Epcoritamab With Dose Adjusted Etoposide, Cyclophosphamide, Vincristine, Doxorubicin, Prednisone and Rituximab (EPOCH-R) for the Treatment of Aggressive B-Cell Non-Hodgkin Lymphoma

Contraindication to any of the individual components of EPOCH-R, including, or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, or known sensitivity or allergy to murine products or if receiving an additional 6 cycles of anthracycline would place patient over the anthracycline lifetime cumulative dose (400 mg/m\^2)

Prior systemic treatment for lymphoma. Prior radiotherapy is allowed provided that this site is not used as a measurable site to assess response

Transformation from indolent lymphoma is allowed provided that the subject has not received prior systemic therapy for their lymphoma and the aggressive component meets one of the criteria listed in inclusion criterion

Prior organ transplantation

Current grade \> 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease

Prior systemic therapy for indolent lymphoma

Prior therapy for large B-cell lymphoma except for patients who require lymphoma symptom control during screening may receive steroids and/or 1 cycle of chemoimmunotherapy in the following manner:

* Up to 30 mg/day of prednisone or equivalent may be used for lymphoma symptom control during screening, including prior to finalization of staging (not included as part of pre-phase treatment). If glucocorticoid treatment is urgently required at higher doses for lymphoma symptom control prior to the start of study treatment, tumor assessments must be completed prior to initiation of \> 30-100 mg/day of prednisone or equivalent. Prednisone \> 30-100 mg/day or equivalent may be given for a maximum of 7 days as a pre-phase treatment. If patients exceed the allowed dosing of corticosteroids, patients may still be eligible for the study provided that baseline imaging is performed (or repeated) after completion of the course of higher dose of steroids. Allowed corticosteroid dosing resets from the point of imaging forward and patients who do not exceed the allowed corticosteroid dosing from the point of imaging until initiation of study treatment may enroll. A maximum of 1 cycle of chemoimmunotherapy is allowed if needed for urgent disease stabilization if patient had staging PET/CT and LVEF evaluation prior to chemoimmunotherapy; in this situation patients will receive therapy on study starting with cycle (C)1 day (D)8 epcoritamab provided the next cycle of EPOCH-R chemotherapy will not be delayed by \> 7 days. In this situation, the date of receiving the first dose of EPOCH-R is considered C1D1 of the study treatment. Labs collected prior to C1D1, in accordance with SOC for the administration of these drugs, can be used for screening purposes

History of other malignancy that could affect compliance with the protocol or interpretation of results except with permission of the principal investigator. The following are eligible without a specific waiver:

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

* Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible.

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

Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)

Recent major surgery (within 4 weeks prior to the start of cycle 1), other than for diagnosis

History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third degree heart block, or evidence of prior myocardial infarction in the last 6 months

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) which requires systemic treatment. Patients may proceed with screening during treatment for infection, but systemic treatment must be completed by cycle 1 day 1.

* If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the subject must have a negative molecular (e.g., polymerase chain reaction \[PCR\]) test or 2 negative antigen test results at least 24 hours apart. Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen-failed and may only rescreen if the following have been met:

* At least 10 days since first positive test result have passed in asymptomatic patients or at least 10 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms

Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology):

* Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable at the time of screening. These patients must be willing to undergo monthly DNA testing and appropriate antiviral therapy as indicated by institutional standard

Positive test results for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing)

* Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

History of uncontrolled HIV

* Patients with known diagnosis of HIV must have undetectable viral load and be on anti-retroviral therapy

Patients with a history of progressive multifocal leukoencephalopathy

Patients with known active central nervous system lymphoma

Patients needing a treatment regimen which would require use of mid-cycle high dose IV methotrexate for central nervous system (CNS) prophylaxis in the opinion of the treating provider

Pregnancy or lactation or intending to become pregnant during study

What this study is about