R1979-HM-2298 (OLYMPIA-1)

adults with previously untreated, CD20-positive follicular lymphoma, Grade 1–3a, with Stage II bulky, Stage III, or Stage IV disease. Diagnosis should be pathologically confirmed, with measurable disease on CT or MRI and a clinical need for treatment based on modified GELF criteria. Patients should have ECOG 0–2, adequate hematologic, hepatic, renal, and cardiac function, and be fit enough for study treatment. For Part 1, a FLIPI-1 score of 3–5 is also required.

A participant must meet the following criteria to be eligible for inclusion in the study: 1. Have diagnosis of CD20+ FL Grade 1-3a, stage II bulky or stage III / IV: Local histopathologic confirmation of the CD20+ FL Grade 1 to 3a, must be obtained before study enrollment. Biopsies must have been obtained within 18 months prior to study enrollment. A corresponding tumor biopsy sample should be submitted to the central laboratory. a. For Part 1 (Safety Run-In) only: FLIPI-1 score of 3 to 5. 2. Need for treatment as indicated by modified Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria (Dreyling, 2021). Have measurable disease on cross-sectional imaging documented by diagnostic imaging CT or MRI (measurable disease is defined as at least 1 bidimensionally measurable nodal lesion of >1.5 cm or extranodal disease of >1 cm in the greatest transverse diameter (GTD) regardless of the short axis diameter). 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 4. Male or female ≥18 years of age or the legal age of adults to consent to participate in a clinical study per country-specific regulations, whichever is greater, at the time of consent. 5. Adequate bone marrow function as documented by: a. Platelet count ≥ 50 x 109/L. A participant may not have received platelet transfusion therapy within 7 days prior to first dose of study drug in order to meet the platelet eligibility criterion. b. Hemoglobin ≥ 9.0 g/dL. c. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L. A participant may not have received G-CSF within 2 days prior to the first dose of study drug in order to meet the ANC eligibility criterion. d. Participants with bone marrow involvement or splenic sequestration should meet the following hematologic parameters: ▪ Platelet count ≥25 x 109/L. A participant may not have received platelet transfusion therapy within 3 days prior to first dose of study drug in order to meet the platelet eligibility criterion. ▪ Hemoglobin ≥7.0 g/dL ▪ ANC ≥0.5 x 109/L. A participant may not have received G-CSF within 2 days prior to first dose of study drug in order to meet the ANC eligibility criterion. 6. Participants with adequate hepatic function: a. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤3 x ULN if attributed to lymphoma infiltration of liver). b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5  ULN (≤5 x ULN if attributed to lymphoma infiltration of liver). c. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤5 x ULN if attributed to lymphoma infiltration of liver). NOTES: − Irrespective of the presence of lymphoma infiltration of the liver, a participant with an AST >2.5 x ULN and/or ALT >2.5 x ULN concurrent with a total bilirubin > 1.5 x ULN will be excluded. − Participants with known Gilbert syndrome will be excluded if the total bilirubin value is >4 x ULN for the local general population. 7. Calculated creatinine clearance by Cockcroft-Gault formula 50 mL/min. NOTE: Participants with a calculated creatinine clearance <50 mL/min may be considered for enrollment if a measured creatinine clearance (based on 24-hour urine collection or other reliable method) is ≥50 mL/min. 8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information by study participant (in accordance with national and local participant privacy regulations). 9. Willing and able to comply with clinic visits and study-related procedures. 10. Able to understand and complete study-related questionnaires.

CNS or leptomeningeal involvement, transformed/high-grade lymphoma, or non-eligible lymphoma subtypes such as Grade 3b FL, CLL/SLL, or Waldenström macroglobulinemia./have received prior systemic anti-lymphoma treatment, had recent major surgery or radiotherapy, or have a solid organ transplant history. /uncontrolled significant medical illness, active/recent other malignancy, ongoing high-dose systemic steroids, poor cardiac function, recent replication-competent vaccination, and pregnancy or breastfeeding.

A participant who meets any of the following criteria will be excluded from the study: 1. Participants with central nervous system (CNS) lymphoma or leptomeningeal lymphoma. a. Primary CNS lymphoma or known involvement by non-primary CNS lymphoma (even if treated into complete remission). b. Suspected CNS involvement by lymphoma must be evaluated by CNS imaging (MRI or CT) and by lumbar puncture as appropriate. 2. Participants with histological evidence of transformation to a high-grade or diffuse large B-cell lymphoma. 3. Participants with Waldenström macroglobulinemia (WM, lymphoplasmacytic lymphoma), Grade 3b follicular lymphoma, chronic lymphocytic leukemia, or small lymphocytic lymphoma. 4. Treatment with any systemic anti-lymphoma therapy. 5. Recent major surgery (within 4 weeks prior to the start of assigned study treatment). 6. Standard radiotherapy within 14 days of first administration of assigned study treatment. 7. History of solid organ transplantation. 8. Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone/prednisolone or anti-inflammatory equivalent within 72 hours of start of study drug. 9. A malignancy other than NHL unless the participant is adequately and definitively treated and is cancer free for at least 3 years with the exception of localized prostate cancer treated with hormone therapy or local radiotherapy (ie, pellets), cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that was definitively treated. 10. Any other significant active disease or medical condition that could interfere with the conduct of the study or put the participant at significant risk, including but not limited to significant cardiovascular disease (eg, New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina); significant pulmonary disease (eg, obstructive pulmonary disease and history of symptomatic bronchospasm); or gastrointestinal, hepatic, renal, endocrine, hematologic, autoimmune, psychiatric, or neurologic disorder. 11. History of or current relevant CNS pathology, such as epilepsy, seizure, paresis, aphasia, apoplexy, severe brain injury, cerebellar disease, organic brain syndrome, psychosis, inflammatory lesions, and/or vasculitis. 12. Vaccination within 28 days prior to first study drug administration with a vector that has replicative potential. Regarding COVID-19 vaccination, participants should not have received COVID-19 vaccine within 1 week of planned start of study drug. 13. Cardiac ejection fraction <50% by echocardiogram or multigated acquisition (MUGA) scan. 14. Pregnant or breastfeeding women. NOTE: Female study participants must agree to abstain from breastfeeding during study treatment and for at least 6 months after discontinuation of rituximab (MabThera [SmPC], 2023). 15. Women of childbearing potential (WOCBP)* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose of odronextamab or 12 months after the last dose of cyclophosphamide or rituximab (MabThera [SmPC], 2023), whichever is longer. Male participants who are unwilling to use a condom as contraception with all female partners of childbearing potential using a highly effective method of contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months after the last dose of vincristine, or 6 months after the last dose of odronextamab, cyclophosphamide, bendamustine, or doxorubicin. Sperm or egg donation are prohibited during the study and for 6 months after the last dose of study drug. Highly effective contraceptive measures include: a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening. In addition, WOCBP who are using oral hormonal contraception must use an additional barrier method such as condoms; b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS); c. bilateral tubal occlusion/ligation; d. vasectomy / vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or e. sexual abstinence**. NOTE: Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are post-menopausal or permanently sterile. *WOCBP are defined as women who are fertile following menarche until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The below definitions are according to the Clinical Trial Facilitation Group (CTFG) guidance. **Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together. 16. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric, or neurological disease, as assessed by the investigator, that may confound the results of the study or poses an additional risk to the participant by study participation. 17. Has a history of tuberculosis or systemic fungal diseases that has been active within 6 months. 18. Infections: • Infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first administration of assigned study treatment. There should be evidence that the infection has cleared or is well controlled by start of study therapy. • Evidence of any active infection (bacterial, viral, fungal, mycobacterial, parasitic, or other) at study enrollment or within 2 weeks of study enrollment, if requiring ongoing treatment and/or has the potential to cause disseminated disease or severe infection upon immunosuppression. • Active COVID-19 infection defined as PCR+ • Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV). • Cytomegalovirus (CMV) infection as noted by detectable levels on peripheral blood PCR assay. Participants who show detectable levels of CMV at screening will need to be treated with appropriate antiviral therapy and demonstrate at least 2 undetectable levels of CMV by PCR assay (at least 7 days apart) before being re-considered for eligibility. NOTE: Participants with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/μL either spontaneously or on a stable antiviral regimen) are permitted. NOTE: Participants who are hepatitis B surface antigen positive or who are hepatitis B core antibody positive should undergo evaluation by a specialist and be considered for antiviral prophylaxis, before they are permitted onto study. NOTE: Participants who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti- HCV therapy) are permitted. 19. Allergy/hypersensitivity: a. History of severe allergic reaction attributed to compounds with a similar chemical or biologic composition as that of the study drug or excipient. b. Known hypersensitivity to both allopurinol and rasburicase. 20. Participated in any clinical research study evaluating another investigational drug including biologics or therapy, including specific immunotherapy, within 90 days or at least 5 halflives (whichever is longer) of an investigational biologic drug, or at least 4 weeks for other investigational drug, prior to the screening visit. 21. Participants who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.