Epcoritamab in Combination With R-CHOP for Patients With Aggressive Non-Hodgkin Lymphoma

Inclusion Criteria: 1. Participants must have confirmed CD20-positive aggressive B-cell lymphoma, including de novo or transformed diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; primary mediastinal large B-cell lymphoma (PMBCL); T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL); Epstein-Barr virus-positive DLBCL, NOS; or follicular lymphoma grade 3b. 2. Measurable disease per Lugano 2014 criteria. 3. No prior therapy for DLBCL or FL G3B other than corticosteroids or palliative radiotherapy. Of note, a cycle of anthracycline-containing regimen (given as standard of care prior to study enrollment) is allowed, provided that patients will receive a total of six cycles of chemotherapy as part of their treatment plan. Patients who received one cycle of an anthracycline-containing regimen prior to enrollment will proceed directly to Cycle 2 on study. 4. Age ≥18 years 5. Participants must have an International Prognostic Index (IPI) score of 2-5. 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%) 7. Demonstrates adequate organ function as defined below: Adequate bone marrow function: absolute neutrophil count platelets * 1.0 × 10⁹/Litre (L) (with growth factor use allowed) * 75 × 10⁹/L Exceptions: Patients may be enrolled despite not meeting the thresholds above if either of the following applies, provided the Absolute Neutrophil Count (ANC) is ≥0.75 × 10⁹/L: 1. The patient has received one prior cycle of chemotherapy off study, and cytopenias at Cycle 2, Day 1 of protocol therapy are believed to be due to recent chemotherapy, provided there is evidence of marrow recovery and no other contraindications. 2. The patient has documented bone marrow involvement by lymphoma, and cytopenias are believed to be disease-related rather than indicative of poor marrow reserve or unrelated pathology. In such cases, enrollment is permitted at the discretion of the investigator if the patient is otherwise eligible and deemed safe to proceed. Adequate hepatic function: Total bilirubin ≤2 × upper limit of normal (ULN) (unless due to Gilbert's) Aspartate aminotransferase (AST) Serum glutamic-oxaloacetic transaminase (SGOT) ≤3 × institutional upper limit of normal Alanine aminotransferase (ALT) Serum glutamic-pyruvic transaminase (SGPT) ≤3 × institutional upper limit of normal Adequate renal function: As assessed by estimated glomerular filtration rate (eGFR) Coagulation: Prothrombin time (PT) International Normalized Ratio (INR) and Activated partial thromboplastin time aPTT ≤1.5 × ULN, unless receiving anticoagulation therapy 8. Left ventricular ejection fraction (LVEF) ≥50% by multigated acquisition (MUGA) or echocardiography at screening. 9. Ability to understand and the willingness to sign a written informed consent document. 10. .Human immunodeficiency virus (HIV)-infected individuals are eligible if the following criteria are met: 1. Serum HIV viral load is \< lower limit of detection (LLD) and controlled with antiretroviral therapy for at least 1 year prior to enrollment, with confirmatory testing at screening; 2. CD4 count ≥ 200 cells/microliter (μL) at screening; 3. Subject is receiving antiretroviral regimens in accordance with current International Acquired Immunodeficiency Syndrome (AIDS) Society guidelines; 4. No evidence of AIDS-defining illnesses (other than lymphoma diagnosis) or active opportunistic infections; 5. Antiretroviral therapy does not interfere with study medications. 11. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. 12. Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. 13. Individuals 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. 14. The effects of epcoritamab on the developing human fetus are unknown. For this reason, and because bispecific antibodies may be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, or abstinence). Woman with reproductive potential must agree to use adequate contraception during the trial, and for 12 months after the last administration of epcoritamab or according to the local prescribing information of the standard of care (SOC) regimens, whichever is the longest. Adequate contraception is defined as highly effective methods of contraception. Also refer to the local prescribing information for information regarding contraceptive requirements for the SOC regimens. 15. A woman of childbearing potential must have a negative serum (beta-hCG) pregnancy test at screening and a negative urine pregnancy test before treatment administration on Day 1 of every cycle. 16. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for 12 months after receiving the last dose of epcoritamab or according to the local prescribing information of the SOC regimens, whichever is the longest. 17. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the trial and for 12 months after receiving the last dose of epcoritamab or according to the local prescribing information of the SoC regimens, whichever is the longest. 18. Participants must agree not to donate blood for 60 days after receiving the last dose of trial treatment. 19. Participants must have a treating physician at University of California, San Francisco (UCSF) or Zuckerberg San Francisco General Hospital (ZSFGH), receive study treatment under the supervision of the study Principal Investigator or qualified study sub-investigators at the enrolling site, and be willing to comply with study procedures. Exclusion Criteria: 1. History of severe allergic or anaphylactic reactions to anti-CD20 mAb therapy or known allergy or intolerance to any component or excipient of epcoritamab. 2. Any prior treatment with a bispecific antibody targeting CD3 and CD20. 3. Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to the first dose of epcoritamab. 4. Requiring immunosuppressive therapy for an ongoing baseline medical condition. For corticosteroids, prednisolone \>10 mg daily (or equivalent) qualifies as immunosuppressive and thus be excluded for this use. Note: corticosteroids at any dose are permitted for control of lymphoma related symptoms, including during screening, and for any adverse events (AE) management during study. 5. Vaccination with live vaccines within 28 days prior to the first dose of epcoritamab. 6. Clinically significant cardiovascular disease, including: 1. Myocardial infarction within 6 months prior to the first dose of epcoritamab, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure New York Heart Association Class III-IV), cardiac arrhythmia (NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5 Grade 3 or higher), or clinically significant electrocardiogram (ECG) abnormalities 2. Screening 12-lead ECG showing a baseline QT Corrected for Heart Rate using Fridericia's Formula (QTcF) \>470 msec 3. Stroke within 6 months prior to first epcoritamab dose 7. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at trial enrolment or significant infections within 2 weeks prior to the first dose of epcoritamab. 8. Active hepatitis B Virus (HBV) (Deoxyribonucleic Acid Polymerase Chain Reaction (DNA PCR) -positive) or hepatitis C (Ribonucleic Acid Polymerase Chain Reaction (RNA PCR) -positive infection). Subjects with evidence of prior HBV but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy. Subjects who received treatment for Hepatitis C Virus (HCV) that was intended to eradicate the virus may participate if hepatitis C Ribonucleic acid (RNA) levels are undetectable. 9. 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 Prostate-Specific Antigen (PSA) level \< 0.1 ng/milliliter (mL) 5. Any curable cancer with a complete response (CR) of \> 2 years duration. 10. Neuropathy \> grade 1 with the exception of neuropathy directly related to lymphoma (e.g., direct nerve compression from tumor). 11. . Female who is pregnant, breast-feeding, or planning to become pregnant while enrolled in this trial or within 12 months after the last dose of epcoritamab; female subjects must also agree not to breastfeed during the entire trial and until 12 months after the last administration of study drug. 12. Male who plans to father a child while enrolled in this trial or within 12 months after the last dose of epcoritamab. 13. Contraindication to any of the individual drugs of the R-CHOP regimen.