Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation (COBALT)
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|ClinicalTrials.gov Identifier: NCT02431988|
Recruitment Status : Active, not recruiting
First Posted : May 1, 2015
Last Update Posted : April 30, 2021
|Condition or disease||Intervention/treatment||Phase|
|Diffuse Large B-Cell Lymphoma||Procedure: Leukapheresis Drug: Cyclophosphamide Drug: Fludarabine Biological: CAR19 T-Cells||Phase 1|
Patients with Diffuse Large B Cell Lymphoma (DLBCL) resistant to or relapsing following rituximab-containing chemotherapy regimens have a poor prognosis. Patients may receive salvage chemotherapy and possibly an autologous stem cell transplant (auto-SCT). A proportion of these patients, however, will not respond to the chemotherapy or may relapse after the auto-SCT and therefore require novel treatment options. Such patients may benefit from an allogeneic stem cell transplantation (allo-STC).
In this study the investigators aim to administer CAR19 T-cells to act as a bridge to the transplant strategy. Specifically, (1) the feasibility of generating CD19 specific Chimeric Antigen Receptor T-cells called CAR19 T-cells, (2) the safety of administering the CD19 CAR T-cells in this setting, (3) how well the CAR19 T-cells engraft and (4) to evaluate how effective these cells are as a bridge to allogeneic transplantation.
Following informed consent and registration to the trial, patients will undergo an unstimulated leucapheresis for generation of the CAR19 T cells. Whilst the cells are being generated, patients will proceed with a further cycle of standard salvage (recommended ifosfamide, epirubicin and etoposide (i.e. the IVE regime), and should not receive rituximab. Patients will receive pre-conditioning with intravenous fludarabine and cyclophosphamide prior to infusion of a single dose of CAR-modified T-cells. An escalating dose protocol will be employed to identify a minimum effective dose of CAR19 T-cells.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||COBALT: Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation|
|Actual Study Start Date :||June 2016|
|Actual Primary Completion Date :||February 2, 2020|
|Estimated Study Completion Date :||March 2022|
Experimental: CAR19 T-cells
Patients will receive a single infusion of CAR19 T-cells following standard pre-conditioning with cyclophosphamide and fludarabine.
The CAR19 T-cells are to be administered on day 0.
Patients will undergo leukapheresis prior to pre-conditioning chemotherapy to provide the immune cells required to produce the therapeutic product.
Patients will receive a standard pre-conditioning regime with cyclophosphamide 60mg/kg/day IV over 1 hour for 2 days (day-7 and day-6).
Fludarabine 25mg/m2/day IV over 15/30 minutes for 5 days (Day-5 to day-1).
Biological: CAR19 T-Cells
The CAR19 T-cells are to be administered on day 0 at the dose specified by the Cancer Trials Centre (CTC) at the time of registration.
Three dose cohorts are planned:
Other Name: CD19 specific Chimeric Antigen Receptor T-cells
- Feasibility of adequate leucapheresis collection and generation of CAR19 T cells. [ Time Frame: 1 month ]The number of CAR19 T cells successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients registered).
- Toxicity evaluation following CAR19 T-cell administration. [ Time Frame: 1 year ]Toxicity will be examined for each patient receiving CAR19 T cells, using the maximum grade for each toxicity type, all summarized as number of patients with adverse events.
- Efficacy of CAR19 T-cells. [ Time Frame: 1 year ]Efficacy will be defined as the number of patients that meet the clinical complete responders criteria.
- CAR19 T-cell engraftment [ Time Frame: 1 year ]1. Engraftment, expansion and persistence of CAR19 T-cells. Detection of any level of CAR19 expression in circulating T cells (ie PBMC) by quantitative polymerase chain reaction (qPCR) and flow cytometry following infusion.
- B cell compartment [ Time Frame: 1 year ]2. Depletion of B cell compartment. The percentage reduction from baseline. Absolute B cell numbers measured by flow of PBMC (cells/ul) .
- Cytokine profile [ Time Frame: 1 year ]
3. Timing and magnitude of cytokine release. Data on timing (kinetic of change) as the mean (or median) amount of cytokine (pg/ml) over a number of days post-infusion. Using the individual patient data, the mean (or median) time to peak value can be obtained.
Magnitude - kinetic and peak of cytokine levels, notably Tumour Necrosis Factor-alpha (TNF-a), Interleukin- 6 (IL-6) and Interferon-gamma (IFN-g) (pg/ml), can be plotted for each patient, as means (or medians).
- Clinical complete response [ Time Frame: 1 month ]4. Clinical response evaluated using standard PET-CT criteria at day 28 compared to baseline scan. Proportion of patients with complete response will be calculated.
- Eligibility to allogeneic transplantation [ Time Frame: 1-3 years ]5. Number of patients proceeding to allogeneic transplantation out of all patients registered to the trial, and also only for those who received CAR19 T cells.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02431988
|University College London Hospital|
|London, United Kingdom|
|Study Chair:||Karl Peggs||University College, London|