A Trial to Evaluate the Efficacy and Safety of Tafasitamab With Bendamustine (BEN) Versus Rituximab (RTX) With BEN in Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

INCLUSION CRITERIA:

1. Age ≥18 years

2. Histologically confirmed diagnosis, according to the World Health Organization (WHO,

2008. classification, of: DLBCL NOS, THRLBCL, EBV-positive DLBCL, composite lymphomawith a DLBCL component with a DLBCL relapse subsequent to DLBCL treatment, diseasetransformed from an earlier diagnosis of low grade lymphoma (i.e. an indolentpathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with aDLBCL relapse subsequent to DLBCL treatment.

3. Fresh tumour tissue for central pathology review must be provided as an adjunct toparticipation in this study. Should it not be possible to obtain a fresh tumourtissue sample, archival paraffin embedded tumour tissue acquired ≤3 years prior toscreening for this protocol must be available for this purpose.

4. Patients must have:

5. relapsed or refractory DLBCL

6. at least one bidimensionally measurable disease site. The lesion must have agreatest transverse diameter of ≥1.5 cm and greatest perpendicular diameter of ≥1.0 cm at baseline. The lesion must be positive on PET scan

7. received at least one, but no more than three previous systemic therapy linesfor the treatment of DLBCL. At least one previous therapy line must haveincluded a CD20-targeted.

8. ECOG 0 to 2

9. Patients after failure of ASCT or patients considered in the opinion of theinvestigator currently not eligible for HDC with subsequent ASCT.

10. Patients must meet the following laboratory criteria at Screening:

11. ANC ≥1.5 × 109/L (unless secondary to bone marrow involvement by DLBCL)

12. PLTs ≥90 × 109/L (unless secondary to bone marrow involvement by DLBCL) andabsence of active bleeding

13. total serum bilirubin ≤2.5 × ULN unless secondary to Gilbert's syndrome (orpattern consistent with Gilbert's) or documented liver involvement by lymphoma.Patients with Gilbert's syndrome or documented liver involvement by lymphomamay be included if their total bilirubin is ≤5 x ULN

14. ALT, AST and AP ≤3 × ULN or <5 × ULN in cases of documented liver involvementby lymphoma

15. serum creatinine ≤2.0 x ULN or creatinine clearance must be ≥40 mL/mincalculated using a standard Cockcroft-Gault formula (Cockroft & Gault, 1976)

16. For a female of childbearing potential (FCBP), a negative pregnancy test must beconfirmed before enrolment. An FCBP must commit to take highly effectivecontraceptive precautions without interruption during the study and for 3, 6 or 12months after the last dose of Tafasitamab, BEN or RTX respectively, whichever islater. An FCBP must refrain from breastfeeding and donating blood or oocytes duringthe course of the study and for 3, 6 or 12 months after the last dose ofTafasitamab, BEN or RTX respectively, whichever is later. Restrictions concerningblood donations apply as well to females who are not of childbearing potential.

17. Males must use an effective barrier method of contraception without interruptionduring the study and for 3, 6 or 12 months after the last dose of Tafasitamab, BENor RTX respectively, whichever is later, if the patient is sexually active with anFCBP. Males must refrain from donating blood or sperm during study participation andfor 3, 6 or 12 months after the last dose of Tafasitamab, BEN or RTX respectively,whichever is later.

18. In the opinion of the investigator, the patients must:

19. be able to comply with all study-related procedures, medication use, andevaluations

20. be able to understand and give informed consent

21. not be considered to be potentially unreliable and/or not cooperative.

EXCLUSION CRITERIA:

1. Patients who have: any other histological type of lymphoma including, e.g., primarymediastinal (thymic) large B-cell lymphoma (PMBL) or Burkitt's lymphoma, primaryrefractory DLBCL, patients with known "double/triple hit" DLBCL genetics, CNSlymphoma involvement in present or past medical history

2. Patients who had a major surgery less than 30 days prior to Day 1 dosing

3. Patients who have, within 14 days prior to Day 1 dosing:

4. not discontinued CD20-targeted therapy, chemotherapy, radiotherapy,investigational anticancer therapy or other lymphoma-specific therapy

5. received live vaccines

6. required parenteral antimicrobial therapy for active, intercurrent systemicinfections

7. Patients who:

8. in the opinion of the investigator, have not recovered sufficiently from theadverse toxic effects of prior therapies, major surgeries or significanttraumatic injuries

9. were previously treated with CD19-targeted therapy or BEN

10. have a history of previous severe allergic reactions to compounds of similarbiological or chemical composition to Tafasitamab, RTX, murine proteins or BEN,or the excipients contained in the study drug formulations

11. have undergone ASCT within a period of ≤3 months prior to signing the informedconsent form. Patients who have a more distant history of ASCT must exhibitfull haematological recovery before enrolment into the study.

12. have undergone previous allogeneic stem cell transplantation

13. concurrently use other anticancer or experimental treatments

14. Prior history of malignancies other than DLBCL, unless the patient has been free ofthe disease for ≥3 years prior to Screening. Exceptions to the ≥3-year time limitinclude history of the following:

15. basal cell carcinoma of the skin

16. squamous cell carcinoma of the skin

17. carcinoma in situ of the cervix, breast and bladder f) incidental histological finding of prostate cancer (Tumour/Node/Metastasis [TNM]stage of T1a or T1b)

18. Patients with:

19. positive hepatitis B and/or C serology

20. known seropositivity for or history of active viral infection with HIV

21. evidence of active, severe uncontrolled systemic infections or sepsis

22. a history or evidence of severely immunocompromised state

23. a history or evidence of severe hepatic impairment (total serum bilirubin > 3mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liverinvolvement by lymphoma

24. a history or evidence of clinically significant cardiovascular,cerebrovascular, CNS and/or other disease that, in the investigator's opinion,would preclude participation in the study or compromise the patient's abilityto give informed consent