Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation

Diffuse Large B-Cell Lymphoma Clinical Trial

— COBALT  

Official title:

COBALT: Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02431988
• Other study ID #: UCL/14/0385
• Secondary ID: 2015-000348-40
• Status: Completed
• Phase: Phase 1
• Start date: June 2016
• Est. completion date: March 21, 2022

Study information

• Verified date: April 2023
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to administer novel cluster of differentiation antigen 19 (CD19) specific Chimeric Antigen Receptor T-cells (CAR19 T-cells) to patients with relapsed or resistant Diffuse Large B Cell Lymphoma (DLBCL) to assess the safety and efficacy of this strategy as a bridge to allogeneic transplantation.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: March 21, 2022
• Est. primary completion date: February 2, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Age 16-65 years

2. Confirmed diagnosis of CD19+ DLBCL

3. Primary resistant or relapsed disease failing to achieve metabolic Complete Response (CR) to 1st line salvage, or relapse post autograft failing to achieve metabolic CR following a single further cycle of salvage

4. Potential allogeneic transplant candidate

5. Agreement to have a pregnancy test, use adequate contraception for 12 months post-CAR19 T-cell infusion

6. Karnofsky performance status >60

7. Written informed consent

Exclusion Criteria:

1. Women who are pregnant or lactating

2. Prior allogeneic transplantation

3. Progressive disease following most recent salvage prior to planned leucapheresis (those with mixed response are eligible)

4. Prior history of ischaemic heart disease, dysrhythmias, abnormal electrocardiogram (ECG)(Left Bundle Branch Block (LBBB)), Multiple Gated Acquisition (MUGA) left ventricular ejection fraction (LVEF) <40%

5. Exclusions for proceeding to allogeneic transplantation (active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV); liver function test (LFT) >3 x upper limit of normal (ULN); Creatinine Clearance (CrCl) <40 ml/min; or other comorbidity that precludes transplantation)

6. Known central nervous system (CNS) involvement or cerebral vascular accident (CVA) within prior 3 months

7. Patients receiving corticosteroids at a dose of > 10mg prednisolone per day (or equivalent)

8. Use of rituximab within the last 2 months prior to CAR19 T-cell infusion

9. Active autoimmune disease requiring immunosuppression

10. Life expectancy <3 months

11. Known allergy to albumin or dimethylsulfoxide (DMSO)

12. Any contraindication to the administration and use of ifosfamide, epirubicin, etoposide, fludarabine and cyclophosphamide.

Related Conditions & MeSH terms

• Diffuse Large B-Cell Lymphoma
• Lymphoma, Large B-Cell, Diffuse

Intervention

Procedure:
• Leukapheresis
Patients will undergo leukapheresis prior to pre-conditioning chemotherapy to provide the immune cells required to produce the therapeutic product.

Drug:
• Cyclophosphamide
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
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: Dose Level 1: 2x105 CAR19 T-cells/kg Dose Level 2: 1x106 CAR19 T-cells/kg Dose Level 3: 5x106 CAR19 T-cells/kg

Locations

Country	Name	City	State
United Kingdom	University College London Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
University College, London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of adequate leucapheresis collection and generation of CAR19 T cells.	The number of CAR19 T cells successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients registered).	1 month
Primary	Toxicity evaluation following CAR19 T-cell administration.	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.	1 year
Primary	Efficacy of CAR19 T-cells.	Efficacy will be defined as the number of patients that meet the clinical complete responders criteria.	1 year
Secondary	CAR19 T-cell engraftment	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.	1 year
Secondary	B cell compartment	2. Depletion of B cell compartment. The percentage reduction from baseline. Absolute B cell numbers measured by flow of PBMC (cells/ul) .	1 year
Secondary	Cytokine profile	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).	1 year
Secondary	Clinical complete response	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.	1 month
Secondary	Eligibility to allogeneic transplantation	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.	1-3 years