Epcoritamab Plus Lenalidomide in Relapsed/Refractory Large B-cell Lymphoma After Second-Line CAR T-cell Therapy

Inclusion Criteria: 1. Participant (or their legally acceptable representative / trusted person) who understand and voluntarily signs and dates an informed consent form prior to any study-specific assessments/procedures being conducted 2. Aged ≥ 18 years at the time of signing the informed consent form (ICF) with no upper age limit 3. Diagnosis at relapse/progression post CAR T-cells of LBCL (de novo or histologically transformed from follicular lymphoma) with histologically confirmed CD20+ disease, inclusive of the following according to WHO 2022 classification and documented in pathology report: * Diffuse large B-cell lymphoma (DLBCL), NOS * Large B-cell lymphoma (LBCL) * T-cell/histiocyte-rich large B-cell lymphoma * Transformed follicular lymphoma * DLBCL/High-grade B cell lymphoma with MYC and BCL-2 translocations per WHO 2022. * High-grade B-cell lymphoma, NOS * Follicular lymphoma Grade 3B Note: The following, non-exhaustive list of histologies excluded from enrollment: patients with CLL, Richter's, indolent non-Hodgkin lymphoma, transformed WM, transformed MZL and Burkitt lymphoma 4. Participant must have no prior treatment with epcoritamab or any other bispecific antibody targeting CD3 and CD20 5. Relapsing or refractory after two systemic lines of treatment including CAR T-cells therapy (Note: bridging therapy is not considered as a line of treatment) R/R status will be determined by a PET scan performed approximately 1 month after CAR T cells infusion or on subsequent PET scans Note: Participant who received a combination of CAR T-cells therapy and immunomodulatory drugs (IMids) as second line are not eligible 6. ECOG performance status 0 to 2 7. Presence of disease specific criteria allowing response evaluation: * Bi-dimensionally measurable disease defined by at least one lymph node \> 15 mm or extranodal lesion \> 10mm * At least one hypermetabolic lesion demonstrated by 18FDG PET-CT (PET0) 8. Adequate hematopoietic function at screening as follows (unless cytopenia is clearly due to bone marrow involvement, or hypersplenism): * Hemoglobin level \> 8g/dL without RBC transfusion performed within 7 days before epcoritamab infusion * ANC ≥ 1 G/L (except if related to lymphoma involvement, ANC must be \> 0.5 G/L) * Platelets ≥ 50 G/L without platelet transfusion performed within 7 days before epcoritamab (except if related to lymphoma, hypersplenism, platelets must be \> 30 G/L) 9. Adequate renal function (calculated MDRD or Cockcroft-Gault): Creatinine Clearance ≥ 40 ml/min 10. Adequate liver function: * Total bilirubin ≤ 1.5 x ULN * Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 x ULN Note: Patients with documented history of Gilbert's Syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible 11. No persistent CAR-T neurotoxicity symptoms (regardless of grade) 12. Other adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1 (excepted the events previously described in criteria 8 to 11) 13. Negative HIV test at screening, with the following exception: Individuals with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy for at least 4 weeks, have a CD4 count ≥ 200/uL, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months. 14. Participant must not have documented refractoriness to IMids and must be suitable for treatment with lenalidomide in the opinion of the investigator. Note: Refractoriness to IMids is defined as: * Best response to prior IMids regimen of SD or PD, OR * Progressive disease within 6 months of completion of prior IMids regimen 15. Participant must not have had lenalidomide exposure within 12 months prior to screening. 16. Participant must be willing to take aspirin prophylaxis or prophylactic anticoagulation for thromboembolic event (or per local guidelines for lenalidomide administration). 17. Participant must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction). 18. Women of childbearing potential (WOCBP): * should have a negative result for pregnancy test (minimum sensitivity of 25mIU/mL, urine or serum) at screening * should agree to use at least one efficient method of birth control from 4 weeks prior to study treatment initiation, during study treatment administration and until 4 weeks after the last dose of lenalidomide and until 19. Men of reproductive potential should agree to use an acceptable method of birth control (condom) and must agree not to donate sperm during treatment and for 7 days after the last dose of lenalidomide and until 12 months after the last dose of epcoritamab Exclusion Criteria: 1. Previously known CD20 negative status, excepted if a new biopsy or cytometry analysis proving a CD20 positive status is available before enrollment 2. Prior solid organ transplantation 3. Prior allogeneic SCT 4. Autologous SCT within 100 days prior to epcoritamab infusion 5. Known or current central nervous system or meningeal involvement by lymphoma 6. Current or past history of Progressive Multifocal Leukoencephalopathy (PML) 7. Current or past history of aphasia, delirium, dementia, cerebellar disease, cognitive disorder, epilepsy under treatment, CNS vasculitis, neurodegenerative disease or dysarthria 8. History of cerebrovascular ischemia / hemorrhage with sequelae 9. Any serious psychiatric illness that would prevent the participant from signing the informed consent form 10. Patients with known active infection, or reactivation of a latent infection, whether bacterial, viral (including, but not limited to symptomatic SARS CoV-2 infection), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 1 week prior epcoritamab first injection Note: positive PCR EBV related to lymphoma could be enrolled 11. Known positive HTLV1 serology 12. Active Hepatitis C Virus (HCV) infection (RNA PCR-positive). Participants who received treatment for HCV infection that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable, 13. Active Hepatitis B Virus (HBV) infection (DNA PCR-positive). 14. LVEF \< 45% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan 15. Any serious active disease or co-morbid medical condition (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including uncontrolled obstructive pulmonary disease and history of bronchospasm or other according to investigator's decision) 16. Uncontrolled cirrhosis 17. Major surgery or significant traumatic injury \< 28 days prior to the epcoritamab infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment 18. Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception ofcorticosteroid treatment \< 25 mg/day prednisone or equivalent within 2 weeks prior to epcoritamab first infusion. Inhaled and topical steroids are permitted. 19. Active malignancy other than the one treated in this Study. 20. Prior history of malignancies unless the participant has been free of the disease (in CR) for ≥ 2 years. However, participants with the following history/concurrent conditions are allowed: 1. Non-invasive basal cell or epidermoid carcinoma 2. In situ carcinoma of the cervix 3. In situ carcinoma of the breast 4. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis \[TNM\] clinical staging system Note: Woman with adjuvant endocrine therapy (i.e., hormonotherapy) after breast cancer treatment can be enrolled if hormonotherapy was started for ≥ 2 years 21. Known or suspected hypersensitivity to the active substance or to any of the excipients. 22. Prior treatment within 4 weeks or five half-lives of the drug, whichever is shorter, before epcoritamab infusion with: - standard radiotherapy * any chemotherapeutic agent or treatment with any other investigational anti-cancer agents (defined as treatment for which there is currently no regulatory authority approved indication) * systemic immunotherapeutic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (e.g., anti-CTLA4, anti-PD1 and anti-PDL1) 23. Pregnant, planning to become pregnant or lactating or breastfeeding woman of childbearing potential 23. Pregnant, planning to become pregnant or lactating or breastfeeding woman of childbearing potential 24. Any significant medical conditions, or laboratory abnormality or psychiatric illness likely to interfere with participation in this clinical study (according to the investigator's decision) 25. Participant deprived of his/her liberty by a judicial or administrative decision 26. Participant hospitalized without consent 27. Adult participant under legal protection