The purpose of this phase 2 study is to evaluate the efficacy and safety of epcoritamab in subjects with relapsed or refractory primary diffuse large B-cell lymphoma of the Central Nervous System treated with rituximab and lenalidomide.

Primary CNS DLBCL has an altered prognostic compared to systemic DLBCL mostly due to an increased relapse rate. PCNSL patients for whom the global prognostic remains poor, calling for improved treatment at relapse.

Considering the good results of R2 regimen in R/R PCNSL and the efficacy and favorable safety profile of epcoritamab in R/R systemic DLBCL, the addition of Epcoritamab to the combination of R2 might significantly improve the prognosis of PCNSL patients at relapse. In addition, it is expected that IMiDs could potentially increase the efficiency of epcoritamab by stimulating the immune system.

Inclusion Criteria:

1. Subject (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. Subject ≥ 18 years old at the time of signing the informed consent form (ICF)

3. Confirmed histology of primary diffuse large B-cell lymphoma of the CNS (according to the 2022 WHO classification) or confirmed cytology of primary vitreoretinal diffuse large B-cell lymphoma, with CD20 positivity in immunohistochemical staining or flow cytometry at any point in the disease history.

4. Subjects with relapsed or refractory (R/R) PCNSL or PVRL after at least one line of systemic therapy. Subject with R/R PCNSL must have previously received at least high dose methotrexate. Subject with R/R PVRL must have received either intravenous high dose methotrexate or intraocular methotrexate (PVRL cohort). Subjects can have received radiotherapy or intensive chemotherapy with hematopoietic stem cell rescue as part of treatment of the PCNSL or PVRL.

5. ECOG performance status 0 to 2.

6. Estimated minimum life expectancy of ≥ 2 months.

7. R/R PCNSL subjects with evaluable disease on brain MRI.

8. Able to swallow capsules (stomach tube not allowed)

9. Adequate hematopoietic function:

   • Absolute neutrophil count of ≥ 1.0 G/L without G-CSF support for at least 7 days before screening
   • Platelet count of ≥ 50 G/L without platelet transfusion within 7 days before screening
   • Hemoglobin ≥ 8.0 g/dL without RBC transfusion within 7 days before screening

10. Adequate renal function: calculated by Cockcroft-Gault equation creatinine clearance > 40 ml/min. Subjects with calculated creatinine clearance > 40 and < 60ml/min lenalidomide dose will be adjusted.

11. Adequate liver function: Serum total bilirubin level ≤ 2.0 mg/dl [34 µmol/L] (unless bilirubin rise is due to Gilbert's syndrome) and serum transaminases (AST or ALT) ≤ 3 upper normal limits.

12. Able to understand teratogenic risks of the treatment (Lenalidomide).

13. Women of childbearing potential (WOCBP) should agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study treatment, 2) while participating in the study, 3) dose interruptions, and 4) for at least 12 months after the final dose of rituximab, or for at least 12 months after the final dose of epcoritamab, or for at least 28 days after the final dose of lenalidomide . WOCBP should also agree to abstain from breastfeeding during study participation and for at least 4 months after discontinuation of all study treatments.

14. WOCBP should have a negative serum (beta-hCG) pregnancy test at screening and a negative serum or urine pregnancy test before treatment administration on Day 1 of every cycle.

15. Women should agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire study, until 12 months after the last administration of study treatment.

16. Man who is sexually active with a female of reproductive potential and has not had a vasectomy should agree to use a highly effective / an acceptable method of birth control (ie, condom) and must agree not to donate sperm, until 28 days after the final dose of lenalidomide and/or until 12 months after the final dose of epcoritamab and rituximab.

17. Subject covered by any social security system (France).

18. Subject (or their legally acceptable representative/trusted person) who understands and speaks one of the country official languages unless local regulation authorizes independent translators.

Exclusion criteria:

Subject who meets any of the following criteria should be excluded from enrollment in the study:

1. T-cell lymphoma.

2. Cerebral localization of a systemic lymphoma.

3. Prior history of organ transplantation or other cause of severe immunodeficiency.

4. Known Human Immunodeficiency Virus (HIV) or Positive HTLV1 serology.

5. Active Hepatitis B Virus (HBV) infection (DNA PCR-positive) or active hepatitis C Virus (HCV) infection (RNA PCR-positive). Subjects with evidence of prior HBV infection but who are PCR-negative are permitted in the study but should receive prophylactic antiviral therapy. Subjects who received treatment for HCV infection that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable.

6. Persistent SARS-CoV-2 infection. Subjects who have had or currently have a SARS-CoV-2 infection must demonstrate symptom resolution and provide a negative nasopharyngeal PCR test at time of inclusion. Both of these requirements must be met for the subject to be considered clear of the virus.

7. Impossibility to follow the calendar of exams because of geographic, social, or psychological reasons.

8. Active malignancy other than the one treated in this Study. Prior history of malignancies (other than inclusion diagnosis) unless the subject has been free of the disease for ≥ 2 years. However, subjects 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. Non-invasive, superficial bladder cancer
   5. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis [TNM] clinical staging system
   6. Any curable cancer with a complete response of >2 years duration

9. Known or suspected hypersensitivity to the active substance or to any of the excipients.

10. Any previous treatment with CAR-T therapy within 30 days prior to enrollment.

11. Receiving immunosuppressive therapy, including more than the equivalent of 20 mg of prednisolone daily, unless for control of lymphoma or intermittent prophylaxis/treatment of allergic reactions.

12. Any previous treatment with a bispecific antibody targeting CD3 and CD20 and/or with lenalidomide, regardless of the time and duration.

13. Seizure disorder requiring anti-epileptic therapy unless related to lymphoma.

14. Vaccination with live, attenuated vaccines within 28 days prior of enrollment (except severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Experimental and/or non-authorized SARS-CoV-2 vaccinations are not allowed.

15. Use of any standard or experimental anti-cancer drug therapy within 28 days of the start (Day 1) of study treatment.

16. Major surgery within 4 weeks prior to enrollment

17. Clinically significant cardiovascular disease, including:

    1. Myocardial infarction within 1 year prior to enrollment, or unstable or uncontrol disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV) cardiac arrhythmia (CTCAE Version 5.0 Grade 2 or higher), or clinically significant ECG abnormalities.
    2. Stroke within 6 months prior to enrollment.

18. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec.

19. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment at time of enrollment.

20. Contraindication to all uric acid lowering agents.

21. Clinically significant liver disease, including active hepatitis, current alcohol abuse, or cirrhosis.

22. Active tuberculosis or history of treatment for active tuberculosis within the past 12 months.

23. Receiving immunostimulatory agent.

24. Prior allogeneic hematopoietic stem cell transplantation.

25. Any significant medical conditions, laboratory abnormality or psychiatric illness likely to interfere with participation in this clinical study (according to the investigator's decision).

26. Subject deprived of his/her liberty by a judicial or administrative decision.

27. Subject hospitalized without consent.

28. Adult subject under legal protection.