The purpose of this trial is to measure the following in participants with relapsed and/or refractory B-cell lymphoma who receive epcoritamab, an antibody also known as EPKINLY™ and GEN3013 (DuoBody®-CD3xCD20):

• The dose schedule for epcoritamab
• The side effects seen with epcoritamab
• What the body does with epcoritamab once it is administered
• What epcoritamab does to the body once it is administered
• How well epcoritamab works against relapsed and/or refractory B-cell lymphoma

The trial consists of 3 parts:

• a dose-escalation part (Phase 1, first-in-human [FIH])
• an expansion part (Phase 2a)
• a dose-optimization part (OPT) (Phase 2a)

The trial time for each participant depends on which trial part the participant enters:

• For the dose-escalation part, each participant will be in the trial for approximately 1 year, which is made up of 21 days of screening, 6 months of treatment (the total time of treatment may be different for each participant), and 6 months of follow-up (the total time of follow-up may be different for each participant).
• For the expansion and dose-OPT parts, each participant will be in the trial for approximately 1.5 years, which is made up of 21 days of screening, 1 year of treatment (the total time of treatment may be different for each participant), and 6 months of follow-up (the total time of follow-up may be different for each participant).

Participation in the study will require visits to the sites. During the first month, participants must visit every day or every few days, depending on which trial part the participant enters. After that, participants must visit weekly, every other week, once a month, and once every 2 months, as trial participation ends.

All participants will receive active drug, and no participants will be given placebo.

The purpose of the dose-escalation part of the trial is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), as well as to establish the safety profile of epcoritamab in participants with relapsed or refractory B-cell lymphoma.

In the expansion part, additional participants will be treated with epcoritamab, at the RP2D and the purpose is to further explore and determine the safety and efficacy of epcoritamab.

The dose-OPT part will evaluate alternative priming and intermediate dose regimens of epcoritamab in participants with:

• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma (FL)
• Mantle cell lymphoma (MCL)

All participants will receive epcoritamab at the RP2D.

Main Inclusion Criteria - Escalation Part (recruitment completed)

• Documented CD20+ mature B-cell neoplasm

  1. DLBCL - de novo or transformed
  2. HGBCL
  3. PMBCL
  4. FL
  5. MCL
  6. SLL
  7. MZL (nodal, extranodal or mucosa associated)

• Relapsed and/or refractory disease following treatment with an anti-CD20 monoclonal antibody (e.g. rituximab) potentially in combination with chemotherapy and/or relapsed after autologous stem cell rescue.

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

• Participants must have measurable disease by computed tomography (CT), magnetic resonance imaging (MRI) or Positron emission tomography-Computed tomography (PET-CT) scan

• Acceptable renal function.

• Acceptable liver function.

Main Inclusion Criteria - Expansion & Dose-OPT Parts

• Documented CD20 positive mature B cell neoplasm or CD20+ MCL.
• DLBCL, de novo or transformed (including double hit or triple hit).
• PMBCL
• FL grade 3B
• Histologic confirmed FL
• MZL
• SLL
• MCL (prior Bruton's tyrosine kinase inhibitor [BTKi] or intolerant to BTKi)
• At least 2 therapies including an anti-CD20 monoclonal antibody containing chemotherapy combination regimen.
• Either failed prior autologous hematopoietic stem cell transplantation (HSCT) or ineligible for autologous stem cell transplantation due to age or comorbidities.
• At least 1 measurable site of disease based on CT, MRI or PET-CT scan with involvement of 2 or more clearly demarcated lesions and or nodes.

Main Exclusion Criteria - All Parts

• Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening.
• Known past or current malignancy other than inclusion diagnosis.
• Aspartate aminotransferase (AST), and/or alanine transaminase (ALT) >3 × upper limit of normal.
• Total bilirubin >1.5 × upper limit of normal, unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin.
• Estimated Creatinine clearance (CrCl) <45 milliliters (mL)/min.
• Known clinically significant cardiovascular disease.
• Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment (excluding prophylactic treatment). Past coronavirus disease 2019 (COVID-19) infection may be a risk factor.
• Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy.
• Seizure disorder requiring therapy (such as steroids or anti-epileptics).
• Any prior therapy with an investigational bispecific antibody targeting CD3 and CD20.
• Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days prior to first epcoritamab administration.
• Eligible for curative intensive salvage therapy followed by high dose chemotherapy with HSCT rescue.
• Autologous HSCT within 100 days prior to first epcoritamab administration, or any prior allogeneic HSCT or solid organ transplantation.
• Active hepatitis B (deoxyribonucleic acid [DNA] polymerase chain reaction [PCR]-positive) or hepatitis C (ribonucleic acid [RNA] PCR-positive infection). Participants with evidence of prior hepatitis B (HBV) but who are PCR-negative are permitted in
• Known human immunodeficiency virus (HIV) infection.
• Exposed to live or live attenuated vaccine within 4 weeks prior to signing Informed consent form (ICF).
• Pregnancy or breast feeding.
• Participant is known or suspected of not being able to comply with the study protocol or has any condition for which, participation would not be in the best interest of the participant.
• Contraindication to all uric acid lowering agents.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.