Clinical trial NCT06071871: A Trial of Polatuzumab Vedotin, Obinutuzumab and Glofitamab As a Peri-CAR-T Cell Treatment Strategy in Large B-cell Lymphoma
Official title: A Phase II Trial of Polatuzumab Vedotin, Obinutuzumab and Glofitamab As a Peri-CAR-T Cell Treatment Strategy in Large B-cell Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Large B-cell Lymphoma
Keywords: Glofitamab
Polatuzumab vedotin
Obinutuzumab
Bridging therapy
Large B-cell Lymphoma
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2023-10-10
Enrollment: 99
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Part 1: 42 patients, Part 2: 42-57 patients (some Part 1 patients may also participate in Part 2)
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Overall Response Rate (ORR) to Pola-Glofit as bridging prior to CAR-T cell infusion
timeFrame: At Cycle 2 Day 14-19 (or earlier) (each cycle is 21 days)
measure: Part 2: Progression Free Survival (PFS) at 6 months
timeFrame: 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 outcomes:
measure: Part 1: Complete Metabolic Response (CMR) rate to Pola-Glofit as bridging prior to CAR-T cell infusion
timeFrame: At Cycle 2 Day 14-19 of bridging treatment (each cycle is 21 days)
measure: Part 1: Overall Survival (OS) and Progression Free Survival (PFS)
timeFrame: 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.
measure: Part 1: Safety and toxicity of Pola-Glofit as bridging therapy
timeFrame: 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)
measure: Part 1: CAR-T associated toxicity post Pola-Glofit bridging following CAR-T therapy
timeFrame: Between Day 0 and Day 28 following CAR-T therapy
measure: Part 1: Response rate post CAR-T for all infused patients
timeFrame: From CAR-T infusion until 6 months post CAR-T therapy
measure: Part 1: Duration of Response (DoR) and Duration of Complete Response (DoCR) for Pola-Glofit and CAR-T
timeFrame: From the date of first response until disease progression. This will be assessed from the date of registration until up to 4 years.
measure: Part 1: Non-Relapse Mortality (NRM)
timeFrame: From the date of registration until the date of NRM. This will be assessed from the date of registration until up to 4 years.
measure: Part 2: Complete Metabolic Response (CMR) rate to Pola-Glofit/Glofitamab at any point
timeFrame: From the date of registration until up to 4 years
measure: Part 2: Response rate for patients who received Pola-Glofit bridging versus those who have not
timeFrame: From the date of registration until Cycle 5 (approximately 12 weeks. Each cycle is 21 days).
measure: Part 2: Safety and toxicity of Pola-Glofit post CAR-T therapy
timeFrame: 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)
measure: Part 2: Overall Survival (OS)
timeFrame: From the date of registration for Part 2 until the date of death, assessed up to 4 years.
measure: Part 2: Duration of Response (DoR)
timeFrame: From the date of first response until disease progression, assessed up to 4 years.
measure: Part 2: Duration of Complete Response (DoCR)
timeFrame: From the date of first complete metabolic response (CMR) until disease progression, assessed up to 4 years.
measure: Part 2: Non-Relapse Mortality (NRM)
timeFrame: 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.
measure: Part 2: Progression Free Survival (PFS) (at 12 months)
timeFrame: 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.
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Kings College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
affiliation: University College London Hospitals
name: William Townsend
role: PRINCIPAL_INVESTIGATOR
References: