A Study of Glofitamab-based Treatment in People With Diffuse Large B-cell Lymphoma

Inclusion Criteria:

1. Age 65-79 years with a fitness assessment of unfit or frail per simplified GA (Appendix 1, www.filinf.it/epi)

2. Age ≥80 years with any fitness level

3. Pathologically confirmed DLBCL, HGBCL or transformed lymphoma

4. No prior systemic anti-lymphoma therapy (prednisone/equivalent up to 100 mg daily x 7 days is permissible)

5. Ann Arbor Stage 2 bulky, 3 or 4 disease (Appendix 1)

6. Any IPI score (Appendix 1)

7. Anthracycline eligible: LVEF ≥ 45% by echocardiogram or MUGA scan.

8. Must have at least one bi-dimensionally measurable lesion (>1.5 cm in its largestdimension for nodal lesions, or >1.0 cm in its largest dimension for extranodallesions by computerized tomography [CT] scan or MRI)

9. Eastern Cooperative Oncology Group performance status ≤ 2 (Appendix 1)

10. Must have adequate organ and marrow status:

11. Absolute neutrophil count (ANC) ≥1,000/mm3 or ≥500/mm3 if due to diseaseinvolvement in the bone marrow

12. Platelet count ≥50,000 cells/mm3 or ≥25,000/mm3 if due to disease involvementin the bone marrow

13. Patients who do not meet criteria for bone marrow function due to marrowinvolvement of lymphoma and/or other disease-related cytopenias (e.g., immunethrombocytopenia) may be enrolled into the study after discussion with, andconfirmation by the PI.

14. Serum creatinine ≤ULN OR estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault formula or other institutional standard methods)

15. Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3 x upperlimit of normal (ULN)

16. Total bilirubin ≤ 1.5 x ULN (≤3 if due to Gilbert's syndrome or liverinvolvement by the lymphoma

17. Patients who do not meet criteria for liver function due to liver involvementof lymphoma may be enrolled into the study after discussion with, andconfirmation by the PI.

18. Negative HIV test at screening, with the following exception: Individuals with apositive HIV test at screening are eligible provided, prior to enrollment, they arestable on antiretroviral therapy, have a CD4 count ≥200/µL, and have an undetectableviral load.

19. Signed Informed Consent Form(s)

20. Ability to comply with all the study-related procedures, in the investigator'sjudgement

21. Female patients who are not of child bearing potential (i.e., who are postmenopausalor surgically sterile). For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agree torefrain from donating sperm, as defined below: With a female partner of childbearingpotential or pregnant female partners, male participants must remain abstinent oruse a condom plus an additional contraceptive method that together result in afailure rate of < 1% per year during the treatment period and for at least 6 monthsafter pretreatment with obinutuzumab, 6 months after the last dose of polatuzumab, 160 days after the last dose of rituximab, 2 months after the final dose ofglofitamab or 2 months after the last dose of tocilizumab (as applicable), whicheveris longer. Male participants must refrain from donating sperm during this sameperiod. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of theindividual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods of contraception. Ifrequired per local guidelines or regulations, locally recognized adequate methods ofcontraception and information about the reliability of abstinence will be describedin the local Informed Consent Form.

Exclusion Criteria:

1. Prior systemic anti-lymphoma therapy (localized radiation, steroids and antibioticsare permitted)

2. Prior solid organ transplantation

3. Prior allogeneic stem cell transplantation

4. Active CNS involvement

5. Uncontrolled HIV or active HBV or HCV infection (controlled HIV with undetectableviral load and previously treated HBV and HCV are allowed) 5.1 Participants withoccult or prior hepatitis B infection (defined as positive total hepatitis B coreantibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA isundetectable at the time of screening. Such participants must be willing to undergoHBV DNA testing on Day 1 of every cycle and every 3 months for at least 12 monthsafter the final cycle of study treatment and appropriate antiviral therapy asindicated.

5.2 Participants positive for HCV antibody are eligible only if polymerase chainreaction (PCR) is negative for HCV RNA

6. Uncontrolled active systemic infection

7. Major surgery within 4 weeks of the first dose of study drug (exceptions may beallowed after discussion with PI if patient has fully recovered from procedure andantilymphoma therapy is urgently needed)

8. Significant or extensive history of cardiovascular disease such as New York HeartAssociation Class III or IV cardiac disease or Objective Assessment Class C or D,myocardial infarction within the last 3 months prior to the start of Cycle 1,unstable arrhythmias, or unstable angina.

9. Uncontrolled autoimmune disorder

10. A history of confirmed progressive multifocal leukoencephalopathy

11. Any life-threatening illness, medical condition, or organ system dysfunction that,in the investigator's opinion, could compromise the subject's safety or risk studyoutcomes

12. Inability to comply with all the study-related procedures, in the investigator'sjudgement.

13. Contraindication to any of the individual components of polatuzumab, R-miniCHP andglofitamab or history of severe allergic or anaphylactic reactions to humanized ormurine monoclonal antibodies or known sensitivity or allergy to murine products

14. Prior treatment with systemic immunotherapeutic agents, including but not limitedto, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines andmonoclonal antibodies (mAbs) (e.g., anti-cytotoxic T lymphocyte associated protein 4, anti-PD-1, and anti-PD-L1) within 4 weeks or five half-lives of the drug,whichever is shorter 15. Prior use of any monoclonal antibody for the purposes oftreating cancer within 3 months of the start of Cycle 1

15. Prior use of any monoclonal antibody for the purposes of treating cancer within 3months of the start of Cycle 1

16. Any investigational therapy for the purposes of treating cancer within 28 days priorto the start of Cycle 1

17. Prior radiotherapy to the mediastinal/pericardial region. Radiotherapy to non-targetlesion sites will be permitted.

18. Corticosteroid use > 50 mg/day of prednisone or equivalent, for purposes other thanlymphoma symptom control 18.1 Participants receiving corticosteroid treatment with ≤ 50 mg/day of prednisone or equivalent for reasons other than lymphoma symptomcontrol (e.g., rheumatoid arthritis) must be documented to be on a stable dose of atleast 4 weeks duration prior to the start of cycle 18.2 Corticosteroid therapy forcontrol of cancer symptoms or side effects of prior treatment (e.g., nausea orB-symptoms) is permitted.

18.3 The use of inhaled corticosteroids is permitted. 18.4 The use ofmineralocorticoids for management of orthostatic hypotension is permitted.

18.5 The use of physiologic doses of corticosteroids for management of adrenalinsufficiency is permitted.

19. Participants who require lymphoma symptom control during screening may receivesteroids in the following manner: - Up to 100 mg of prednisone PO (or equivalentsteroids) per day for up to 7 days are allowed. Prednisone dose is at the discretionof the treating physician, provided that the dose is within the above specifieddosage range. - As part of the pre-phase treatment, vincristine or rituximab may notbe administered.

20. History of other malignancy that could affect compliance with the protocol orinterpretation of results:

20.1 Participants with a history of curatively treated basal or squamous cellcarcinoma or melanoma of the skin or in situ carcinoma of the cervix at any timeprior to the study are eligible.

20.2 Participants with any malignancy appropriately treated with curative intent andthe malignancy has been in remission without treatment for ≥ 2 years prior toenrollment are eligible.

20.3 Participants with low-grade, early-stage prostate cancer (Gleason score 6 orbelow, Stage 1 or 2) with no requirement for therapy at any time prior to study areeligible.

20.4 Patients with other concomitant malignancies may be eligible after discussionwith, and confirmation by the PI

21. Live, attenuated vaccine within 4 weeks before study treatment infusion on Day 1 ofCycle 1 or anticipation that such a live, attenuated vaccine will be required duringthe study. Live vaccines during the study and until participants B cells recover,are prohibited.

21.1 Influenza vaccination should be given during influenza season only. Participants must not receive live, attenuated influenza vaccine at any time during the study treatment period.