Inclusion Criteria:

• Previously untreated, histologically confirmed DLBCL according to World Health Organization (WHO) 2016 classification

  • Documented CD20+ mature B-cell neoplasm according to WHO classification (Swerdlow et al., 2016) or WHO classification (WHO, 2008) based on representative pathology report

    • Diffuse large B-cell lymphoma note: Other double-/triple-hit lymphomas are not eligible

  • Untreated patients who transform from low grade marginal zone lymphoma (MZL)

  • Other aggressive B-non-hodgkin lymphoma (NHL):

    • Primary mediastinal (thymic) large B-cell lymphoma (PMBCL)
    • High-grade B-cell lymphoma
    • Newly diagnosed follicular lymphoma grade 3B (FL 3B)

• At least one bi-dimensionally measurable nodal lesion, defined as > 1.5 cm in its longest dimension, or one bi-dimensionally measurable extranodal lesion, defined as > 1.0 cm in its longest diameter

• Age > 80 years, or age 70-79 years and not considered a candidate for full-dose aggressive chemotherapy (R-CHOP) with at least one of the following:

  • Impairment in > 2 activity of daily living (ADL) component and/or
  • Impairment in > 2 instrumental activity of daily living (IADL) component and/or
  • Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score of at least 1 comorbidity with a severity score of 3-4 (not including lymphoma and hematologic deficiencies due to lymphoma) or a score of 2 in > 8 comorbidities.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Life expectancy of at least 24 weeks

• No significant pulmonary comorbidities (e.g., history of pneumonitis, severe chronic obstructive pulmonary disease [COPD])

• Left ventricular ejection fraction ≥ 45%

• Creatinine clearance > 40 mL/min

  • Exceptions may be made for patients with creatinine clearance < 40 mL/min, provided creatinine is within normal range

• Hemoglobin > 9 g/dL

• Absolute neutrophil counts ≥ 1.0 × 10^9/L; growth factor support allowed in case of bone marrow involvement

• Platelet counts ≥ 75 × 10^9/L or, in the presence of bone marrow involvement or splenomegaly, ≥ 50 × 10^9/L

• Lymphocyte counts < 5 × 10^9/L

• If receiving glucocorticoid treatment at screening, must be a maximum daily dose of prednisone 100 mg (or equivalent) and a total of no more than 140 mg over the last 14 days prior to the first dose of epcoritamab, unless for disease control

• Before the first dose of epcoritamab, during the trial and for 12 months after last administration of epcoritamab, a woman must be either:

  • Not of childbearing potential: premenarchal; postmenopausal (> 45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone [FSH] level > 40 IU/L or milli-International unit mIU/mL); permanently sterilized (e.g., bilateral tubal occlusion [which includes tubal ligation procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy

• A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control (that is the use of condom) during the trial and for 12 months after receiving the last dose of epcoritamab

• COVID-19 ELIGIBILITY CRITERIA: Subject has no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

• COVID-19 ELIGIBILITY CRITERIA: If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with 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, to rule out SARS-CoV-2 infection.

  • Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/recommendations

• COVID-19 ELIGIBILITY CRITERIA: 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

• COVID-19 ELIGIBILITY CRITERIA: Patients with SARS-CoV-2 antigen or PCR testing positivity within 30 days prior to cycle 1 day 1 are not eligible

• COVID-19 ELIGIBILITY CRITERIA: Any patient with documented SARS-CoV-2 infection within 6 months prior to planned cycle 1 day 1 must have no persistent respiratory symptoms, no evidence of residual sequelae, and a negative PCR test for SARS-CoV-2

• COVID-19 ELIGIBILITY CRITERIA: Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment (excluding prophylactic treatment) at the time of enrollment or within the previous 2 weeks prior to the first dose of epcoritamab, including COVID-19 infection. Note that a past COVID-19 infection may be a risk factor, but if resolved and the subject is vaccinated, it may be allowable to enroll the subject

Exclusion Criteria:

• Prior treatment for DLBCL with chemotherapy, immunotherapy, and biologic therapy

  • Exception: patients who are treated with prednisone as part of pre-phase treatment

• Current grade > 1 peripheral neuropathy by clinical examination

• Known or suspected chronic active Epstein-Barr virus infection

• Subjects that have transformed from indolent (i) NHL, who have previously been treated with an anthracycline-containing regimen or a CD3-CD20 bispecific antibody

• Patients with known history or suspected history of hemophagocytic lymphohistiocytosis (HLH)

• Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening as confirmed by mandatory magnetic resonance imaging (MRI)/computed tomography (CT) scan (brain) and, if clinically indicated, by lumbar puncture

• Aspartate aminotransferase (AST), and/or alanine aminotransferase (ALT) > 3 × upper limit of normal (within 14 days of initiation of study treatment)

• Total bilirubin > 1.5 × upper limit of normal, unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin (within 14 days of initiation of study treatment)

  • Patients with a documented history of Gilbert syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible

• International normalization ratio (INR) > 1.5 x upper limit of normal (ULN) in the absence of therapeutic anticoagulation (within 14 days of initiation of study treatment)

• Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) > 1.5 x ULN in the absence of a lupus anticoagulant or therapeutic anticoagulant (within 14 days of initiation of study treatment)

• Estimated creatinine clearance (CrCl) < 40 mL/min (within 14 days of initiation of study treatment)

• Known clinically significant cardiovascular disease or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm) including:

  • Unstable arrhythmias
  • Onset of unstable angina pectoris within 6 months of signing informed consent form (ICF)
  • Acute myocardial infarction within 6 months of signing ICF
  • Congestive heart failure (New York Heart Association Class III or IV cardiac disease and/or known decrease ejection fraction of < 45%)
  • Stroke or intracranial hemorrhage within 6 months prior to signing ICF
  • In case of any history of cardiovascular disease, a cardiology consult is required within 60 days of enrollment.
  • For patients who are ≥ 75 years old, 2 or more active cardiovascular diseases (any type, ≥ grade 2)

• Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy including, but not limited to, myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

• Low-dose (≤ 10 mg/day) prednisolone (or equivalent) for rheumatoid arthritis or similar conditions is allowed

• Received systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment < 10 mg/day prednisone or equivalent within 2 weeks prior to first the dose of study drug

• 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 DNA is undetectable at the time of screening. These patients must be willing to undergo monthly DNA testing and appropriate antiviral therapy as indicated

• Acute or chronic hepatitis C virus (HCV) infection

  • Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction

• Known human immunodeficiency virus (HIV) infection with a cluster of differentiation 4 (CD4) count greater than 200 cells/µL; HIV testing is required at screening only if required per local health authorities or institutional standards

• History of other malignancy that could affect compliance with the protocol or interpretation of results

  • Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix, or early-stage localized prostate cancer (Gleason score < 6 or below, Stage I or II) with no requirement for therapy at any time prior to study are eligible.
  • Patients with a malignancy that has been treated with curative intent will also be excluded unless the malignancy has been in documented remission without treatment for > 2 years before enrollment. Exception will be made for patients with a history of breast cancer that is estrogen receptor-/progesterone receptor-positive for more than 2 years before enrollment who are treated with adjuvant hormonal therapy

• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks before cycle 1 day 1 (C1D1)

• Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis

• Recent major surgery within 4 weeks before the start of C1D1

• Superficial lymph node biopsies for diagnosis is allowed