PRIMARY OBJECTIVE:~I. To evaluate the efficacy of venetoclax, glofitamab and lenalidomide in newly diagnosed patients with high risk mantle cell lymphoma (MCL) as measured by progression free survival (PFS) at 24 months.~SECONDARY OBJECTIVES:~I. To evaluate the safety and tolerability of the combination of lenalidomide, venetoclax and glofitamab in patients with newly diagnosed MCL.~II. To determine overall response rate (ORR) of patients with newly diagnosed MCL who are treated with the combination of lenalidomide, venetoclax and glofitamab.~III. To determine the complete remission rate of the combination in patients with untreated MCL.~IV. To determine the PFS at 24 months of the patients with p53 mutation versus (vs.) those who lack this abnormality.~V. To determine duration of response of patients treated with the combination lenalidomide, venetoclax and glofitamab.~VI. To determine progression free survival of patients who obtain minimal residual disease (MRD) negativity.~EXPLORATORY OBJECTIVES:~I. To evaluate changes in T-cell repertoire at baseline and on treatment based on exposure to glofitamab utilizing immune-sequence (seq) assay.~II. To determine if any other baseline genetic feature impacts response and/or duration of response to the treatment regimen.~III. To evaluate outcomes of treated patients based on segregation into distinct MCL clusters using whole exome sequencing (WES).~IV. To determine if rates of cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) are impacted by co-administration of lenalidomide/venetoclax in conjunction with glofitamab.~V. To determine if utilization and efficacy of tocilizumab for CRS is impacted by co-administration of lenalidomide/venetoclax in conjunction with glofitamab.~OUTLINE:~Patients receive venetoclax orally (PO), obinutuzumab intravenously (IV), glofitamab IV, and lenalidomide IV on study. Patients undergo bone marrow biopsy, blood sample collection, and computed tomography (CT) scan and/or positron emission tomography (PET) scan throughout the study. Patients may undergo tumor biopsy throughout the study.~Patients are followed-up every 3 months for the first two years, and then every 6 months starting in the third year until disease recurrence.
This phase I/II trial tests the safety and effectiveness of glofitamab (with obinutuzumab pretreatment), venetoclax, and lenalidomide in treating patients with newly diagnosed, high risk mantle cell lymphoma. Glofitamab and obinutuzumab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Lenalidomide works by helping the immune system kill cancer cells and by helping the bone marrow to produce normal blood cells. Giving venetoclax, glofitamab with obinutuzumab, and lenalidomide together may kill more cancer cells in patients with newly diagnosed, high risk mantle cell lymphoma.