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

NCT ID: NCT02431988

Last Updated: 2023-04-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2022-03-21

Brief 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.

Detailed 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.

Conditions

Diffuse Large B-Cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Leukapheresis

Intervention Type: PROCEDURE

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

Cyclophosphamide

Intervention Type: DRUG

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

Intervention Type: DRUG

Fludarabine 25mg/m2/day IV over 15/30 minutes for 5 days (Day-5 to day-1).

CAR19 T-Cells

Intervention Type: BIOLOGICAL

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

Interventions

Leukapheresis

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

Intervention Type: PROCEDURE

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).

Intervention Type: DRUG

Fludarabine

Fludarabine 25mg/m2/day IV over 15/30 minutes for 5 days (Day-5 to day-1).

Intervention Type: DRUG

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

Intervention Type: BIOLOGICAL

Other Intervention Names

CD19 specific Chimeric Antigen Receptor T-cells

Eligibility Criteria

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.

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Karl Peggs

Role: STUDY_CHAIR

University College, London

Locations

University College London Hospital

London, , United Kingdom

Countries

United Kingdom

References

Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Reference Type: DERIVED

PMID: 34515338 (View on PubMed)

Other Identifiers

2015-000348-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

UCL/14/0385

Identifier Type: -

Identifier Source: org_study_id