cut off does not apply) * PTT within institutional normal range (unless on anticoagulation expected to affect PTT, in which case PTT cut off does not apply) * Participants with known history or current symptoms of cardiac disease should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. * Ability to remain within 60 minutes of the administration site for 24 hours following cycle 1 day 15 dose of study drug. * The effects of epcoritamab on the developing human fetus are unknown. Women of child-bearing potential must agree to use adequate contraception starting with the first dose of study drug, for the duration of study participation, and for at least 4 months after the last dose of study intervention. Women must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. * Adequate contraception methods (see Appendix B for further guidance): 1. Male Partner Sterilization: When the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. 2. Use of a combination of any two of the following (one from "a" and one from "b"): 1. Placement of an intrauterine device (IUD) or intrauterine system or established use of oral, injected, or implanted hormonal methods of contraception 2. Barrier methods of contraception: Male Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 3. True abstinence, defined as refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject. Nonchildbearing potential is defined as follows: * ≥45 years of age and has not had menses for at least 12 consecutive months. * Subjects who have been amenorrhoeic for \<1 year must have, on at least two occasions prior to first dose of study drug, a follicle stimulating hormone value greater than 40 IU/L; historical follicle stimulating hormone values are eligible * Post-bilateral oophorectomy (with or without hysterectomy) or post-tubal ligation at least six weeks prior to first dose of study drug. Documented oophorectomy can be confirmed with medical records of the actual procedure or confirmed by imaging (ultrasound or CT). Tubal ligation must be confirmed with medical records of the actual procedure. In the case of oophorectomy alone, reproductive status must be confirmed by follicle stimulating hormone level assessment as above. * Women of childbearing potential (WOCBP) must have a negative highly sensitive serum pregnancy test at screening. * Fertile men, defined as all males physiologically capable of conceiving offspring who are sexually active with a female partner of childbearing potential, must agree to use adequate contraception starting with the first dose of study drug, for the duration of study participation, and 4 months after completion of administration. Men must also agree not to donate sperm during this period. Men may agree to remain abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term or persistent basis) OR agree to use a male condom, and their female partner must use an additional highly effective contraceptive method with a failure rate of \<1% per year when having sexual intercourse if they are a WOCBP (including pregnant females). Please see Appendix B for contraception guidance. * Ability to understand and the willingness to sign a written informed consent document by the participant or a legally authorized representative. Exclusion Criteria: * Participant must not have used an investigational drug or approved systemic lymphoma therapy within 28 days preceding the first dose of study drug. Steroids for lymphoma disease control are permitted but must be stopped at least 7 days prior to the first dose of study drug. * Participants must not have received prior CD20/CD3 bispecific antibody. * Participants must not have received prior autologous or allogeneic stem cell transplant. * Participants must not have received prior anti-CD19 CAR T-cell therapy. * Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) with the exception of alopecia. At the discretion of the overall PI, participants with residual toxicities \> Grade 1 may be considered eligible if in the opinion of the overall PI the residual toxicity is not likely to interfere with the safety or efficacy assessment of the investigational regimen. For residual hematologic toxicities greater than Grade 1, see 3.1.7. * Participants must not have known central nervous system involvement by lymphoma. * Participants must not have a current life-threatening illness, medical condition, or organ system dysfunction (other than the disease under study) which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk. Patients that have mild cognitive impairment or dementia are eligible per investigators' opinion. * Participants must not have an uncontrolled active infection. Localized fungal infection of skin or nails are permitted. * Participants must not have active uncontrolled autoimmune disease. Autoimmune disease under control with chronic systemic corticosteroids at a dose of 10 mg/day of prednisone or less, or equivalent corticosteroid, are eligible. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to epcoritamab. A history of an infusion reaction to CD20-directed therapy is not considered an allergic reaction. * Women who are pregnant are excluded from this study because it is unknown if epcoritamab can cause embryo-fetal harm when administered to a pregnant woman. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with epcoritamab, breastfeeding should be discontinued if the mother is treated with epcoritamab on study. * Participant must not have active uncontrolled HIV infection. Participants with HIV are eligible if disease is adequately controlled on an antiretroviral regimen that is in accordance with the current international AIDS Society guidelines, with adequate control defined by presence of both an undetectable viral load, a CD4 count \>350, no evidence of AIDS-defining illness (with the exception of a lymphoma diagnosis), and no active opportunistic infections (infections controlled on appropriate anti-infective therapy are permitted). * Participant must not have active hepatitis B infection. Participants with positive HBV core antibody or HBV surface antigen at screening are eligible if HBV viral load is negative by PCR and they are on appropriate antiviral therapy. * Participant must not have active hepatitis C infection. Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Note: Participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing. -Subject has no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or has had recent known exposure to someone with SARS-CoV-2 infection, the subject 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 AND negative testing (molecular (e.g., PCR) result or 2 negative antigen test results at least 24 hours). * Participants must not have received a live virus vaccine within 28 days of first dose of study drug. * Participants must not have any known past or current malignancy other than inclusion diagnosis, except for: 1. Cervical carcinoma of Stage 1B or less. 2. Non-invasive basal cell or squamous cell skin carcinoma. 3. Non-invasive, superficial bladder cancer. 4. Prostate cancer with a current PSA level \<0.1 ng/mL. 5. Any curable cancer with a complete response (CR) of \>2 years duration * Uncontrolled seizure disorder * History of Progressive Multifocal Leukoencephalopathy (PML)