SOUNDTRACK-D3

Adults 18–<80 with newly diagnosed CD19/CD20+ LBCL (DLBCL/HGBL spectrum), Stage I bulky–IV, IPI 2–5, measurable FDG-avid disease, ECOG 0–2, adequate organ/marrow function, tumour tissue available.

Age 1. Male or female participants aged 18 to < 80 years at the time of signing the ICF. Type of Participant and Disease Characteristics 2. Disease characteristics: a. Histologically locally confirmed diagnosis of previously untreated CD19/CD20-positive LBCL as per 5th edition of WHO Classification of Haematolymphoid Tumours (WHO-HEM5), with tumour CD19 and CD20 expression confirmed locally by either flow or IHC, including: • DLBCL, NOS • T-cell/histiocyte-rich large B-cell lymphoma • DLBCL/HGBL with myelocytomatosis (MYC) and B-cell lymphoma 2 (BCL2) rearrangements • ALK-positive large B-cell lymphoma • LBCL with IRF4 rearrangement • HGBL with 11q aberrations • EBV-positive DLBCL • Primary cutaneous DLBCL, leg type • DLBCL associated with chronic inflammation • HGBL, NOS • Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-positive DLBCL Excluding: Burkitt lymphoma; lymphomatoid granulomatosis; primary mediastinal (thymic) LBCL; mediastinal grey zone lymphoma; primary LBCL of immune-privileged sites; intravascular LBCL; fibrin-associated LBCL; fluid overload-associated LBCL; primary effusion lymphoma; plasmablastic lymphoma or any CD20-negative lymphoma, such as CD20-negative ALK-positive LBCL; Richter's transformation. b. Stage I bulky (lesion ≥ 7.5 cm) to Stage IV c. IPI score 2 to 5 d. Measurable disease per Lugano 2014 Response Criteria: o at least one nodal lesion > 1.5 cm long axis or one extranodal lesion > 1.0 cm long axis, measurable in 2 perpendicular dimensions by CT or MRI AND o FDG-avid on PET/CT scan at baseline. The FDG-avid is defined as a score of 4 or 5 on a 5-point scale, or, if a baseline 5-point scale score is not available, the standard uptake value of the hottest lesion to be higher than the standard uptake value of liver 3. Performance status: ECOG 0 to 2 prior to initiation of any study treatment. 4. Tissue availability: Confirmed availability of tumour tissue; archival (paraffin-embedded) or freshly collected. Sex and Contraceptive/Barrier Requirements 5. A WOCBP must be only included after a confirmed menstrual period and negative highly sensitive urine or serum pregnancy test within 72 hours prior to study treatment. A positive urine pregnancy test should be confirmed with a serum pregnancy test. 6. Contraceptive use by men or women should be consistent with methods of contraception for those participating in clinical studies as described in Appendix J. Informed Consent 7. Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 8. Must provide signed and dated informed consent before any study-specific procedures; able and willing to comply with protocol procedures, visits, and assessments. 9. Separate informed consent is required for optional genetics (DNA and plasma additional sampling). 10. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional Genomics Initiative research that supports the Genomic Initiative (see Appendix D 2). Other inclusion criteria 11. Haematologic and laboratory function: a. Adequate haematologic function (unless due to underlying disease, as established for example, by extensive BM involvement or due to hypersplenism secondary to involvement of the spleen by LBCL per the investigator) defined as: o Absolute neutrophil count ≥ 1× 10^9/L, or ≥ 0.5 × 10^9/L if due to underlying lymphoma infiltration o Platelets ≥ 75 × 10^9/L; or ≥ 25 × 10^9/L in the presence of BM involvement or splenomegaly o Haemoglobin ≥ 8 g/dL with no transfusion within 72 hours of Cycle 1 Day1 b. Aspartate aminotransferase and ALT must be ≤ 3.0 × ULN (except if abnormality is due to liver involvement of the lymphoma in which case AST/ALT must be < 5 × ULN) c. Total bilirubin: Participants must have TBL ≤ 1.5 × ULN, except if the participant has a known diagnosis of Gilbert's syndrome, in which case bilirubin must be < 3 × ULN) d. INR (or prothrombin time) and aPTT ≤ 1.5 × ULN, unless receiving anticoagulation (though INR should not be > 4.0) e. Creatinine clearance ≥ 40 mL/min (as calculated by the Cockcroft-Gault formula, modified as needed for factors such as body weight) f. Left ventricular ejection fraction ≥ 50% by ECHO or MUGA 12. Treatment intent: a. Eligible to receive 6 cycles of curative intent chemo-immunotherapy (R-CHOP or Pola-R-CHP). 13. Infectious disease screening: No active or uncontrolled infection requiring systemic therapy which places participant at unacceptable risk if he/she were to participate in the study. a. HIV infection: As per SoC, results of HIV serology should be known prior to start of study intervention. In the acute situation, registration may occur without the results of the HIV serology but must be available prior to start of study intervention. Participants with HIV infection are eligible if they have been on effective antiretroviral therapy with a sustained undetectable viral load for more than 6 months and have had no opportunistic infections attributable to acquired immunodeficiency syndrome within the 12 months before enrolment. HIV RNA will be monitored during the study as clinically indicated b. Hepatitis B: Participants with occult or previous hepatitis B infection (defined as positive total HBcAb and negative HBsAg) may be included if HBV DNA is undetectable at the time of screening with agreement to prophylaxis and serial monitoring per protocol c. HCV: antibody negative or RNA PCR negative if antibody positive d. Tuberculosis: IFN-γ release assay testing must be performed if active or latent tuberculosis is suspected (eg, clinical signs and symptoms of tuberculosis, contact history, or if the participant lives in or has travelled to or lived in the WHO high tuberculosis burden countries) e. SARSCoV2: Participants with recent (within 1 month) COVID-19 infections should have 2 negative COVID-19 antigen tests (48 hours apart) or a single negative PCR (preferable) f. CMV: No active CMV disease g. EBV: No active EBV infection h. HTLV: No positive human T-lymphotropic virus-1 test in endemic regions (HTLV testing is required for participants at sites in endemic regions, including but not limited to Japan and Melanesia and countries in the Caribbean basin, South America, Central America, and sub-Saharan Africa) i. No history of progressive multifocal leukoencephalopathy

Indolent/FL3B/CNS lymphoma; prior antilymphoma therapy or mediastinal RT; recent malignancy <2 yr; uncontrolled CV/liver disease; HLH/MAS; prior G≥3 CRS/ICANS from TCE/CAR-T; live vaccine ≤28 d.

Medical Conditions 1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant, and active bleeding diseases) which in the investigator's opinion makes it undesirable for the participant to participate in the study, or that would jeopardise compliance with the protocol 2. History of indolent lymphoma (eg, FL, marginal zone lymphoma, Waldenström macroglobulinaemia) 3. Follicular lymphoma Grade 3B 4. Primary or secondary CNS lymphoma at the time of recruitment or history of CNS lymphoma 5. Prior/Concomitant anticancer Therapy: a. Participant has history of prior systemic antilymphoma therapy for LBCL (including any definitive radiotherapy with curative intent) other than corticosteroids with or without vincristine during pre-phase treatment. b. Prior radiotherapy to the mediastinal/pericardial region. Radiotherapy to non-target lesion sites will be permitted, with the stipulation that radiated lesions cannot be selected as target lesion for response assessment. 6. Immunosuppressive and prohibited medications a. General: Participants must not be receiving medications known to decrease T-cell numbers or activity or other concurrent immunosuppressive therapy, except for prednisone (or equivalent) up to 20 mg/day (or equivalent). b. Pre-phase steroid: Prior to Cycle 1 Day 1, a short pre-phase steroid course is permitted at approximately 100 mg prednisone (or equivalent) per day for a maximum of 14 consecutive days (including tapering). 7. Participants who have any concurrent or history of malignancy within 2 years prior to Cycle 1 Day 1, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (eg, 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non‑melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer a. Participants who have prostate cancer with no evidence of metastatic disease and are not on active therapy except for anti-androgen therapy may be allowed study entry b. Participants with early-stage breast cancer, receiving hormonal therapy in the adjuvant setting after curative surgery, may be allowed study entry c. Participants who have a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are allowed d. Participants who have a malignancy that has been in remission without treatment for 2 years prior to the first study intervention administration will be allowed. 8. Surgical and other conditions: a. Major surgery (other than for lymphoma diagnosis) within 14 days prior to first dose without adequate recovery, according to investigator's judgement. b. Any medical/psychiatric/social condition that in investigator's judgement precludes safe participation or protocol compliance. 9. Cardiovascular and organ function exclusions: a. New York Heart Association Class III/IV heart failure; myocardial infarction or stroke within 6 months; unstable angina; uncontrolled arrhythmias; clinically significant ECG abnormalities. b. QTcF > 470 ms (men) or > 480 ms (women); or > 480 ms if using a single threshold. 10. Clinically significant liver disease (active viral hepatitis, current alcohol abuse, or cirrhosis not due to lymphoma involvement). 11. Vaccination: a. Participant has received vaccination with live or live attenuated vaccines within 28 days prior to randomisation or is expected to need any live vaccination during study participation or prior to B-cell recovery 12. Neurologic and immune conditions: a. History of CNS disease or pathology that required treatment in the preceding year, or presence of symptomatic or clinically relevant CNS disease that the treating investigator considers to have the potential to interfere with the evaluation of safety b. Known history of HLH/MAS and HLH-like syndrome c. History of Grade ≥ 3 CRS or ICANS based on ASTCT criteria, following prior T-cell directed therapies (TCE or CAR-T therapies, either approved or experimental) administered for other indication (eg, autoimmune diseases) d. Baseline Grade ≥ 2 peripheral neuropathy; demyelinating CharcotMarieTooth disease 13. Hypersensitivity: a. Participant has history of severe allergic or anaphylactic reactions to anti-CD19/CD20 therapy or known allergy or intolerance to any component or excipient of surovatamig or the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone [or equivalent]) or Pola-CHP (cyclophosphamide, doxorubicin, polatuzumab, prednisone) regimens Prior/Concurrent Clinical Study Experience 14. Participation in another clinical study with an investigational product administered within the last 28 days or 5 half-lives (of that agent), whichever is shorter, prior to the first dose of study treatment. Other Exclusions 15. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 16. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. 17. Previous enrolment in the present study.