Mosunetuzumab or Glofitamab for the Treatment of Relapsed or Refractory Diffuse Large B-cell or Transformed Follicular Lymphoma After Receiving CAR T-cell Therapy

Inclusion Criteria

• Subject must be able and willing to provide informed consent * Informed consent will be obtained after CAR-T cell therapy * In the case where the patient is incapacitated or not otherwise capable, a legally authorized representative (or decision maker when there is not an advanced directive in place) must be willing to provide informed consent on behalf of the patient
• Age >= 18 years
• Able to comply with the study protocol, in the investigator’s judgment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Life expectancy of at least 12 weeks
• History of relapsed or refractory (r/r) LBCL (including transformation of indolent lymphoma) who have relapsed after or failed to respond to at least two prior standard systemic treatment regimens that include at least one prior regimen containing an anthracycline and at least one containing an anti-CD20 directed therapy and for whom there is no available therapy expected to improve survival (e.g., standard chemotherapy, autologous or allogeneic stem cell transplant). Any line of therapy utilized with the intent of treating the aggressive LBCL prior to leukapheresis will be counted as a treatment regimen. Any line of therapy utilized after leukapheresis with a documented imaging response of stable disease or progressive disease will also be considered a line of therapy. * The following other LBCL subtypes will be excluded: ** Primary DLBCL of CNS ** Plasmablastic lymphoma ** HHV8-postive DLBCL ** Primary effusion lymphoma ** B-cell lymphoma, unclassifiable ** Lymphomatoid granulomatosis (all grades other than III) ** Burkitt lymphoma will be excluded
• Patients must have had a positron emission tomography (PET)/computed tomography (CT) scan (preferred), diagnostic CT scan, or magnetic resonance imaging (MRI) prior to CAR T cell therapy, with at least one bi-dimensionally measurable lesion (>= 1.5 cm for nodal lesion or >= 1cm for extra-nodal lesions in largest dimension by low-dose computerized tomography [CT] scan with fluorodeoxyglucose (FDG)-uptake >= liver); this imaging must have been obtained within 56 days of receiving CAR T cell therapy.
• Patients must have a PET/CT scan (preferred), diagnostic CT scan, or MRI with at least one bi-dimensionally measurable lesion (>= 1.5 cm for nodal lesion or >= 1 cm for extra-nodal lesions in largest dimension by low-dose computerized tomography [CT] scan with FDG-uptake >= liver); this imaging documenting measurable disease must be obtained at least day +30 after CAR T cell infusion and prior to cycle 1 day 1
• Although patients may be consented and screened for eligibility any time after CAR T cell infusion, patients must be at least 30 days after CAR T-cell infusion at time of study enrollment
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the upper limit of normal
• Total bilirubin < 1.5 times the upper limit of normal; patients with a documented history of Gilbert syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible
• Platelet count >= 50,000/mm^3 (transfusions permitted) (within 21 days prior to first dose of bi-specific antibody)
• Absolute neutrophil count (ANC) >= 1000/mm^3 (granulocyte colony-stimulating factor [G-CSF] permitted) (within 21 days prior to first dose of bi-specific antibody)
• Hemoglobin >= 9.0 g/dL (transfusions permitted) (within 21 days prior to first dose of bi-specific antibody)
• Patients who do not meet criteria for hematologic function because of extensive marrow involvement by lymphoma and/or disease-related cytopenias, e.g., hypersplenism, may be enrolled into the study.
• Serum creatinine < 2.0 mg/dL or estimated creatinine clearance (CrCl) >= 45 mL/min by Cockcroft-Gault method
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, and agreement to refrain from donating eggs, during the treatment period and for at least 3 months after the last dose of bispecific antibody and for at least 18 months after the last dose of obinutuzumab. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a post-menopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm. With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 60 days after the last dose of bispecific antibody or obinutuzumab, whichever comes last, to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception

Exclusion Criteria

• Inability or unwillingness of the patient or legally authorized representative (or decision-maker when there is not an advanced directive in place) to provide informed consent
• Patients who had > grade 3 cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy (ASTCT) criteria after CAR-T therapy or who have unresolved cytokine release syndrome (CRS) after CAR-T therapy
• Patients who had >= grade 2 neurologic toxicity by ASTCT criteria after CAR-T therapy or who have active neurologic toxicity after CAR-T therapy
• Inability to comply with protocol-mandated hospitalization and activities restrictions in the investigators’ decision
• Pregnant or lactating, or intending to become pregnant during the study or within 3 months after the last dose of bispecific antibody or 18 months of obinutuzumab, whichever comes later
• Persons who are not postmenopausal (> 12 months of non-therapy-induced amenorrhea) or surgically sterile (removal of ovaries and/or uterus) must have a negative serum pregnancy test result prior to initiation of study drug
• Prior solid organ transplantation
• History of systemic autoimmune disease, including but not limited to myocarditis, pneumonitis (if related to autoimmune disease), myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, uveitis, vasculitis, or glomerulonephritis * Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study if approved by the medical monitor * Patients with a history of lymphoma-related immune thrombocytopenic purpura or autoimmune hemolytic anemia in remission may be eligible for this study if approved by the medical monitor * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous months * Patients with a history of non-serious autoimmune disease, including polymyalgia rheumatic, that is in remission or that requires the corticosteroid equivalent of prednisone < 20 mg/mg day are not excluded * Note that drug-induced hypersensitivity pneumonitis would not be exclusionary
• Patients with history of confirmed progressive multifocal leukoencephalopathy (PML)
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
• History of other malignancy that could affect compliance with the protocol or interpretation of results * Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are allowed * Patients with a malignancy that has been treated with curative intent will also be allowed if the malignancy is in remission prior to first mosunetuzumab or glofitamab administration
• Significant cardiovascular disease such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina
• Significant active pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease) requiring oxygen or continuous corticosteroid use at time of study drug start
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major documented infection requiring treatment with IV antibiotics or hospitalization within 2 weeks prior to first mosunetuzumab or glofitamab administration. Empiric or prophylactic antibiotics administered during neutropenia or neutropenic fever without microbiologic evidence of infection do not exclude patients
• Recent major surgery within 4 weeks prior to first mosunetuzumab or glofitamab administration
• Patients with the following active or chronic infection(s) would have increased risks for toxicity if treated with bispecific antibody therapy, thus will be excluded: * Positive serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection. Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation. * Acute or chronic hepatitis C virus (HCV) infection. Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation * Positive serologic test results for human immunodeficiency virus (HIV) infection
• Administration of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study * Patients must not receive live, attenuated vaccines (e.g., FluMist) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges. Killed vaccines or toxoids should be given at least 4 weeks prior to the first dose of study treatment to allow development of sufficient immunity. SARS-CoV-2 vaccines that have been granted "Emergency use authorization" are not considered "investigational" therapy for the purposes of study inclusion/exclusion criteria. Subjects who receive a SARS-CoV-2 vaccine should ideally complete the vaccination course at least 1 week prior to starting/initiating treatment on this trial. If a SARS-CoV-2 vaccine is administered while the patient is already receiving treatment with bispecific antibody therapy, administration of the vaccine should ideally be timed to take place after completion of bispecific antibody step-up dosing (at least 1 week after administration of target dose, with resolution of treatment-emergent AEs). Additionally, SARS-CoV2 vaccine should ideally be administered in the middle of a treatment cycle, i.e. 1 week before or after a dose of bispecific antibody study therapy, if feasible. Subjects may receive the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination any time at the discretion of the treating physician and with approval from the study Sponsor-Investigator.” * Investigators should review the vaccination status of potential study patients being considered for this study and follow the United States (U.S.) Centers for Disease Control and Prevention guidelines for adult vaccination with any other non-live vaccines intended to prevent infectious diseases prior to study.
• Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment < 20 mg/day prednisone or equivalent within 2 weeks prior to first dose of bispecific antibody * Patients who received acute, systemic immunosuppressant medications (e.g., dexamethasone for nausea or B symptoms) may be enrolled if approved by the sponsor and medical monitor * The use of inhaled corticosteroids is permitted * The use of mineralocorticoids for management of orthostatic hypotension is permitted * The use of physiologic doses of corticosteroids (< 20mg/day of prednisone or equivalent) for uses such as management of adrenal insufficiency is permitted
• History of drug or alcohol abuse within 12 months prior to screening in the investigator’s judgment
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s and/or Medical Monitor’s judgment, precludes the patient’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results