Overview
The PORTAL study will test a new combination of drugs (glofitamab, polatuzumab vedotin and obinutuzumab) in patients with large B-cell lymphoma (LBCL) that has come back (relapsed) or not responded to previous treatment. It will determine how safe and effective the combination of these cancer drugs is in treating LBCL before and after CAR-T cell therapy.
Description
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.
Eligibility
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