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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Trial of Polatuzumab Vedotin, Obinutuzumab and Glofitamab as a Peri-CAR-T Cell Treatment Strategy in Large B-cell Lymphoma

Conditions
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Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Glofitamab
* Drug: Polatuzumab vedotin
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Part 1: 42 patients, Part 2: 42-57 patients (some Part 1 patients may also participate in Part 2)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>Patients whose large B-cell lymphoma has progressed/not responded to previous treatment and are due to start standard CAR-T therapy. All patients receive 2 cycles of glofitamab and polatuzumab vedotin (Glofit-Pola). Obinutuzumab pre-treatment is given on cycle 1 day 1. Patients have a PET-CT scan to check the response after cycle 2. If the scan shows a response and patients are still suitable for CAR-T cell therapy, patients will proceed to receive planned CAR-T therapy and will not receive further Glofit-Pola in Part 1. If not, patients can receive 4 more cycles of glofitamab and polatuzumab vedotin, and then 6 cycles of glofitamab. | Drug: Glofitamab<br>* 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).<br>* Other names: Columvi;Drug: Polatuzumab vedotin<br>* 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.<br>* Other names: Polivy;Drug: Obinutuzumab<br>* Obinutuzumab pre-treatment is given intravenously at a dose of 1g on Cycle 1 Day 1.<br>* Other names: Gazyvaro;|
| Experimental: Part 2<br>Patients whose large B-cell lymphoma has progressed/not responded after standard CAR-T cell therapy. All patients receive 6 cycles of glofitamab and polatuzumab vedotin (Glofit-Pola), and then 6 cycles of glofitamab alone. Obinutuzumab pre-treatment is given on cycle 1 day 1. | Drug: Glofitamab<br>* 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).<br>* Other names: Columvi;Drug: Polatuzumab vedotin<br>* 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.<br>* Other names: Polivy;Drug: Obinutuzumab<br>* Obinutuzumab pre-treatment is given intravenously at a dose of 1g on Cycle 1 Day 1.<br>* Other names: Gazyvaro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Overall Response Rate (ORR) to Pola-Glofit as bridging prior to CAR-T cell infusion | 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. | At Cycle 2 Day 14 (or earlier) (each cycle is 21 days) | 
| Part 2: Progression Free Survival (PFS) at 6 months | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Complete Metabolic Response (CMR) rate to Pola-Glofit as bridging prior to CAR-T cell infusion | Per Lugano 2014 criteria | At Cycle 2 Day 14 of bridging treatment (each cycle is 21 days) | 
| Part 1: Overall Survival (OS) and Progression Free Survival (PFS) | Medians (if reached), rates at 6 months and 1 year and plots will be presented | 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. | 
| Part 1: Safety and toxicity of Pola-Glofit as bridging therapy | 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. | 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) | 
| Part 1: CAR-T associated toxicity post Pola-Glofit bridging 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. | Between Day 0 and Day 28 following CAR-T therapy | 
| Part 1: Response rate post CAR-T for all infused patients | Per Lugano 2014 criteria. Response rates at 1, 3 and 6 months post CAR-T therapy. | From CAR-T infusion until 6 months post CAR-T therapy | 
| Part 1: Duration of Response (DoR) and Duration of Complete Response (DoCR) for Pola-Glofit and CAR-T | Response defined as PR (partial response) or better. | From the date of first response until disease progression. This will be assessed from the date of registration until up to 4 years. | 
| Part 1: Non-Relapse Mortality (NRM) | NRM rates at 6 months and 1 year | From the date of registration until the date of NRM. This will be assessed from the date of registration until up to 4 years. | 
| Part 2: Complete Metabolic Response (CMR) rate to Pola-Glofit/Glofitamab at any point | Per Lugano 2014 criteria | From the date of registration until up to 4 years | 
| Part 2: Response rate for patients who received Pola-Glofit bridging versus those who have not | Per Lugano 2014 criteria. Response rates following 2 and 6 cycles of Part 2 treatment. | From the date of registration until Cycle 6 (approximately 15 weeks. Each cycle is 21 days). | 
| Part 2: Safety and toxicity of Pola-Glofit post CAR-T therapy | 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. | 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) | 
| Part 2: Overall Survival (OS) | Median (if reached), rates at 6 months and 1 year (with 95% CIs) and plots will be presented. | From the date of registration for Part 2 until the date of death, assessed up to 4 years. | 
| Part 2: Duration of Response (DoR) | Response defined as PMR (partial metabolic response) or better. | From the date of first response until disease progression, assessed up to 4 years. | 
| 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 rates will be presented at 6 months and 1 year. | 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. | 
| Part 2: Progression Free Survival (PFS) (at 12 months) | Median (if reached), rate at 12 months (with 95% CI) and plot will be presented | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glofitamab, Polatuzumab vedotin, Obinutuzumab, Bridging therapy, Large B-cell Lymphoma