CELL INTELLIGENCE · 肿瘤细胞治疗研究

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

主要终点：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 14-19 (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
次要终点：Part 1: Complete Metabolic Response (CMR) rate to Pola-Glofit as bridging prior to CAR-T cell infusion；Part 1: Overall Survival (OS) and Progression Free Survival (PFS)；Part 1: Safety and toxicity of Pola-Glofit as bridging therapy；Part 1: CAR-T associated toxicity post Pola-Glofit bridging following CAR-T therapy；Part 1: Response rate post CAR-T for all infused patients；Part 1: Duration of Response (DoR) and Duration of Complete Response (DoCR) for Pola-Glofit and CAR-T；Part 1: Non-Relapse Mortality (NRM)；Part 2: Complete Metabolic Response (CMR) rate to Pola-Glofit/Glofitamab at any point

• Part 1 · EXPERIMENTAL · 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.
• Part 2 · EXPERIMENTAL · 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.

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.