Combining Loncastuximab Tesirine and Epcoritamab in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Inclusion Criteria: Disease: 1. Subjects with histologically confirmed relapsed/refractory DLBCL based on pathology report (WHO 2022 criteria) 1. DLBCL (de novo or transformed) 2. High-grade B-cell lymphoma with MYC and BCL2 rearrangements 3. High-grade B-cell lymphoma, not otherwise specified (NOS) 4. Follicular lymphoma grade 3B Diagnostic biopsy performed at the time of relapse/progressive disease no longer than 3 months before study entry must be available, with sufficient material for central review and complimentary scientific analyses. CD20 expression (or a high likelihood of CD20 expression) based on immunohistochemistry should be documented prior enrollment into the study. Refractory disease is defined as no remission to the last therapy. Subjects intolerant to previous therapy are excluded. Two groups of patients are eligible: * Progressive disease (PD) or stable disease (SD) as best response to previous therapy. * Complete (CR) or partial response (PR) as the best response after previous therapy, with biopsy-proven relapse occurring \< 6 months after end of treatment. Relapsed disease is defined as subjects achieving complete or partial remission to previous therapy, followed by biopsy-proven relapse ≥6 months after treatment completion. Subjects with refractory and early relapsed (≤12 months) disease after first line anti-CD20-/anthracycline-containing therapy are eligible. Subjects with late relapsed (\>12 months) disease after first line anti-CD20-/anthracycline-containing therapy can be enrolled in the study only if deemed ineligible to high dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT)) or if refuse to undergo HDCT/ASCT. Subjects relapsed/refractory to second line CAR-T cell therapy are eligible. 2. Subject must be 18 years or older. 3. Subject must be eligible to receive and in need of treatment initiation based on symptoms and/or disease burden, as assessed by the investigator. 4. Eastern Cooperative Oncology Group Performance (ECOG) status 0-2. 5. Subject must have one or more measurable disease sites defined as follows: 1. A positron emission tomography/computed tomography (PET/CT) scan demonstrating PET- positive lesion(s) AND 2. At least one measurable nodal lesion (long axis \> 1.5 cm and short axis \> 1.0 cm) or ≥ one measurable extra-nodal lesion (long axis \> 1.0 cm) on CT scan or MRI. 6. Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure. Contraception: 7. Women of childbearing potential and sexually active men must practice a highly effective method of birth control during and after the study, consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of giving informed consent until at least 7 months after the patient receives his last dose of study treatment. Men must agree not to donate sperm from the time of giving informed consent until at least 7 months after the patient receives his last dose of study treatment. For female subjects, they apply for 12 months after the last dose of the study drug. A woman is considered to be of childbearing potential until becoming post-menopausal or permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Post-menopausal status is defined as no menstrual periods for a continuous 12-month period without an alternative medical cause. A post-menopausal state can be confirmed by a high follicle-stimulating hormone (FSH) level within the postmenopausal range, especially in women not using hormonal contraception or replacement therapy. The investigator or a designated associate will provide guidance to patients on achieving highly effective contraception (with a failure rate of less than 1%), such as intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, having a vasectomized partner, or sexual abstinence. Male patients are required to use condoms unless their female partner is permanently sterile. 8. Women of childbearing potential participating in the study will be required to undergo a pregnancy test using either urine or serum beta-human chorionic gonadotropin (beta-hCG) at the screening visit. A negative result is necessary for inclusion in the study. Adequate baseline organ function tests collected no more than 7 days before starting study treatment: 9. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), except for patients with Gilbert syndrome, cholestasis due to hepatic hilum adenopathies or liver involvement, or biliary obstruction due to lymphoma, who may have a total bilirubin ≤ 3 times the ULN. 10. Alanine transaminase (ALT) and aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) ≤ 2.5 times the ULN, or ≤ 5 times the ULN for patients with liver involvement by lymphoma. 11. Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m² according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. If not initially within target range, this evaluation may be repeated after at least 24 hours, either using the CKD-EPI formula or by 24-hour sampling. If the subsequent result is within the acceptable range, it may be used to fulfill the inclusion criteria. 12. Prothrombin time/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 times the ULN, unless the patient is receiving anticoagulation (although the INR should not exceed 4.0). 13. Platelet count ≥ 75,000/mm³ without transfusion in the prior 7 days. 14. Hemoglobin ≥ 8 g/dL. 15. Absolute neutrophil count ≥ 1,000/mm3 (off growth factors at least 72 hours). 16. Left ventricular ejection fraction \> 4