R1979-HM-2299 (OLYMPIA-4)

Adults (≥18) with histology-confirmed aggressive B-NHL (DLBCL/DHL-THL/PMBCL/T-HRBCL/FL3b), primary refractory or relapsed ≤12 mo after anti-CD20+anthracycline frontline, measurable disease, ECOG 0–1, ASCT intent, adequate organ function.

A participant must meet the following criteria to be eligible for inclusion in the study: 1. Disease type: As per 2016 WHO classification, have histologically proven aggressive B-NHL: DLBCL, not otherwise specified (de novo or transformed indolent NHL), high-grade B-cell lymphoma with MYC and BCL2 ± BCL6 rearrangements with diffuse LBCL histology (DHL/THL), PMBCL, T/HRBCL, or FL3b. Availability of tumor tissue for submission to central laboratory is required for study enrollment. Archival tumor tissue for histological assessment prior to enrollment is allowed. 2. Have primary refractory or relapse ≤ 12 months from initiation of frontline therapy. Treatment at frontline should have included anti-CD20 antibody and anthracycline-containing regimen. • For participants who crossover to odronextamab treatment, this criterion is not applicable at time of crossover. 3. Have measurable disease with at least one nodal lesion with LDi greater than 1.5 cm or at least one extranodal lesion with LDi greater than 1.0 cm, documented by diagnostic imaging (CT or MRI). 4. Intent to proceed to ASCT • For participants who crossover to odronextamab treatment, this criterion is not applicable at time of crossover. 5. Age ≥ 18 years 6. ECOG performance status of 0 to 1 7. Adequate hematologic function, as measured by: • Platelet count ≥ 75 x 10^9/L. A participant may not have received platelet transfusion within 7 days of first dose of assigned treatment in order to meet this eligibility requirements • Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L. A participant may not have received granulocyte colony stimulating factor (G-CSF) within 2 days of first dose of assigned treatment in order to meet this eligibility requirement • Hemoglobin level ≥ 9 g/dL NOTE: Patients with cell counts below thresholds listed above may be considered for enrollment if, in the opinion of the investigator, the reason is believed to be due to bone marrow infiltration or splenic sequestration by the underlying disease. NOTE: Patients with bone marrow involvement or splenic sequestration should meet the following hematologic parameters: • Platelet count ≥ 25 x 10^9/L. A participant may not have received platelet transfusion therapy within 3 days prior to first dose of odronextamab in order to meet the platelet eligibility criterion • Hemoglobin ≥ 7.0 g/dL • ANC ≥ 0.5 x 10^9/L. A participant may not have received G-CSF within 2 days prior to first dose of odronextamab in order to meet the ANC eligibility criterion 8. Adequate organ function, as documented by: • Cardiac ejection fraction > 50% by echocardiogram or multigated acquisition (MUGA) scan • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤ 3 x ULN if attributed to lymphoma infiltration of liver) • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN if attributed to lymphoma infiltration of liver) • Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN if attributed to lymphoma infiltration of liver) • Calculated creatinine clearance by Cockcroft-Gault formula ≥ 50 mL/min • Pulmonary function defined as oxygen saturation > 90% on room air, forced expiratory volume in one second ≥ 50%, and diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 50%. NOTE: Irrespective of the presence of lymphoma infiltration of the liver, a patient with an AST > 3 x ULN and/or ALT > 3 x ULN concurrent with a total bilirubin > 1.5 x ULN will be excluded. NOTE: Patients with known Gilbert syndrome will be excluded if the total bilirubin value is > 4 x ULN. NOTE: Patients 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. 9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations) by study participant or legally acceptable representative 10. Willing and able to comply with clinic visits and study-related procedures 11. Able to understand and complete study-related questionnaires

Exclude CNS lymphoma/CNS pathology, recent anti-lymphoma or investigational therapy, major comorbidity or active infection (incl active COVID/uncntrl HIV-HBV-HCV/CMV+), prior organ transplant, severe hypersensitivity, pregnancy/breastfeeding, contraception noncompliance.

A participant who meets any of the following criteria will be excluded from the study: 1. Primary CNS lymphoma or known involvement by non-primary CNS NHL 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 (CT or MRI), and by lumbar puncture as appropriate 2. History of or current relevant CNS pathology, such as: • Epilepsy, seizure, paresis, aphasia, apoplexy, severe brain injury, cerebellar disease, organic brain syndrome, psychosis, or • Evidence for presence of inflammatory lesions and/or vasculitis on cerebral MRI 3. 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 4. 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) or significant pulmonary disease (eg, obstructive pulmonary disease and history of symptomatic bronchospasm), gastrointestinal, hepatic, renal, endocrine, hematologic, autoimmune, psychiatric or neurologic disorder. 5. Prior treatments: a. Prior use of any anti-lymphoma therapy within 28 days or 5 half-lives of the drug, whichever is shorter, prior to the start of assigned treatment,b. Any investigational therapy within 28 days or 5 half-lives of the drug, whichever is shorter, prior to the start of assigned treatment, c. Recent major surgery (within 4 weeks prior to the start of assigned treatment), d. Standard radiotherapy within 14 days of first administration of assigned treatment. NOTE: Palliative radiotherapy to a symptomatic lymph node/lesion is allowed provided the irradiated lesion(s) or node(s) is not included as a target lesion for tumor assessments. e. Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours of start of assigned treatment. f. Prior organ transplantation 6. 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 7. Infections: a. 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. There should be evidence that the infection has cleared or is well controlled by start of study therapy. b. Active COVID-19 infection c. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) d. Cytomegalovirus (CMV) infection as noted by detectable levels on peripheral blood polymerase chain reaction (PCR) assay. Patients 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: Patients 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: Patients who are hepatitis B surface antigen positive or who are hepatitis B core antibody positive should undergo evaluation by a specialist and be considered to have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti viral therapy for hepatitis B) before they are permitted onto study. NOTE: Patients who are HCV antibody positive 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. 8. Administration of live vaccination within 28 days of start of assigned treatment. 9. Patients who are committed to an institution by an order issued either by the judicial or the administrative authorities. 10. Members of the clinical site study team and/or his/her immediate family, unless prior approval granted by the sponsor. 11. Pregnant or breastfeeding women. 12. Women of childbearing potential (WOCBP) or men 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. 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 b. Intrauterine device (IUD); intrauterine hormone-releasing system (IUS) c. Bilateral tubal occlusion/ligation d. Vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the study participant and that the partner has obtained medical assessment of surgical success for the procedure) e. Sexual abstinence f. Male study participants with WOCBP partners are required to use condoms unless they are vasectomized or practice sexual abstinence Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are post-menopausal or permanently sterile. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to confirm a post-menopausal 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 post-menopausal state.