The purpose of this study is to evaluate the efficacy and safety of glofitamab in combination with gemcitabine plus oxaliplatin (GemOx) versus standard of care (SOC) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) who have relapsed early (within 1 year) or are primary refractory to first-line therapy. Participants will be randomly assigned in a 1:1 ratio to receive either the Glofitamab-GemOx combination regimen or SOC. The SOC arm consists of investigator's choice of salvage chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) for eligible patients. The primary endpoint of the study is event-free survival (EFS).

Inclusion Criteria:

• Signed Informed Consent Form.
• Age 18 years or older at the time of signing the Informed Consent Form.
• Histologically proven large B-cell lymphoma (LBCL), including transformation from follicular lymphoma.
• Relapsed or refractory disease after first-line chemoimmunotherapy, defined as refractory disease (no complete remission to first-line therapy, progressive disease as best response, stable disease after 3-4 cycles, or partial response after 6-8 cycles/progression within 12 months) or relapsed disease (complete remission followed by biopsy-proven relapse within 12 months of initiating first-line therapy).
• No known history or suspicion of central nervous system (CNS) involvement by lymphoma.
• Life expectancy of at least 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• At least one bi-dimensionally measurable nodal lesion (1.5 cm or larger) or extranodal lesion (1 cm or larger) as measured on a CT scan.
• Negative HIV test at screening.
• Adequate hematologic function defined as hemoglobin 9.0 g/dL or higher without transfusion in the past 7 days, absolute neutrophil count 1.0 x 10^9/L or higher, and platelet count 75 x 10^9/L or higher.
• Adequate organ function defined as estimated creatinine clearance 60 mL/min or higher, ALT/AST 2.5 times the upper limit of normal (ULN) or lower, and total bilirubin 1.5 mg/dL or lower (or 3 x ULN or lower in subjects with Gilbert's syndrome).
• Cardiac ejection fraction greater than 50%, no evidence of pericardial effusion, and no clinically significant electrocardiogram findings.
• No clinically significant pleural effusion.
• Baseline oxygen saturation greater than 92% on room air.
• Able to understand and complete study-related questionnaires.
• Agreement to remain abstinent or use adequate contraceptive methods for both female and male participants during the treatment period and for the protocol-specified duration after the final dose.

Exclusion Criteria:

• Contraindication to glofitamab components or a history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
• Not eligible for autologous stem cell transplantation (ASCT).
• Prior solid organ transplantation.
• History of Richter's transformation or of indolent disease to diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL).
• Peripheral neuropathy assessed to be greater than Grade 1 at enrollment.
• Prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3.
• Use of any investigational therapy for treating cancer within 28 days prior to Cycle 1, any monoclonal antibody within 3 months, or systemic immunotherapeutic agents within 4 weeks or five half-lives (whichever is shorter).
• Prior radiotherapy to the mediastinal or pericardial region.
• History of autologous or allogeneic stem cell transplant.
• Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better, except for alopecia and anorexia.
• Administration of a live, attenuated vaccine within 4 weeks before the first study treatment administration.
• Received more than one line of therapy for DLBCL.
• Corticosteroid use greater than 50 mg/day of prednisone or equivalent for purposes other than lymphoma symptom control.
• Recent major surgery within 4 weeks before the first study treatment.
• History of other malignancy that could affect compliance or interpretation of results, with exceptions for adequately treated low-grade or in situ carcinomas and malignancies in remission for at least 2 years.
• Significant cardiovascular disease, such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 3 months, unstable arrhythmias, or unstable angina.
• Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS lymphoma.
• Known or suspected history of hemophagocytic lymphohistiocytosis (HLH).
• Current or past history of Waldenstrom macroglobulinemia.
• History or presence of a clinically significant abnormal ECG.
• Known or suspected active infection, reactivation of a latent infection, or any major episode of infection requiring hospitalization or IV antibiotics within 4 weeks of dosing.
• History of severe treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents.
• History of autoimmune disease, with specific protocol-defined exceptions for well-controlled conditions.
• Clinically significant liver disease, including active viral/other hepatitis or cirrhosis.
• Abnormal coagulation laboratory values defined as INR or PT greater than 1.5 x ULN, or PTT/aPTT greater than 1.5 x ULN.
• Suspected active or latent tuberculosis.
• Positive test results for chronic hepatitis B infection (HBsAg positive) or positive test results for hepatitis C with positive HCV RNA.
• Diagnosis with SARS-CoV-2 infection within 30 days prior to first study treatment, or documented infection within 6 months with persistent respiratory symptoms.
• History of progressive multifocal leukoencephalopathy (PML).
• Pregnancy, breastfeeding, or intention of becoming pregnant during the study.