M22-132

DLBCL (de novo or histologically transformed from follicular lymphoma or nodal marginal zone lymphoma) with histologically confirmed CD20+ disease, inclusive of the Following the WHO 2016 classification and documented in pathology report: a.DLBCL, not otherwise specified (NOS) b.High-grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations per World Health Organization (WHO) 2016 ("double-hit" or "triple-hit") Note: High-grade B-cell lymphomas NOS or other double-/triple-hit lymphomas (with histologies not consistent with DLBCL) are not eligible c.FL Grade 3B

1. Laboratory values meeting the following criteria within the screening period prior to the first dose of study treatment: * Absolute neutrophil count (ANC) ≥ 1.5 × 10*9/L (growth factor use is allowed if evidence of bone marrow involvement, but subject must not have received growth factor within 14 days prior to screening labs) * Hemoglobin ≥ 8.0 g/dL (red blood cell transfusions permitted, but subject must not have received blood transfusions within 7 days prior to screening labs) * Platelet count ≥ 75 × 10 9/L, or ≥ 50 × 10*9/L if bone marrow infiltration or hypersplenism (platelet transfusions permitted, but subject must not have received blood transfusions within 7 days prior to screening labs) * Serum aspartate transaminase (AST) AND alanine transaminase (ALT) level ≤ 3 × upper limit of normal (ULN) * Direct bilirubin must be ≤ 2 × ULN * Estimated Creatinine Clearance (CrCl) (as calculated by Cockcroft-Gault Formula, modified as needed for factors such as body weight) or eGFR (as calculated by MDRD equation) ≥ 50 mL/min * Prothrombin time (PT) or International normalized ratio (INR), and Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, unless receiving anticoagulation (although INR should not be > 4.0) 2. Subject is willing and able to comply with procedures required in this protocol. 3. Subject must be able to tolerate subcutaneous injections. 4. Subject must have available adequate fresh or paraffin-embedded tissue at Screening. Disease/Condition Activity 5. Diagnosis of:  DLBCL (de novo or histologically transformed from follicular lymphoma or nodal marginal zone lymphoma) with histologically confirmed CD20+ disease at most recent representative tumor biopsy pathology report, inclusive of the following according to WHO 2016 classification and documented in pathology report: * DLBCL, NOS * High-grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations per WHO 2016 ("double-hit" or "triple-hit") STUDY M22-132 | Version 7.0 | EU CT 2023-505347-38 CONFIDENTIAL INFORMATION No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. Note: High-grade B-cell lymphomas NOS or other double-/triple-hit lymphomas (with histologies not consistent with DLBCL) are not eligible * Follicular lymphoma Grade 3B 6. Subject must have no prior treatment with epcoritamab or any other bispecific antibody targeting CD3 and CD20 7. Subject must have 1 or more measurable disease sites: * A PET-CT scan demonstrating PET-positive lesion(s) AND * At least 1 measurable nodal lesion (long axis > 1.5 cm) or ≥ 1 measurable extra-nodal lesion (long axis > 1.0 cm) on CT scan or MRI 8. Subject must be eligible to receive and have a need for treatment initiation based on symptoms and/or disease burden as per investigator assessment. 9. Subject must have ECOG performance status 0-2, except for Arm 6A where ECOG performance status must be 0-1. 10. Subject has no current evidence of primary central nervous system (CNS) tumor or known CNS involvement, including leptomeningeal disease, at screening. 11. Subject has no clinically significant cardiovascular disease, including: * Myocardial infarction or stroke within 6 months prior to enrollment, OR * The following conditions within 6 months prior to enrollment: unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV), uncontrolled cardiac arrhythmia, and uncontrolled hypertension OR * Other clinically significant ECG abnormalities within 6 months prior to enrollment unless deemed stable and appropriately treated. OR * Left ventricular ejection fraction < 45% * In case of any history of cardiovascular disease, a cardiology consult is required within 60 days prior to enrollment. 12. Subject has no clinically significant liver disease, including hepatitis, current alcohol abuse, or cirrhosis. 13. Subject does not have active Hepatitis B Virus or Hepatitis C Virus infection. Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. 14. Subject has no known history of Human Immunodeficiency Virus infection. Note: Human immunodeficiency virus testing does not need to be conducted at screening unless it is required per local guidelines or institutional standards. 15. Subject has no known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail beds) requiring intravenous (IV) therapy within 2 weeks prior to enrollment. 16. Subject has no evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results. 17. Subject has no history of other prior malignancies, except for the following: * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study treatment and felt to be at low risk for recurrence by the treating physician * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease * Localized prostate cancer, post-radical prostatectomy or with no known active disease present, with stable (non-rising) current prostate-specific antigen levels < 0.1 ng/mL 24. Subject has not had radiation therapy, except for palliative radiation therapy to non-target lesions and must have at least 1 target lesion that has not received radiation therapy within 6 weeks prior to enrollment. 18. Subject has no Grade > 1 peripheral (sensory) neuropathy with the exception of neuropathy related directly to lymphoma (e.g., nerve compression from tumor). 19. Subject must not have active tuberculosis (TB) or history of completed treatment for active TB within the past 12 months. Note: Interferon gamma release assay (IGRA) testing does not need to be performed at screening unless active or latent TB is suspected. For subjects with positive IGRA, active pulmonary TB must be excluded with clinical evaluation and radiologic imaging. Subjects with positive IGRA and no evidence of active disease may be enrolled after treatment for latent tuberculosis infection (recommendation isoniazid monotherapy for total of 6 months) has been initiated. 20. Subject does not have active (symptomatic) cytomegalovirus (CMV) disease. If preemptive or prophylactic antiviral treatment is initiated, eligibility criteria #3 and #21 would have to be met on Cycle 1 Day 1. 21. Subject has no current autoimmune disease requiring immunosuppressive therapy except for up to 20 mg prednisone daily (or equivalent). 22. Subject has no life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk. 23. Subject has no current seizure disorder requiring therapy. 24. Subject has no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or have recent known exposure to someone with SARS-CoV infection, they should undergo molecular (e.g., PCR) or 2 negative antigen test results at least 24 hours apart to rule out SARS-CoV-2 infection. Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/regulations. 25. Subjects who do not meet SARS-CoV-2 infection eligibility criteria and/or cannot complete all screening required activities within the 28 day screening window once SARS-CoV-2 criteria have been met, must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria: * At least 10 days since first positive test result have passed in asymptomatic subjects or at least 10 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms. 26. Subject must not have had major surgery within 4 weeks prior to the first dose of study treatment. 27. Subject has a life expectancy of > 3 months from standard of care treatment from time of enrollment 28. Subject has no known history of Progressive Multifocal Leukoencephalopathy (PML). 29. Subject must have newly diagnosed, treatment-naïve (not including prior treatments for indolent lymphoma that has transformed) DLBCL. 30. Subject must be suitable for treatment with polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone in the opinion of the investigator. 31. Subject must have International Prognostic Index score of 2 - 5. 32. Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control that is effective from 30 days prior to enrollment through at least 12 months after the last dose of study treatment. Female subjects of non-childbearing potential do not need to use birth control. 33. Female subject who is not pregnant or considering becoming pregnant during the study or for 12 months after the last dose of study treatment. 34. Female subject who is not breastfeeding or considering breastfeeding during the study or for 6 months after the last dose of study treatment. 35. Female subject who is not considering donating eggs (ova, oocytes) during the study or for 12 months after the last dose of study treatment. 36. If male, and subject is sexually active with female partner(s) of childbearing potential, the must agree, from 30 days prior to enrollment through 12 months after the last dose of study treatment, to practice the protocol-specified contraception. 37. Male subject who is not considering fathering a child or donating sperm during the study or for 12 months after the last dose of study treatment.