The goal of this clinical trial is to evaluate clinical efficacy of incorporating Epcoritamab into the salvage treatment routine for relapsed-refractory aggressive B-cell lymphoma, followed by autologous stem-cell transplantation (ASCT) and consolidation Epcoritamab. The main questions it aims to answer are:

• Will the addition of epcoritamab to intensive salvage chemotherapy be safe and increase the proportion of patients with relapsed or refractory (R/R) large B-cell lymphoma who achieve a complete remission prior to planned transplant?
• Is consolidation epcoritamab after ASCT deliverable and safe?
• Will consolidation epcoritamab will result in improved clearance of molecularly detectable residual disease?
• Will the combination of pre- and post-ASCT epcoritamab lead to higher rates of progression-free survival (PFS) and event free survival (EFS) at 12 months compared to historical estimates in this population.

Participants will undergo three phases in this trial:

1. Epcoritamab-Salvage treatment: consists of 3 cycles of R-DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin) plus Epcoritamab
2. ASCT: Pre-autograft eligibility assessment for ASCT will be performed according to local practice. ASCT may be administered at local referring centre and will follow local standard operative procedures.
3. Consolidation treatment: consists of six 28-day cycles of subcutaneous Epcoritamab, commencing 6 - 12 weeks post ASCT.

Inclusion Criteria:

1. Age 18 years or older

2. Confirmed diagnosis of DLBCL, Not-otherwise specified (NOS), Transformation of indolent B-cell lymphoma, High-grade B-cell lymphoma (HGBCL), NOS, Diffuse-large BCL (DLBCL)/ High-grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangements or Follicular large B-cell lymphoma according to World Health Organization (WHO) 2016 or 2022 criteria that has relapsed or progressed after one line of chemoimmunotherapy

3. Transplant eligible according to local assessment

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

5. Measurable disease on computed tomography (CT) scan, defined as a nodal site greater than 1.5cm in longest axis or an extranodal site greater than 1.0cm in longest axis AND baseline fluorodeoxyglucose (FDG) positron emission tomography (PET) scans must demonstrate positive lesion compatible with CT defined anatomical tumour sites

6. Histological confirmation of tumour CD20 positivity, analysed by immunohistochemistry, on a pre-enrolment tissue sample performed after most recent prior therapy

7. Adequate renal function

   - Creatinine clearance greater than 45mL per min (Cockcroft Gault formula)

8. Adequate hepatic function:

   • Aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 3x Upper Limit of Normal (ULN)
   • Bilirubin less than or equal to 1.5x Upper Limit of Normal (ULN) or less than or equal to 3 if documented liver involvement and/or Gilbert's disease.

9. Adequate haematologic function:

   • Haemoglobin greater than or equal to 90g/L (transfusion support permitted)
   • Absolute neutrophil count greater than or equal to 1.0 x 109 per L; growth factor support allowed in case of bone marrow involvement
   • Platelet count greater than 75 x 109 per L or greater than or equal to 50 x 109 per L if documented marrow involvement

10. Able to take oral medications

11. Adequate washout of prior therapies:

    • At least 4 weeks since last dose of immunochemotherapy, radio-conjugated or toxin-conjugated compound, or other investigational anti-cancer therapy
    • At least 6 weeks since chimeric antigen-receptor T-cell therapy

12. Resolution of toxicities from prior therapy to a grade that does not contraindicate trial participation in the opinion of the investigator

13. If 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

14. Before the first dose of Epcoritamab, during the trial and for 12 months after last administration of Epcoritamab, a woman must be either:

    1. Not of childbearing potential, defined as: premenarchal; postmenopausal (greater than 45 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
    2. Of childbearing potential and practicing a highly effective method of birth control (as defined by the European Clinical Trial Facilitation Group) consistent with local regulations regarding the use of birth control methods for patients participating in clinical trials: 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); male partner sterilization (the vasectomized partner should be the sole partner for that patient); true abstinence (when this is in line with the preferred and usual lifestyle of the patient) * If the childbearing potential changes after start of the trial (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described under 16b

15. A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control (that is the use of condom) during the trial and for 12 months after receiving the last dose of Epcoritamab

16. Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for 12 months after receiving the last dose of Epcoritamab. Men must also not donate sperm during the trial and for 12 months after receiving the last dose of Epcoritamab

17. The patient understands the purpose of the trial and procedures required for the trial and is capable of giving signed informed consent which includes compliance with the requirements (no medical or psychiatric reason precluding participation) and restrictions listed in the informed consent form (ICF) and in this protocol

Exclusion Criteria:

1. Diagnosis of primary Central Nervous System (CNS) lymphoma

2. Active secondary CNS involvement of lymphoma at time of screening

   - A prior history of secondary CNS lymphoma is allowed provided that it has been successfully treated and there are no features of recurrence.

3. Prior autologous stem cell transplant

4. Known past or current malignancy other than inclusion diagnosis, except for:

   1. Cervical carcinoma of Stage 1B or less.
   2. Non-invasive basal cell or squamous cell skin carcinoma.
   3. Non-invasive, superficial bladder cancer.
   4. Prostate cancer with a current Prostate Specific Agent (PSA) level less than 0.1 ng per mL e. indolent lymphoma
   5. Indolent lymphoma
   6. Other malignancy that has been treated with curative intent and has remained in remission for 2 years

5. Any prior therapy with a bispecific antibody targeting CD3 and CD20

6. Uncontrolled systemic infection

7. Known HIV infection

8. Known active hepatitis B or C infection based on criteria below:

   • Hepatitis B virus (HBV): Patients with positive HbsAg are excluded. Patients with positive hepatitis B core antibody (antiHBc) and negative HbsAg require negative hepatitis B polymerase chain reaction (PCR) before enrolment and must be treated with antiviral therapy. Patients who are hepatitis B PCR positive will be excluded.
   • Hepatitis C virus (HCV): If positive hepatitis C antibody, patient will need to have a negative hepatitis C ribonucleic acid (RNA) before enrolment. Patients who are hepatitis C RNA positive will be excluded.

9. Seizure disorder, unless seizure-free for 12 months on established anticonvulsant therapy without the requirement for modification to anticonvulsants within the prior 12 months

10. Known clinically significant cardiac disease, including:

    1. Onset of unstable angina pectoris within 6 months of signing the patient informed consent form (PICF)
    2. Acute myocardial infarction within 6 months of signing the PICF
    3. Congestive heart failure (grade III or IV as classified by the New York Heart Association
    4. Decreased ejection fraction of less than 45%

11. Confirmed history or current autoimmune disease requiring permanent immunosuppressive therapy. Low-dose prednisolone (less than or equal to 10mg/day or equivalent) for rheumatoid arthritis or similar conditions is allowed.

12. Exposed to live or live attenuated vaccine within 4 weeks prior to signing PICF

13. Women who are pregnant or lactating.

14. Patient has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

15. Known hypersensitivity or adverse reaction to rituximab, tocilizumab or any elements of DHAOx

16. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial

Individual patient data will not be shared publicly. Aggregate patient data and final results will be presented in the final report.