1. Evaluation of CD19 specific Chimeric Antigen Receptor T cells (CAR19 T-cells) as an optimal bridge to allogeneic transplantation.
Phase I trial for patients with resistant or relapsed Diffuse Large B cell Lymphoma (DLBCL) The primary objective is to assess whether adoptive immunotherapy with CAR19 T-cells can be safely used as a bridge to allogenic stem cell transplantation.
This is a single centre, single arm dose-escalation phase I study in adults with resistant or relapsed Diffuse Large B cell Lymphoma (DLBCL).
Following informed consent, registered patients will undergo an unstimulated leucapheresis for generation of the CD19 specific Chimeric Antigen Receptor T-cells (CAR19 T-cells). Briefly, the CAR19 T-cells will be manufactured by activating autologous peripheral blood mononuclear cells (PBMC) with CD3/28 beads and interleukin-2 for 24 hours followed by transduction with a lentiviral vector encoding the specific CAR19 gene. Cells are then expanded, the CD3/28 beads removed and the final product CAR19 T-cells tested for quality control.
The CAR19 T-cells will take ~3 weeks to generate, in which time patients should proceed with a further cycle of standard salvage (recommended IVE (ifosfamide, epirubicin and etoposide)) and should not receive rituximab. Patients will receive pre-conditioning with cyclophosphamide 60mg/kg/day IV for 2 days (day-7 and day-6) followed by fludarabine 25mg/m2/day IV for 5 days (day-5 to day-1) prior to infusion of a single dose of CAR19 T-cells. An escalating dose protocol (2x105 – 5x106 cells/kg) will be employed to identify a minimum effective dose of CAR19 T-cells. Patients will be followed up regularly during the interventional phase (12 months post-CAR19 T- cells infusion) and thereafter annually for a further 2 years.
Trial design
Trial outline
Eligibility Criteria
Main Patient Inclusion Criteria
Age years
Confirmed diagnosis of CD19+ DLBCL
Primary resistant or relapsed disease failing to achieve metabolic CR to 1st line salvage, or relapse post autograft failing to achieve metabolic CR following a single further cycle of salvage
Potential allogeneic transplant candidate
Agreement to have a pregnancy test, use adequate contraception for 12 months post-CAR19 T-cell
Karnofsky performance status >60
Main Patient Exclusion Criteria
Women who are pregnant or lactating
Prior allogeneic transplantation
Progressive disease following most recent salvage prior to planned leucapheresis
Prior history of ischaemic heart disease, dysrhythmias, abnormal ECG, MUGA LVEF<40%
Exclusions for proceeding to allogeneic transplantation (active HBV, HCV, HIV; LFT >3 x ULN; CrCl <40 ml/min; or other comorbidities)
Known CNS involvement or CVA within 3 months
Patients receiving corticosteroids at a dose of > 10mg prednisolone per day (or equivalent)
Use of rituximab within the last 2 months
Trial end points
Primary endpoint:
Toxicity evaluation following CAR19 T-cell administration
Complete tumour response
Feasibility of adequate leucapheresis collection and generation of CAR19 T-cells
Secondary endpoints:
Engraftment, expansion and persistence of CAR19 T-cells
Depletion of B cell compartment
Timing and magnitude of cytokine release
PET-CT response at 28 days
Number of patients proceeding to allogeneic transplantation
Contacts
Participating site: UCLH
Sample size: 12 patients