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

University College London (UCL)

Status and phase: Completed; Phase 1

Conditions: Diffuse Large B-Cell Lymphoma

Treatments: Procedure: Leukapheresis; Drug: Fludarabine; Biological: CAR19 T-Cells; Drug: Cyclophosphamide

Study type: Interventional

Funder types: Other

Identifiers

NCT02431988

UCL/14/0385

2015-000348-40 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 10 patients

Sex: All

Ages: 16 to 65 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

---

10 participants in 1 patient group

CAR19 T-cells

Experimental group

Description:

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.

Treatment:

Drug: Cyclophosphamide

Biological: CAR19 T-Cells

Drug: Fludarabine

Procedure: Leukapheresis