The purpose of this study is to determine whether combining Loncastuximab Tesirine with Epcoritamab is tolerable and effective for reducing and/or eliminating lymphoma cells in the body.

Inclusion Criteria:

1. Men and women aged 18 years or older at the time of signing informed consent.

2. Able and willing to sign the informed consent form (ICF).

3. Ability to comply with the trial protocol.

4. Relapsed/refractory (r/r) large B-cell lymphoma (LBCL) as determined by the local hematopathology laboratory from the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms (Swerdlow et al., 2016):

   1. LBCL or DLBCL, not otherwise specified (NOS)
   2. High-grade B-cell lymphoma (NOS or double/triple hit [technically classified in WHO 2016 as high-grade B-cell lymphoma (HGBCL), with Myc and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) translocations])
   3. Transformed from follicular lymphoma, marginal zone lymphoma (MZL), and nodular lymphocyte predominant Hodgkin lymphoma
   4. Follicular lymphoma stage 3B
   5. Primary mediastinal B-cell lymphoma previously treated with checkpoint inhibitor Note: Relapsed disease is defined as disease that has recurred ≥6 months after completion of therapy. Refractory disease is defined as disease that either progressed during therapy or progressed within 6 months (<6 months) of completion of therapy.

5. Participants who have received at least one prior systemic therapy for LBCL including anti-cluster of differentiation 20 (anti-CD20) monoclonal antibody and anthracycline-containing therapy.

6. Measurable disease by 2014 Lugano Classification. (Participants who have measurable disease, defined as at least 1 bi-dimensionally measurable nodal lesion, defined as >1.5 cm in its longest dimension, or at least 1 bi-dimensionally measurable extra nodal lesion, defined as >1.0 cm in its longest dimension.)

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2.

8. Adequate hematologic, hepatic, and renal function tested within 6 weeks prior to the start of therapy (values must not be achieved with growth factors within 72 hs):

   1. Absolute neutrophil count (ANC) ≥ 1.0 × 10^9 cells/L

   2. Hemoglobin ≥8.0 g/dL without blood transfusion in the past week

   3. Platelet count ≥75 × 10^9 platelets/L or ≥ 50 × 10^9 platelets/L if bone marrow involvement or splenomegaly

   4. Total bilirubin ≤1.5 × upper limit normal (ULN). Participants with documented history of Gilbert's syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible (≤3x institutional ULN if lymphoma involvement of the liver).

   5. Alanine transaminase (ALT)/aspartate aminotransferase (AST) ≤3.0 × ULN or ≤5 × ULN in the presence of liver involvement by lymphoma.

      • i. Creatinine within normal institutional limits, or calculated creatinine clearance ≥40 mL/min by the Cockcroft-Gault Equation or other institutional standard methods

9. Willingness to avoid pregnancy during the trial and for at least 12 months after the last dose of the trial intervention.

10. Patients with history of human immunodeficiency virus (HIV) are eligible, provided they are stable on anti-retroviral therapy, have cluster of differentiation 4 (CD4) count ≥200/µL, and have an undetectable viral load. Note: HIV test is optional.

11. Life expectancy of at least 12 weeks

12. For patients receiving glucocorticoid treatment at screening: treatment must be tapered down and administered with a maximum of 25 mg daily in the last 14 days before the first dose of epcoritamab.

Exclusion Criteria:

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

2. Prior treatment with anti-cluster of differentiation 19 (anti-CD19) chimeric antigen receptor T-cell (CAR-T) therapy

3. Prior exposure to bispecific T-cell engaging antiCD20XCD3 antibodies

4. Prior autologous or allogenic stem cell transplant

5. Known clinically significant pulmonary disease, including:

   1. Pulmonary fibrosis affecting patient's exercise tolerance.
   2. Chronic obstructive pulmonary disease (COPD) affecting patient's exercise tolerance.

6. Known clinically significant cardiac disease, including:

   1. Onset of unstable angina pectoris within 6 months of signing ICF
   2. Acute myocardial infarction within 6 months of signing ICF
   3. Congestive heart failure (grade III or IV as classified by the New York Heart Association

7. Pregnant or breast feeding

8. Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.

9. Chronic or current active infectious disease (including severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) requiring systemic antibiotics, antifungal, or antiviral treatment or any major episode of infection requiring treatment with intravenous (IV) antibiotics within 2 weeks of Day 1 of Cycle 1.

10. Exposure to a live vaccine within 30 days of administration or anticipation that a live attenuated vaccine will be required during the study.

    1. Inactivated influenza vaccinations may be given during the influenza season.
    2. An approved coronavirus disease 2019 (COVID-19) vaccine (messenger ribonucleic acid (mRNA), inactivated virus, and replication deficient viral vector vaccines) is allowed.

11. Active hepatitis B infection

    a. Patients who are hepatitis B surface antigen (HbsAg) negative and hepatitis B core antibody (HbcAb) positive must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation

12. Active hepatitis C infection

    a. Patients who are positive for hepatitis C virus (HCV) antibody must be negative for HCV by PCR to be eligible for study participation

13. Patient has no known active SARS-CoV-2 infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the patient must have a negative molecular (eg, PCR) test or 2 negative antigen test results at least 24 hours apart.

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

14. Patients with severe chronic pulmonary disease, or other serious medical condition which is likely to significantly impair the patient's ability to tolerate the study treatment.

15. Patients with seizure disorder requiring therapy with a last convulsion within two years from enrollment.

16. Patients with impaired decision-making capacity.