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

This is a phase 2, open label trial conducted in 2 parts.

The overall aim is:

Part 1: To determine the efficacy of Pola-Glofit as bridging treatment to CAR-T cell therapy in patients with relapsed or refractory large B cell lymphomas.

Part 2: To determine the efficacy of Pola-Glofit in patients with relapsed or refractory large B cell lymphomas who have failed to achieve CMR, or progressed after CAR-T cell therapy.

Treatment consists of:

Part 1: Patients will receive 2 cycles of Pola-Glofit. Obinutuzumab is given 7 days before the first dose of Glofit. After 2 cycles, patients have a PET-CT scan to check the response. If the scan shows a response and the patient is still suitable for CAR-T, patients will receive planned CAR-T therapy. If the patient is not suitable to continue with CAR-T, patients can receive up to 4 more cycles of Pola-Glofit, and then 6 cycles of Glofit.

Part 2: Patients will receive 6 cycles of Pola-Glofit, and then 6 cycles of Glofit. Obinutuzumab is given 7 days before the first dose of Glofit.

For both Part 1 and Part 2, all cycles are 21 days. A step-up dosing regimen will be followed:

• Cycle 1 Day 1: Obinutuzumab is given intravenously at a dose of 1g over 4-5 hours.
• Cycle 1 Day 2: Polatuzumab is given intravenously at a dose of 1.8mg/kg over 90 minutes.
• Cycle 1 Day 8: Glofitamab is given intravenously at a dose of 2.5mg over 4 hours. Patients need to stay in hospital for 24 hours.
• Cycle 1 Day 15: Glofitamab is given intravenously at a dose of 10mg over 2 hours. (Patients may need to stay in hospital for 24 hours.)
• From Cycle 2-6, Polatuzumab is given intravenously at a dose of 1.8mg/kg over 30 minutes on Day 1, and Glofitamab is given intravenously at a dose of 30mg over 2 hours on Day 1.
• From Cycle 7-12, Glofitamab is given intravenously at a dose of 30mg over 2 hours on Day 1.

Patients will be followed up until the last patient completes their 1 year post-treatment follow up visit.

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