Feasibility Trial of Glofitamab in a Response Adapted Approach Incorporating Interim FDG PET and ctDNA to Optimize Primary Therapy of DLBCL (GRAIL)

Inclusion Criteria: 1. Men and women ≥ 18 years of age deemed eligible for treatment with full-dose Pola- R-CHP and possible treatment with glofitamab by the qualified investigator. 2. Histologic diagnosis of DLBCL and variants according to the WHO 201613 or WHO 202254 classification including DLBCL non-organ-specific (NOS), Germinal centre B-cell type, activated B-cell type, T-cell/histiocyte-rich large B-cell lymphoma, Epstein-Barr Virus (EBV) + DLBCL, Primary mediastinal/thymic large B-cell lymphoma, High grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements, High grade B cell lymphoma NOS including lymphomas transformed from previously untreated indolent lymphomas. 3. Previously untreated DLBCL with the following exceptions: (a) prior radiotherapy for palliation (not localized), (b) up to 7 days of corticosteroids (prednisone 100mg/day equivalent). 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 5. Presence of at least one radiologically measurable nodal or extranodal mass. A measurable nodal mass must have a longest diameter ≥1.5 cm. A measurable extranodal mass should have a longest diameter ≥1.0 cm.16 6. Left ventricular ejection fraction (LVEF) ≥ 50%, as determined on cardiac multiple- gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO) 7. Women of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and up to 18 months after the last dose of or protocol therapy. Men who are sexually active must use highly effective methods of contraception during treatment and up to 6 months after the last dose of protocol therapy. Men require an agreement to remain abstinent (ie, refrain from heterosexual intercourse) or use a condom, and an agreement to refrain from donating sperm. Periodic abstinence and withdrawal are not acceptable methods of contraception. Fertility preservation options should be discussed. Examples of highly effective contraceptive methods include an agreement to remain abstinent (ie, refrain from heterosexual intercourse), bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 8. Willing and able to participate in all required evaluations and procedures in this study. 9. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained by the patient or legally acceptable representative before any study-specific procedures are performed. Exclusion Criteria: 1. Current/past history of central nervous system (CNS) lymphoma. 2. Prior exposure to any anthracycline, rituximab or cluster of differentiation 3 (CD3) targeted bispecific antibody. 3. Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to \< 5 years. Subjects receiving adjuvant hormonal therapy for early breast or prostate cancer are eligible. 4. Significant or extensive cardiovascular disease such as New York Heart Association Class III or IV cardiac disease or Objective Assessment Class C or D, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study. 5. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders (bronchospasm, obstructive pulmonary disease), and known autoimmune diseases. 6. Patients with a known or suspected history of hemophagocytic lymphohistiocytosis (HLH) 7. History of illicit drug or alcohol abuse within 12 months prior to screening, in the Investigator's judgment. 8. Known active infection, or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, EBV, cytomegalovirus (CMV), hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks of dosing. Individuals with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a cluster of differentiation 4 (CD4) count ≥ 200/μL, and have an undetectable viral load. HIV positive patients should be monitored per local/institutional standards while receiving study treatment. 9. Known history of drug-specific hypersensitivity or anaphylaxis to study drugs (glofitamab and individual components of Pola-R-CHP), including grade III or greater allergic reactions to any monoclonal antibody. 10. Known Type I hypersensitivity or anaphylactic reactions to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or to any component of Rituximab 11. Current history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Patients with a history of stroke who have not experienced a stroke or transient ischemic attack within the past 2 years and have no residual neurological deficient, as judged by the investigator, are allowed. 12. Active autoimmune disease which is not well controlled by therapy: * Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible. Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. * Participants with active autoimmune disease with dermatologic manifestations are eligible for the study. * Participants with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, multiple sclerosis, or glomerulonephritis will be excluded. * Participants with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune disease will be excluded unless they have not required systemic therapy in the last 12 months 13. Major surgical procedure within 4 weeks of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 14. Administration of a live, attenuated vaccine within 4 weeks before study treatment infusion on Cycle 1/Day 1 or anticipation that such a live, attenuated vaccine will be required during the study. Live vaccines during the study and until participants' B- cells recover, are prohibited. Note: Influenza vaccination should be given during influenza season only. Participants must not receive live, attenuated influenza vaccine (e.g., FluMist) at any time during the study treatment period). 15. Use of any of the prohibited therapies including: investigational or unlicensed/unapproved agents; biologic agents (e.g., bevacizumab, erlotinib); immunotherapy/radio-immunotherapy; radiotherapy (with the exception of limited field palliative radiotherapy for bone pain or for soft tissue lesions after consultation with the Sponsor); chemotherapy (apart from Pola-R-CHP per protocol); hormone therapy (other than contraceptives, hormone-replacement therapy, or megestrol acetate); chronic use of steroids (inhaled, topical or systemic) 16. Positive test results for hepatitis B virus (HBV) infection (defined as positive B surface antigen \[HBsAg\] serology). Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody \[HBcAb\]) may be included if HBV DNA is undetectable, provided that they are willing to undergo DNA testing on Day 1 of every cycle and every three months for at least 12 months after the last cycle of study treatment and appropriate antiviral therapy. 17. Positive test results for hepatitis C virus (HCV) antibody. Patients who are positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Absolute Neutrophil Count (ANC) \<1.0 x109/L (subjects with bone marrow involvement by lymphoma are eligible regardless of ANC). 19. Hemoglobin (Hgb) ≤ 9 g/dL 20. Platelets \<50 x109/L (subjects with bone marrow involvement by lymphoma are eligible regardless of platelet count) 21. Total serum bilirubin \>2 times the upper limit of normal (or \<3 times for Gilbert's disease or documented hepatic involvement by lymphoma), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \>3 times the upper limit of normal (or \>5 times for documented hepatic involvement by lymphoma) 22. Creatinine clearance \<30 mL/min. 23. Prothrombin time (PT)/ international normalized ratio (INR) \>2 times the upper limit of normal in the absence of anticoagulants or partial thromboplastin time (PTT) \>2 times the upper limit of normal in the absence of anticoagulants. 24. Breastfeeding or pregnant, or intending to become pregnant during the study or within 12 months after the final dose of Pola-R-CHP, 3 months after the final dose of tocilizumab (if applicable), or 2 months after the final dose of glofitamab. WOCBP must have a serum pregnancy test done a maximum of 7 days prior to treatment initiation and a negative result must be documented prior to recruitment. 25. Concurrent participation in another therapeutic clinical trial. 26. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 27. Laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug. 28. Current Grade \> 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot Marie Tooth disease. 29. Known history of progressive multifocal leukoencephalopathy. 30. Positive severe acute respiratory syndrome (SARS-CoV-2) test within 7 days prior to enrollment. Rapid antigen test result is also acceptable. 31. Known or suspected chronic active Epstein-Barr viral infection.