D7401C00001 (SOUNDTRACK-F1)

Adult untreated classic FL; stage II-IV and FLIPI 2-5 (Phase III); ECOG 0-2; needs systemic therapy by GELF; FDG-avid measurable disease; adequate liver/renal/heme/cardiac function; contraception and consent criteria met.

Informed Consent 1 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 2 Provision of signed and dated, written informed consent prior to any mandatory study‑specific procedures, sampling, and analyses 3 For participants who agree to the optional genetic testing, provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative Age 4 Participant must be at least 18 years of age, inclusive, at the time of signing the ICF. Type of Participant and Disease Characteristics 5 Histologically confirmed diagnosis of classic FL per WHO 2022 classification, as assessed by Investigators. Local histopathologic confirmation is sufficient to confirm eligibility. 6 Stage II to IV disease [Phase III portion only]. For SRI, all Stages are allowed. 7 FLIPI score 2 to 5 [Phase III portion only]. For SRI, all FLIPI scores are allowed. 8 ECOG performance status of 0 to 2 (Appendix G) 9 Previously untreated disease (no prior systemic lymphoma-directed therapies) 10 Need for systemic treatment based on the presence of at least one of the following GELF criteria (Brice et al, 1997): (a) At least one lesion with diameter ≥ 7.0 cm (b) At least 3 nodal sites, each with a diameter of ≥ 3.0 cm (c) Presence of at least one of the following “B symptoms” (i) unexplained fevers (ii) night sweats (iii) unintentional weight loss greater than 10% within the prior 6 months (d) Symptomatic splenomegaly (e) Pleural effusions or peritoneal ascites (f) Any one of the following cytopenias due to lymphoma (i) Haemoglobin <10 g/dL (6.25 mmol/L) (ii) Platelets < 100 × 10^9/L (iii) ANC < 1.5 × 10^9/L (g) Risk of organ compression or dysfunction due to disease 11 FDG-avid and measurable disease. Defined as at least one bi-dimensionally measurable nodal lesion (defined as > 1.5 cm in its longest dimension), or at least one bi‑dimensionally measurable extranodal lesion (defined as > 1.0 cm in its longest dimension). 12 Adequate liver function: total bilirubin < 1.5 × ULN (or ≤ 3 x ULN in presence of Gilbert’s syndrome). AST and ALT must be ≤ 3 × ULN (or ≤ 5 x ULN in presence of lymphoma involvement). 13 Adequate haematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow) within 28 days prior to C1D1, including: (a) ANC of ≥ 1.0 × 10^9 cells/L* (b) Platelet count of ≥ 75,000/μL* (c) Haemoglobin ≥ 9 g/dL* *Transfusion and/or growth factor support is permitted; however, neutrophils, platelets, and haemoglobin must be stable for at least 72 hours after transfusion and/or growth factor administration prior to screening for the participant to be eligible. If the participant has received a long half-life growth factor (eg, pegylated G-CSF), neutrophil count must be stable for at least 14 days prior to screening. 14 Adequate renal function: A CrCl ≥ 45 mL/min or individualized GFR ≥ 45 mL is required for study entry. The method of calculation should be consistent with the standard of care used at site. (Appendix P) 15 Adequate cardiac function, defined as LVEF ≥ 45% by ECHO or MUGA Reproduction 16 Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. See Appendix F for further details. (a) Male participants must agree to use a condom during the time period specified in Appendix F 2. Male participants must not donate or bank sperm during this same time period. Male participants wishing to father children in the future should be advised to arrange for the freezing of sperm prior to the start of study intervention. (b) Female participants must be either: (i) Females not of childbearing potential, see Appendix F 1 for definition; or (ii) must use highly effective forms of birth control (defined in Appendix F 3) from the signing of the ICF through at least the time specified in Appendix F 1. (c) Females receiving HRT and whose menopausal status is in doubt will be required to use at least one of the contraception methods outlined for FOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation; See Appendix F for further details. (d) All FOCBP must have a negative serum pregnancy test result within 72 hours prior to study intervention.

Exclude FL grade 3B/large B-cell transformation, CNS lymphoma/CNS disorders, major active infection (incl EBV/HLH-MAS), uncontrolled HIV/HBV/HCV, major cardiac disease, prior systemic FL therapy, recent major surgery/live vaccine, pregnancy/breastfeeding.

Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1 Follicular large B-cell lymphoma (WHO 2022 classification), formerly Follicular lymphoma Grade 3B (WHO 2016 classification), or suspicion for histologic transformation to high-grade/aggressive lymphoma based on Investigator’s assessment. NOTE: Participants with baseline PET scan demonstrating distinct sites with distinctly high SUV should have these areas biopsied to confirm no occult transformation, as per Investigator judgement and if clinically safe/feasible(refer to Section 8.2.2) 2 Contraindication to any of the individual components of B-R, R-CVP, or R-CHOP regimens, making a particular combination unfeasible for a patient. A patient can still participate if the subject is eligible to at least one of the remaining combinations. 3 History of or active CNS involvement by lymphoma 4 The presence of > 5000 circulating lymphoma cells/ul in the peripheral blood 5 History of a clinically relevant CNS medical condition or pathology that required treatment in the preceding year, is currently symptomatic or that which the treating investigator considers to have the potential to interfere with the evaluation of safety such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, neurodegenerative disorder including Parkinson’s disease, cerebellar disease, organic brain syndrome,or Psychosis. 6 History of or active autoimmune disease involving the CNS 7 Participants who have any concurrent or history of malignancy within 2 years prior to C1D1, 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 Has any medical or psychiatric condition which, in the opinion of the Investigator, places the participant at an unacceptably high risk for toxicities, could interfere with successful or safe delivery of therapy, or could interfere with evaluation of the study intervention or interpretation of participant safety or study results 9 Participants with: (a) Active or uncontrolled infection (including EBV) requiring systemic therapy and which places participant at unacceptable risk if he/she were to participate in the study. If a participant has a history of COVID-19 within 1 month of C1D1 or contracts COVID while on study treatment, participant must have 2 consecutive negative tests (PCR testing is preferable) performed at least 48 hours apart prior to resuming dosing. All symptoms related to COVID-19 infection should have fully resolved before initiating or resuming treatment (b) Known history of HLH/MAS. 10 HIV infection, or participants with chronic or active infection with HBV or HCV unless: (a) Participants with an HIV infection who are on effective anti-retroviral therapy with undetectable viral load within 6 months prior to study entry with CD4 count ≥ 500 cells/mm3 are eligible for this study. HIV RNA will be monitored during the study as clinically indicated. (b) Those who are HBsAg positive or hepatitis B PCR positive will be excluded. Participants who are anti-HBc positive will need to have a negative PCR result before study entry and must be willing to undergo DNA PCR testing during the study and/or prophylaxis. (c) Participants with a hepatitis C antibody positive should be tested for HCV RNA PCR and must have undetectable viral load by HCV RNA PCR before study entry. 11 Major cardiac abnormalities, including but not limited to the following: uncontrolled angina or unstable life-threatening arrhythmias, history of myocardial infarction ≤ 12 weeks before C1D1, Class ≥ 3 New York Heart Association congestive heart failure, severe cardiac insufficiency, or persistent QTc prolongation (> 480 msec, QTcF). Prior/Concomitant Therapy 12 Requires chronic immunosuppressive therapy for active autoimmune/inflammatory condition. The following are exceptions to this criterion: (a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection). (b) Systemic corticosteroids at physiological doses not to exceed 10 mg/day of prednisone or its equivalent. (c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 13 Has received any systemic therapy to treat the indication including:, chemotherapy, biologics or treatment with any other investigational anti-lymphoma agent. The following is exception to this criterion: Radiation to localized disease prior study entry is allowed. The last dose of radiation should not be within 28 days prior to the first dose of study intervention. Should have recovered from all radiation-induced toxicity prior to the first dose of study intervention. 14 Major surgical procedure within 14 days prior to the first dose of study intervention, (excluding biopsies) or anticipation of the need for major surgery during study intervention 15 Receipt of live attenuated vaccine within 28 days prior to the first dose of study intervention. NOTE: Participants should not receive live vaccine while receiving study intervention and for a period of at least 3 months after the last dose of cyclophosphamide, vincristine, doxorubicin, bendamustine, or a period of at least 6 months after the last dose of surovatamig, or rituximab, and until B-cell recovery within a normal range is confirmed. Prior/Concurrent Clinical Study Experience 16 Participation in another clinical study (for a separate medical comorbidity) with an investigational product administered within the last 28 days or 5 half-lives (of that agent), whichever shorter 17 Known hypersensitivity to study interventions or any product excipients. Other Exclusions 18 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 19 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 20 Females currently pregnant (confirmed with positive pregnancy test) or breastfeeding