Polatuzumab Vedotin and Combination Chemotherapy With or Without Glofitamab for the Treatment of Untreated Aggressive Large B-cell Lymphoma

Contraindication to any of the individual components of glofitamab, tocilizumab or EPCH-R, including prior receipt of anthracyclines, or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, or known sensitivity or allergy to murine products

Prior systemic treatment for lymphoma with the exception of corticosteroids. Prior radiotherapy is allowed provided that this site is not used as a measurable site to assess response.

Richter's transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma is not allowed. Transformation from follicular or other indolent lymphomas is allowed provided that the subject has not received prior systemic therapy for their lymphoma and the aggressive component meets one of the criteria listed in inclusion criterion 1

Diagnosis of Burkitt lymphoma

Prior organ transplantation

Current Grade \> 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease

Prior systemic therapy for indolent lymphoma

Prior use of any monoclonal antibody within 3 months of the start of cycle 1; any investigational therapy within 28 days prior to the start of cycle 1; vaccination with live vaccines within 28 days prior the start of cycle 1 and at any time during the study treatment period

Prior therapy for large B-cell lymphoma except for patients who require lymphoma symptom control during screening may receive steroids in the following manner: Up to 30 mg/day of prednisone or equivalent may be used for lymphoma symptom control during screening, including prior to finalization of staging (not included as part of pre-phase treatment) If glucocorticoid treatment is urgently required at higher doses for lymphoma symptom control prior to the start of study treatment, tumor assessments must be completed prior to initiation of \> 30-100 mg/day of prednisone or equivalent. Prednisone \> 30-100 mg/day or equivalent may be given for a maximum of 7 days as a pre-phase treatment. If patients exceed the allowed dosing of corticosteroids, patients may still be eligible for the study provided that baseline imaging is performed (or repeated) after completion of the course of higher dose of steroids. Allowed corticosteroid dosing resets from the point of imaging forward and patients who do not exceed the allowed corticosteroid dosing from the point of imaging until initiation of study treatment may enroll

History of other malignancy that could affect compliance with the protocol or interpretation of results except with permission of the principal investigator. The following are eligible without a specific waiver:

* Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible

* Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for \>= 2 years prior to enrollment are eligible

* Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible

Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)

Recent major surgery (within 4 weeks prior to the start of cycle 1), other than for diagnosis

History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) which requires systemic treatment. Patients may proceed with screening during treatment for infection, but systemic treatment must be completed by cycle 1 day 1

Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology):

\* Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. These patients must be willing to undergo monthly DNA testing and appropriate antiviral therapy as indicated by institutional standard

Positive test results for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing)

\* Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

History of uncontrolled human immunodeficiency virus (HIV)

\* Patients with known diagnosis of HIV must have undetectable viral load, have a CD4 count ≥ 200/μL, and be on anti-retroviral therapy. HIV positive patients should be monitored per local/institutional standards while receiving study treatment

Patients with a history of progressive multifocal leukoencephalopathy

Pregnancy or lactation or intending to become pregnant during study

ARM B ONLY: Known or suspected history of hemophagocytic lymphohistiocytosis (HLH)

ARM B ONLY: Known or suspected chronic active Epstein-Barr virus infection

ARM B ONLY: Current or past history of Waldenström macroglobulinemia

ARM B ONLY: Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, CNS lymphoma or neurodegenerative disease

ARM B ONLY: Active autoimmune disease which is not well controlled by therapy

ARM B ONLY: Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible

ARM B ONLY: Participants with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study

ARM B ONLY: Participants with active autoimmune disease with dermatologic manifestations are eligible for the study

ARM B ONLY: 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

ARM B ONLY: 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

ARM B ONLY: Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis

ARM B ONLY: Suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay)

ARM B ONLY: Grade 3 infection within 4 weeks of treatment initiation

What this study is about