Response-adaptive to Epcoritamab In First Relapse: Study to Evaluate the Efficacy of Eptoritamab in Patients With Relapse/Refractory Large B Cell Lymphoma

Inclusion Criteria: 1. Written informed consent must be obtained before any study-specific assessment is performed. 2. Age \>18 years 3. Patients with Relapse/Refractory histologically confirmed LBCL, including, Diffuse Large B Cell Lymphoma (DLBCL); Primary Mediastinal Large B Cell Lymphoma (PMBCL), High-grade B-cell lymphoma (HGBCL); and grade 3B Follicular Lymphoma. Relapsed disease is defined as complete remission to first line therapy followed by a recurrence of the disease after a minimum of 6 months of completion of first-line therapy. A biopsy at the time of relapse is recommended but not mandatory. Refractory disease is defined as no objective response to first line therapy (biopsy not mandatory if diagnostic sample available). Four groups of patients are eligible: * PD as best response to first line therapy. * SD as best response after at least 4 cycles of first line therapy. * PR as best response after at least 6 cycles of first line therapy. * CR and disease recurrence within \< 6 months from the completion of first-line therapy. 4. Patients must have received adequate first-line therapy including at a minimum: an anti-CD20 monoclonal antibody (rituximab or obinutuzumab), and CHOP (cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone) or CHOP-like chemotherapy. 5. At the investigator's discretion, the patient should not be a candidate for 1st relapse CAR-T therapy or unwilling to receive CAR-T therapy. 6. Patients must be autologous stem cell transplantation (ASCT)-ineligible: Age ≥65 and/or HTC-CI ≥3 or or unwilling to receive transplant. 7. PET positive disease. 8. Performance status according to Eastern Cooperative Oncology Group (ECOG) 0 to 2. 9. Patients meeting with the following hematology values: * Hemoglobin ≥8 g/dl (transfusion support permitted but not within 7 days of screening lab collection) * Absolute neutrophil count (ANC) ≥ 1/109/L (growth factor support allowed in case of bone marrow involvement). * Absolute lymphocyte count ≥ 0.1/109/L, * Platelet count ≥ 70/109/L (unless secondary to bone marrow involvement, OR ≥50x/109/L if documented bone marrow involvement). Platelet transfusions permitted but not within 7 days of screening lab collection. 10. Female patients of child-bearing potential must have a negative urine or serum pregnancy test at screening and agree to use highly effective methods of contraception (e.g., established use of oral, injected or implanted combined (estradiol and progesterone containing) hormonal contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS) upon enrollment according to the recommendations provided by Clinical Trial Facilitation Group (CTFG), during the treatment period and for 4 months after the last dose of study medication. Moreover, the patient must agree to ongoing pregnancy testing during the course of the study, and after study therapy has ended. This applies even if the patient practices complete and continued sexual abstinence. Women not of childbearing potential are defined as: premenarchal; postmenopausal (greater than 50 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 greater than 40 IU per L or milli-International unit (mIU) per 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. 11. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential) upon enrollment according to the recommendations provided by CTFG, during the treatment period, and for 4 months following the last dose of investigational drug or agreement to remain abstinent. Agreement to refrain from donating blood or sperm during the study participation and for 4 months after the last dose of study medication. 12. Women must agree not to donate blood or oocytes during the course of the study and for 4 months after the last dose of study medication. Restrictions concerning blood donation apply as well to females who are not of childbearing potential. Men must also not donate sperm during the trial and for 4 months after receiving the last dose of study drug. 13. Females of childbearing potential must refrain from breastfeeding during the course of the study and for 4 months after the last dose of study medication. 14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. 15. Not included in other clinical trial or treated with an experimental drug. Exclusion Criteria: 1. Patients who received more than one prior line of systemic therapy 2. Patients with detectable Central Nervous System (CNS) lymphoma 3. Significant organ function impairment: * creatinine clearance calculated by Cockcroft-Gault ≤ 45 ml/min * direct bilirubin level \< 2 x ULN (except in patients with Gilbert's syndrome), * alanine transaminase (ALT) and aspartate aminotransferase (AST) \>3 × ULN or \>5 × ULN in cases of documented liver involvement. * clinically relevant pleural effusion, * left ventricular ejection fraction (LVEF) ≤ 45% 4. Serious accompanying disorder leading to impaired organ function causing significant clinical problems and reduced life expectancy of less than 3 months. 5. Have a history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia or are at a high risk for a thromboembolic event in the opinion of the investigator and who are not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period 6. Known clinically significant cardiac disease, including: * Onset of unstable angina pectoris within 6 months of signing the patient informed consent form. * Acute myocardial infarction within 6 months of signing the patient informed consent form. * Congestive heart failure (grade III or IV as classified by the New York Heart Association. * Left ventricular ejection fraction ≤45%. 7. Known past or current malignancy other than inclusion diagnosis, except for: Cervical carcinoma of Stage 1B or less; Non-invasive basal cell or squamous cell skin carcinoma; Non-invasive, superficial bladder cancer; Localized low grade prostate cancer (up to Gleason score 6); DCIS of the breast; Other malignancy that has been treated with curative intent and has remained in remission for 3 years. 8. Previous ASCT. 9. Prior anti-CD3 and CD20 bispecific antibodies therapy or prior treatment with tafasitamab. 10. Presence of severe infection that is uncontrolled or requiring IV antimicrobials for management. 11. History of HIV infection or acute or chronic active hepatitis B or C infection. * Individuals with positive HIV serology may be included if negative viral load and CD4 \>200/mm3. For being included, patients should have controlled disease and been on treatment for at least 1 year * Individuals with history of hepatitis infection with positive antibodies (anti-HB and anti-HV) might be included if negative viral load (negative hepatitis B PCR). Patients who are HBcAb positive must receive HBV prophylaxis while on treatment. Patients with positive HbsAg are excluded. Patients who are hepatitis B PCR positive will be excluded. Patients who are hepatitis C RNA positive will be excluded. 12. Females who are pregnant or breastfeeding. 13. Richter's transformation or prior chronic lymphocytic leukemia (CLL). 14. Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 4 weeks prior to Cycle 1 Day 1. 15. Recent major surgery (within 4 weeks before the start of Cycle 1 Day 1) other than for diagnosis. 16. Vaccination with a live vaccine or COVID-19 vaccination within 4 weeks prior to treatment. 17. History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure. History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies. 18. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site.