Clinical trial NCT02431988: Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation
Official title: COBALT: Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diffuse Large B-Cell Lymphoma
Keywords: Relapsed
refractory
DLBCL
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2015-05-01
Enrollment: 10
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Feasibility of adequate leucapheresis collection and generation of CAR19 T cells.
timeFrame: 1 month
measure: Toxicity evaluation following CAR19 T-cell administration.
timeFrame: 1 year
measure: Efficacy of CAR19 T-cells.
timeFrame: 1 year
Secondary outcomes:
measure: CAR19 T-cell engraftment
timeFrame: 1 year
measure: B cell compartment
timeFrame: 1 year
measure: Cytokine profile
timeFrame: 1 year
measure: Clinical complete response
timeFrame: 1 month
measure: Eligibility to allogeneic transplantation
timeFrame: 1-3 years
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: University College London Hospital
Study officials:
affiliation: University College, London
name: Karl Peggs
role: STUDY_CHAIR
References:
citation: 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.