Sonrotoclax, glofitamab and chemotherapy for returning or hard-to-treat large B-cell lymphoma

Who can take part

• Histologically confirmed CD20-positive relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS); large B-cell lymphoma transformed from an indolent B-cell lymphoma; EBV-positive large B-cell lymphoma; high-grade B-cell lymphoma; and double-hit or triple-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements
• At least one prior line of systemic anti-lymphoma therapy. Prior treatment should generally have included an anti-CD20 monoclonal antibody and an anthracycline, unless there was a clear contraindication or the treatment was unavailable
• Age 18 years or older
• At least one evaluable or measurable target lesion, defined as a lymph node lesion with a longest diameter greater than 1.5 cm or an extranodal lesion with a longest diameter greater than 1.0 cm
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Adequate organ function, including left ventricular ejection fraction (LVEF) of at least 50%; creatinine clearance of at least 50 mL/min, although a minimum of 40 mL/min may be acceptable if the investigator determines that treatment can be administered safely; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no greater than 3 × the upper limit of normal (ULN), or no greater than 5 × ULN in the presence of hepatic involvement; total bilirubin no greater than 1.5 × ULN, or no greater than 3 × ULN in participants with Gilbert syndrome or hepatobiliary involvement; and corrected electrolytes and tumor lysis syndrome-related laboratory parameters considered suitable for treatment
• Adequate hematologic function, including absolute neutrophil count (ANC) of at least 1.0 × 10\^9/L, platelet count of at least 50 × 10\^9/L, and hemoglobin of at least 60 g/L. Transfusion support to meet these criteria is permitted. Participants with cytopenias attributable to bone marrow involvement by lymphoma are exempt from these hematologic requirements
• A negative pregnancy test for women of childbearing potential. Male and female participants must agree to use effective contraception during study treatment and for the protocol-specified period after the last dose of study treatment
• Estimated life expectancy greater than 3 months
• Ability and willingness to provide written informed consent and comply with the study protocol

Who cannot take part

• Previous central nervous system involvement by lymphoma, including involvement of the brain parenchyma, meninges, cerebrospinal fluid, spinal cord, or intraocular structures
• Major surgery or serious trauma within 2 weeks before enrollment, or clinically significant treatment-related adverse effects that have not adequately recovered
• History of cerebral infarction or intracranial hemorrhage within 3 months before enrollment
• Prior treatment with glofitamab
• Documented disease progression during or after prior treatment with a BCL-2 inhibitor when, in the investigator's judgment, the participant is unlikely to derive benefit from sonrotoclax
• Failure to meet the required washout period from prior antitumor therapy, including chemotherapy, radiotherapy, or antibody-drug conjugate therapy within 2 weeks or within 5 half-lives; monoclonal antibody or bispecific antibody therapy within 4 weeks; CAR T-cell therapy within 30 days; or autologous stem cell transplantation within 3 months. Prior allogeneic stem cell transplantation or active graft-versus-host disease is also exclusionary
• Use of systemic corticosteroids equivalent to prednisone greater than 20 mg/day within 2 weeks before enrollment when the dose cannot be reduced to an acceptable level
• Severe hypersensitivity to glofitamab, obinutuzumab, gemcitabine, oxaliplatin, sonrotoclax, or any of their excipients
• Active infection that, in the investigator's judgment, cannot be adequately controlled
• Human immunodeficiency virus (HIV) infection or inadequately controlled active hepatitis B virus or hepatitis C virus infection
• High and inadequately controlled risk of tumor lysis syndrome before enrollment
• Severe cardiovascular or pulmonary disease, including New York Heart Association Class III-IV heart failure, myocardial infarction within 6 months, unstable arrhythmia or angina, severe chronic obstructive pulmonary disease, active pneumonia, requirement for long-term supplemental oxygen, or resting oxygen saturation of 90% or lower
• Current malignancy or another malignancy diagnosed within 3 years before enrollment, except for cured low-risk malignancies
• Active bleeding, coagulation disorder, or an unacceptable bleeding risk as determined by the investigator
• Psychiatric illness, cognitive impairment, drug or alcohol dependence, or any other factor that may interfere with understanding the study, providing informed consent, or complying with study procedures and follow-up
• Any other condition that, in the investigator's judgment, may compromise participant safety, interfere with study conduct, or confound interpretation of study data
• Pregnancy or breastfeeding, or plans to become pregnant or father a child during the study period