Large B-cell Lymphoma
Conditions
Keywords
Glofitamab, Polatuzumab vedotin, Obinutuzumab, Bridging therapy, Large B-cell Lymphoma
Brief summary
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.
Detailed 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.
Interventions
DRUGPolatuzumab vedotin
Polatuzumab is given intravenously at a dose of 1.8mg/kg on Cycle 1 Day 2, and then Day 1 of Cycle 2-Cycle 6.
DRUGGlofitamab
Glofitamab is given intravenously at a dose of 2.5mg over 4 hours on Cycle 1 Day 8. Patients need to stay in hospital for 24 hours. Glofitamab is given intravenously at a dose of 10mg over 2 hours on Cycle 1 Day 15. (Patients may need to stay in hospital for 24 hours.) Glofitamab is given intravenously at a dose of 30mg over 2 hours on Day 1 of Cycles 2-12 (as relevant).
DRUGObinutuzumab
Obinutuzumab pre-treatment is given intravenously at a dose of 1g on Cycle 1 Day 1.
Sponsors
Hoffmann-La Roche
University College, London
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part 1: 42 patients, Part 2: 42-57 patients (some Part 1 patients may also participate in Part 2)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Overall Response Rate (ORR) to Pola-Glofit as bridging prior to CAR-T cell infusion | At Cycle 2 Day 14-19 (or earlier) (each cycle is 21 days) | To determine the efficacy of Pola-Glofit as bridging treatment to CAR-T cell therapy in patients with r/r LBCL. ORR i.e. the proportion of patients achieving response (Complete Metabolic Response or Partial Metabolic Response) after Pola-Glofit bridging but prior to CAR-T cell infusion, assessed by central review as per 2014 Lugano Classification. This will be presented as a rate with a 70% confidence interval. |
| Part 2: Progression Free Survival (PFS) at 6 months | From the date of registration at Part 2 until the date of first disease progression or death, whichever comes first, assessed up to 4 years | To determine the efficacy of Pola-Glofit in patients with LBCL who have failed to achieve CMR, or progressed after CAR-T cell therapy. PFS at 6 months will be analysed using Kaplan-Meier survival analysis, with the rate at 6 months (with 70% CI) presented. The median (if reached) and plot will also be given. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Safety and toxicity of Pola-Glofit as bridging therapy | From registration and during Part 1 bridging treatment, until end of post-treatment safety reporting window (up to six months after last dose of obinutuzumab, plus a further 35 days after last dose of polatuzumab vedotin or last dose of glofitamab) | Assessed by CTCAE criteria v5 and ASTCT 2019 criteria for CRS/ICANS adverse events. Assessed in all patients given at least one dose of study treatment in part 1. |
| Part 1: CAR-T associated toxicity post Pola-Glofit bridging following CAR-T therapy | Between Day 0 and Day 28 following CAR-T therapy | Assessed in all patients given at least one dose of study treatment in part 1 and infused. Assessed by CTCAE criteria v5 and ASTCT 2019 criteria for CRS/ICANS adverse events. |
| Part 1: Response rate post CAR-T for all infused patients | From CAR-T infusion until 6 months post CAR-T therapy | Per Lugano 2014 criteria. Response rates at 1, 3 and 6 months post CAR-T therapy. |
| Part 1: Duration of Response (DoR) and Duration of Complete Response (DoCR) for Pola-Glofit and CAR-T | From the date of first response until disease progression. This will be assessed from the date of registration until up to 4 years. | Response defined as PR (partial response) or better. |
| Part 1: Non-Relapse Mortality (NRM) | From the date of registration until the date of NRM. This will be assessed from the date of registration until up to 4 years. | NRM rates at 6 months and 1 year |
| Part 2: Complete Metabolic Response (CMR) rate to Pola-Glofit/Glofitamab at any point | From the date of registration until up to 4 years | Per Lugano 2014 criteria |
| Part 1: Complete Metabolic Response (CMR) rate to Pola-Glofit as bridging prior to CAR-T cell infusion | At Cycle 2 Day 14-19 of bridging treatment (each cycle is 21 days) | Per Lugano 2014 criteria |
| Part 2: Safety and toxicity of Pola-Glofit post CAR-T therapy | Throughout Part 2 treatment until end of post-treatment safety reporting window (up to six months after last dose of obinutuzumab, plus a further 35 days after last dose of polatuzumab vedotin or last dose of glofitamab) | Assessed by CTCAE criteria v5 and ASTCT 2019 criteria for CRS/ICANS adverse events. Assessed in all patients given at least one dose of study treatment in part 2. |
| Part 2: Overall Survival (OS) | From the date of registration for Part 2 until the date of death, assessed up to 4 years. | Median (if reached), rates at 6 months and 1 year (with 95% CIs) and plots will be presented. |
| Part 2: Duration of Response (DoR) | From the date of first response until disease progression, assessed up to 4 years. | Response defined as PMR (partial metabolic response) or better. |
| Part 2: Duration of Complete Response (DoCR) | From the date of first complete metabolic response (CMR) until disease progression, assessed up to 4 years. | — |
| Part 2: Non-Relapse Mortality (NRM) | NRM will be measured from the date of registration until the date of NRM. This will be assessed from the date of registration until up to 4 years. NRM rates will be presented at 6 months and 1 year. | NRM rates will be presented at 6 months and 1 year. |
| Part 2: Progression Free Survival (PFS) (at 12 months) | PSF will be measured from the date of registration at Part 2 until the date of disease progression. This will be assessed from the date of registration until up to 4 years. The median rate at 12 months will be presented. | Median (if reached), rate at 12 months (with 95% CI) and plot will be presented |
| Part 2: Response rate for patients who received Pola-Glofit bridging versus those who have not | From the date of registration until Cycle 5 (approximately 12 weeks. Each cycle is 21 days). | Per Lugano 2014 criteria. Response rates following 2 and 5 cycles of Part 2 treatment. |
| Part 1: Overall Survival (OS) and Progression Free Survival (PFS) | From the date of registration at Part 1 until the date of disease progression or death (PFS), or death (OS). This will be assessed from the date of registration until up to 4 years. | Medians (if reached), rates at 6 months and 1 year and plots will be presented |
Countries
United Kingdom
Contacts
Primary ContactPORTAL Trial Manager
Outcome results
None listed