A Trial of Polatuzumab Vedotin, Obinutuzumab and Glofitamab as a Peri-CAR-T Cell Treatment Strategy in Large B-cell Lymphoma (PORTAL)

Inclusion Criteria: Histologically proven CD20+ LBCL (with CD20 positivity at any timepoint) including diffuse large B cell lymphoma, high grade B cell lymphoma with MYC, BCL2 and/or BCL6 (double/triple hit lymphoma), high grade B cell lymphoma not otherwise specified (NOS), primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Part 1: Relapsed or refractory disease and eligible for CAR T-cell therapy in the UK and in need of systemic bridging in the opinion of the local investigator. Part 2: Failed to achieve CMR (Deauville score 1-3) on PET scan 1-month post CAR-T or progressed at any point post CAR-T (patients in part 2 may have been previously enrolled in Part 1 and responded to Pola-Glofit bridging or be de novo patients who are naïve to this combination) At least one measurable target lesion Patient has recent archival biopsy tissue available or is willing to undergo a new biopsy. ECOG performance status: Part 1: ECOG PS 0/1 Part 2: ECOG PS 0-2 Life expectancy of ≥ 12 weeks Adequate haematological status. Adequate liver and renal function Negative test for hepatitis B, hepatitis C, HIV and SARS-CoV-2 Exclusion Criteria: Patients with known active infection Current ≥ Grade 2 peripheral neuropathy History of confirmed progressive multifocal leukoencephalopathy Current evidence of CNS lymphoma Patients with another invasive malignancy in the last 2 years Significant history of cardiovascular disease Active autoimmune disease or immune deficiency Severe neurological disorder Uncontrolled tumour-related pain Uncontrolled pleural effusion, pericardial effusion, or ascites Treatment with other standard anti-cancer radiotherapy/chemotherapy including investigational therapy and targeted therapy within 4 weeks prior to cycle 1 day 1 Prior solid organ transplantation Prior allogeneic stem cell transplant Autologous SCT within 100 days prior to cycle 1 day 1 Any history of immune related ≥ Grade 3 adverse events Ongoing corticosteroid use > 25 mg/day of prednisone or equivalent within 4 weeks prior to study treatment Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment Administration of a live, attenuated vaccine within 4 weeks prior to cycle 1 day 1 History of severe allergic anaphylactic reactions to chimeric or humanised monoclonal antibodies or recombinant antibody-related fusion proteins. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the obinutuzumab, polatuzumab vedotin and/or glofitamab formulation. Known or suspected history of HLH