This phase II trial tests the safety and side effects of glofitamab and obinutuzumab and how well they work in treating patients with mantle cell lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory) after receiving CD19-directed chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a form of immunotherapy where the immune system cell, T-cell, is changed to attack cancer cells. Glofitamab is a bispecific antibody that can bind to two different antigens at the same time. Glofitamab binds to CD3, a protein found on T cells (a type of white blood cell), and CD20 a protein found on B cells (another type of white blood cell) and some lymphoma cells. This may help the immune system kill cancer cells. Obinutuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Giving glofitamab and obinutuzumab may be safe, tolerable, and/or effective in treating patients with relapsed or refractory mantle cell lymphoma after receiving CD19-directed CAR T-cell therapy.

PRIMARY OBJECTIVE:

I. To determine the proportion of relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients with an objective response (OR) to glofitamab after prior treatment with chimeric antigen receptor (CAR)-T.

SECONDARY OBJECTIVES:

I. To describe the proportion of patients with a complete response (CR). II. To describe the progression-free survival (PFS) and overall survival (OS) at 24 months.

III. To describe the incidence of grade 3-4 cytokine release syndrome (CRS). IV. To describe the incidence of grade 3-4 neurologic toxicity. V. To describe the relationship between glofitamab clearance at baseline, changes in clearance over time, treatment response, and duration of response.

EXPLORATORY OBJECTIVES:

I. To evaluate the relationship between circulating tumor deoxyribonucleic acid (DNA) (ctDNA) detection in plasma, treatment response, and duration of response.

II. To evaluate the relationship between CAR T-cell levels in plasma, immunophenotype, treatment response, and duration of response.

III. To evaluate the relationship between fluorodeoxyglucose positron emission tomography/ computed tomography (FDG PET/CT) interlesional treatment response heterogeneity and survival outcomes.

IV. To evaluate the relationship between organ-specific changes in standardized uptake value (SUV) metrics and immune-related adverse events (AEs).

OUTLINE:

Patients receive obinutuzumab intravenously (IV) on day 1 or on days 1 and 2 of cycle 1 and glofitamab IV over 8 hours on days 8 and 15 of cycle 1 then over 2-8 hours on day 1 of cycles 2-12. Cycles repeat every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and PET/CT throughout the study.

After completion of study treatment, patients are followed every 3 months for up to 2 years.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed diagnosis of mantle cell lymphoma that is relapsed (disease progression after the last treatment regimen) or refractory (failure to achieve a partial or complete response from the last treatment regimen)
• Patients must have been previously treated with an anti-CD19 CAR T-cell therapy and have failed or been intolerant to Bruton's tyrosine kinase (BTK) inhibition. Both commercial and investigational CAR-T products which target CD19 will be allowed, including dual-targeting products
• Patients must have at least one bi-dimensionally measurable (defined as at least 1.5 cm) nodal lesion or one bi-dimensionally measurable (at least 1 cm) extranodal lesion, as measured on CT scan
• Age ≥ 18 years. Because no dosing or adverse event (AE) data are currently available on the use of glofitamab and obinutuzumab in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 50,000/mcL
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or ≤ 3 x institutional ULN if the patient has Gilbert syndrome
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN
• Creatinine ≤ 1.5 x institutional ULN OR glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2
• Patients with human immunodeficiency virus (HIV) infection are eligible if on effective anti-retroviral therapy with undetectable viral load within 6 months
• Patients with a history of hepatitis B virus (HBV) infection or positive total hepatitis B core antibody (HBcAb) are eligible if the hepatitis B surface antigen (HBsAg) is negative and HBV DNA viral load is undetectable by polymerase chain reaction (PCR) at the time of screening. Such patients must be managed with appropriate anti-viral therapy, if indicated, and must be willing to undergo HBV DNA testing on day 1 of each cycle and every 3 months for at least 12 months after the final cycle of study treatment
• Patients with a history of hepatitis C virus (HCV) infection or positive HCV antibody are eligible if HCV ribonucleic acid (RNA) viral load is undetectable by PCR
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression and patients are asymptomatic from CNS involvement
• Patients with new, progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that patients are asymptomatic and immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial, such as patients with prostate cancer or breast cancer receiving hormonal therapy
• The effects of glofitamab and obinutuzumab on the developing human fetus are unknown. For this reason and because glofitamab and obinutuzumab are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 2 months after completion of glofitamab and 6 months after completion of obinutuzumab administration. Women of childbearing potential must use effective contraceptive precautions 2 months after completion of glofitamab treatment and 18 months after the last dose of obinutuzumab treatment
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

• Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to glofitamab and obinutuzumab
• Pregnant women are excluded from this study because glofitamab and obinutuzumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with glofitamab and obinutuzumab, breastfeeding should be discontinued if the mother is treated with glofitamab and obinutuzumab
• Patients with active CRS or requiring intervention for CRS within 14 days prior to study enrollment
• Patients with active neurotoxicity or requiring intervention for neurotoxicity within 14 days prior to study enrollment
• Patients requiring antimicrobial treatment or hospitalization for active infection within 14 days prior to study enrollment for known active bacterial, viral (including severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds). Infection must be completely resolved prior to initiation of study treatment
• Patients receiving systemic immunosuppressive medications within 14 days prior to study enrollment, including, but not limited to: prednisone ≥ 20 mg per day, azathioprine, methotrexate, anti-tumor necrosis factor agents, anti-interleukin-6/6R agents, or anti-interleukin 1 agents, are not eligible. The use of inhaled corticosteroids is permitted
• Patients with known or suspected chronic active Epstein Barr virus (EBV) or cytomegalovirus (CMV) infection
• Patients with known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
• Patients with prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3
• Patients with known history of progressive multifocal leukoencephalopathy
• Patients with current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator are allowed
• Patients with the significant cardiovascular disease, including New York Heart Association class III or IV or otherwise symptomatic heart failure (stage C or D), myocardial infarction within the last 3 months, unstable arrhythmias, or unstable angina
• Patients who have undergone major surgery for non-diagnostic purposes within 4 weeks before first study treatment
• Patients who have received a live attenuated vaccine within 4 weeks before first study treatment administration or anticipation that such a live, attenuated vaccine will be required during the study
• Patients with a positive SARS-CoV-2 test 7 days prior to enrollment
• Patients with current or past history of Waldenström macroglobulinemia
• Patients with an active autoimmune disease that could be exacerbated by immunotherapy, excluding those with a remote history or well-controlled autoimmune disease

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