The Double-T trial is a prospective, randomized, single-arm, open-label, multicenter phase II trial investigating a double T-cell therapy strategy, which includes glofitamab with gemcitabine/oxaliplatin (Glofi-Gem/Ox) prior to and glofitamab monotherapy consolidation after standard of care Chimeric Antigen Receptor (CAR)-T cell therapy in high-risk 2nd line relapsed/refractory Large B-Cell Lymphoma (r/r LBCL) patients.

Data on safety, efficacy, and quality of life (QoL) will be collected and analyzed.

Inclusion Criteria:

1. Patient* has given written informed consent.

2. Patient is 18-80 years of age at time of signing the written informed consent

3. Patient has histologically confirmed diagnosis of large B-cell lymphoma by local pathologist at time of relapse.

4. Patient received R-CHOP based first-line therapy containing a CD20-antibody and anthracyclines.

5. Patient has relapsed/refractory disease, defined as follows:

   • Relapsed: disease that had recurred following partial or complete response (PR/CR) within 12 months of adequate first-line therapy
   • Refractory: disease that did not respond to, or that progressed <6 months after, completion of first-line therapy

6. Patient has at least one FDG-PET positive bi-dimensionally measurable (≥1.5 cm) nodal lesion, or one bi dimensionally measurable (>1 cm extranodal lesion, as measured on computed tomography (CT) scan

7. Patient has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 - 2

8. Patient has an absolute lymphocyte count > 200/µL

9. Patient is eligible for CAR-T cell therapy as per investigator´s discretion meeting all of the following criteria of adequate organ function:

   1. Adequate kidney function, defined as: Serum creatinine estimated glomerular filtration rate (MDRD) ≥ 60 mL/min.

   2. Adequate hepatic function, defined as: ALAT and ASAT ≤ 5 ULN. Bilirubin

      ≤ 2.0 mg/dl (except for Meulengracht disease)

   3. Adequate bone marrow function, defined as: Absolute neutrophil count (ANC) ≥ 1000/µL, Platelets ≥ 50.000/µL and Hemoglobin > 8.0 g/dL.

   4. Adequate cardiac function, defined as: Cardiac ejection fraction ≥ 45%.

   5. Adequate pulmonary function as per investigators discretion

10. Patient successfully performed MNC-leucapheresis procedure for a commercially available CAR-T-cell product

11. Patient is willing and able to provide baseline biopsy material (archival or fresh tumor sample) for central review

12. Male patients with female partners of childbearing potential are eligible to participate if they agree to contraceptive methods throughout the duration of the trial and at least 18 months after obinutuzumab administration, 12 months after lost dose oxaliplatin, 6 months after lymphodepletion or 2 months after last dose glofitamab, whatever is last

13. Female participants of childbearing potential must agree to use a highly effective method of contraception (e.g., hormonal contraception, intrauterine device (IUD), or surgical sterilization) throughout the duration of the trial and at least 18 months after obinutuzumab administration, 15 months after lost dose oxaliplatin, 6 months after lymphodepletion or 2 months after last dose glofitamab, whatever is last. * There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the trial gender-independently

Exclusion Criteria:

1. Patient has HIV infection of any stage as determined by presence of anti-HIV antibodies (confirmatory test) and / or presence of RNA confirmed by PCR during screening

2. Patient has previous or concurrent malignancies with the following exceptions:

   1. Surgically cured carcinoma in-situ
   2. Other kinds of cancer without evidence of disease for at least 3 years

3. Patient has known hypersensitivity to any component of the Glofitamab, Obinutuzumab, Yescarta and/or Breyanzi formulation formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to one of the other trial drugs

4. Patient has severe active infection requiring iv treatment within 14 days prior first dose of study drugs

5. Patient has congenital or acquired immunodeficiency including previous organ or allogeneic stem cell transplantation

6. Patient received prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3

7. Patient received prior treatment with gemcitabine and oxaliplatin in prior lymphoma treatment line

8. Patient had a major surgery within 4 weeks prior to first dose of study drugs

9. Patient has primary or secondary central nervous system (CNS) lymphoma at the time of enrollment or history of CNS lymphoma

10. Patient has current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease

11. Patient has significant or extensive cardiovascular disease such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 3 months, unstable arrhythmias, or unstable angina

12. Patient has an active autoimmune disease requiring systemic treatment

13. Patient receives ongoing corticosteroid use >20 mg/day of prednisone or equivalent. Patients on stable low-dose corticosteroids (≤20 mg/day of prednisone or equivalent for at least 7-14 days prior to first IMP administration) or on short courses of higher-dose corticosteroids that are completed before first IMP administration are eligible.

14. Female patients who are pregnant or breast feeding or planning to become pregnant within up to 18 months after start of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of trial treatment.

15. Patient has a relationship of dependence or employer-employee relationship to the sponsor or the investigator

16. Patient lacks accountability and inability to appreciate the nature, meaning and consequences of the trial

17. Patient is non-compliant, for reasons including, but not limited to the following:

    • Increased alcohol consumption, drug dependency or substance abuse that would interfere with cooperation with requirements of the trial
    • Refusal of blood products during treatment
    • Any similar circumstances that appear to make protocol treatment or follow-up impossible