search
Back to results

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

Primary Purpose

Diffuse Large B-Cell Lymphoma

Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Leukapheresis
Cyclophosphamide
Fludarabine
CAR19 T-Cells
Sponsored by
University College, London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large B-Cell Lymphoma focused on measuring Relapsed, refractory, DLBCL

Eligibility Criteria

16 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • University College London Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CAR19 T-cells

Arm 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.

Outcomes

Primary Outcome Measures

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).
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.
Efficacy of CAR19 T-cells.
Efficacy will be defined as the number of patients that meet the clinical complete responders criteria.

Secondary Outcome Measures

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.
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) .
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).
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.
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.

Full Information

First Posted
March 23, 2015
Last Updated
April 26, 2023
Sponsor
University College, London
search

1. Study Identification

Unique Protocol Identification Number
NCT02431988
Brief Title
Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation
Acronym
COBALT
Official Title
COBALT: Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
June 2016 (Actual)
Primary Completion Date
February 2, 2020 (Actual)
Study Completion Date
March 21, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B-Cell Lymphoma
Keywords
Relapsed, refractory, DLBCL

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CAR19 T-cells
Arm Type
Experimental
Arm 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.
Intervention Type
Procedure
Intervention Name(s)
Leukapheresis
Intervention Description
Patients will undergo leukapheresis prior to pre-conditioning chemotherapy to provide the immune cells required to produce the therapeutic product.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
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
Intervention Name(s)
Fludarabine
Intervention Description
Fludarabine 25mg/m2/day IV over 15/30 minutes for 5 days (Day-5 to day-1).
Intervention Type
Biological
Intervention Name(s)
CAR19 T-Cells
Other Intervention Name(s)
CD19 specific Chimeric Antigen Receptor T-cells
Intervention Description
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
Primary Outcome Measure Information:
Title
Feasibility of adequate leucapheresis collection and generation of CAR19 T cells.
Description
The number of CAR19 T cells successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients registered).
Time Frame
1 month
Title
Toxicity evaluation following CAR19 T-cell administration.
Description
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.
Time Frame
1 year
Title
Efficacy of CAR19 T-cells.
Description
Efficacy will be defined as the number of patients that meet the clinical complete responders criteria.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
CAR19 T-cell engraftment
Description
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.
Time Frame
1 year
Title
B cell compartment
Description
2. Depletion of B cell compartment. The percentage reduction from baseline. Absolute B cell numbers measured by flow of PBMC (cells/ul) .
Time Frame
1 year
Title
Cytokine profile
Description
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).
Time Frame
1 year
Title
Clinical complete response
Description
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.
Time Frame
1 month
Title
Eligibility to allogeneic transplantation
Description
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.
Time Frame
1-3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 16-65 years Confirmed diagnosis of CD19+ DLBCL 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 Potential allogeneic transplant candidate Agreement to have a pregnancy test, use adequate contraception for 12 months post-CAR19 T-cell infusion Karnofsky performance status >60 Written informed consent Exclusion Criteria: Women who are pregnant or lactating Prior allogeneic transplantation Progressive disease following most recent salvage prior to planned leucapheresis (those with mixed response are eligible) 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% 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) Known central nervous system (CNS) involvement or cerebral vascular accident (CVA) within prior 3 months Patients receiving corticosteroids at a dose of > 10mg prednisolone per day (or equivalent) Use of rituximab within the last 2 months prior to CAR19 T-cell infusion Active autoimmune disease requiring immunosuppression Life expectancy <3 months Known allergy to albumin or dimethylsulfoxide (DMSO) Any contraindication to the administration and use of ifosfamide, epirubicin, etoposide, fludarabine and cyclophosphamide.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karl Peggs
Organizational Affiliation
University College, London
Official's Role
Study Chair
Facility Information:
Facility Name
University College London Hospital
City
London
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
34515338
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.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs