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Diffuse Large B-Cell LymphomaPhase 1COBALTNCT02431988

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

A Phase 1 study testing Leukapheresis, Cyclophosphamide and Fludarabine in people with Diffuse Large B-Cell Lymphoma, run by University College, London at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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… Read more about this study

Who is it for?
Ages 16 to 65 years
Conditions the study is for
Diffuse Large B-Cell Lymphoma
What is being tested?
Leukapheresis, Cyclophosphamide and Fludarabine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
1 siteUnited Kingdom
Study dates
Jun 2016to 21 Mar 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 to 65 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 12Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • University College London Hospital

    London

Other trials in United Kingdom

About this study

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

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.

Read the 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.

Being tested
Leukapheresis, Cyclophosphamide, Fludarabine, CAR19 T-Cells
Keywords
Relapsed, refractory, DLBCL
Medical subject headings
Lymphoma, Large B-Cell, Diffuse, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LeukapheresisProcedure or surgery

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

  • CyclophosphamideDrug

    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).

  • FludarabineDrug

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

  • CAR19 T-CellsBiological

    Also called CD19 specific Chimeric Antigen Receptor 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
Study groups in NCT02431988
Study groupRoleWhat they receive
CAR19 T-cellsExperimentalPatients 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.
Receives: Procedure: Leukapheresis; Drug: Cyclophosphamide; Drug: Fludarabine; Biological: CAR19 T-Cells

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: 1 month

  2. 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.

    Measured: 1 year

  3. Efficacy of CAR19 T-cells.

    Efficacy will be defined as the number of patients that meet the clinical complete responders criteria.

    Measured: 1 year

Secondary outcomes (5)

  1. 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.

    Measured: 1 year

  2. B cell compartment

    1. Depletion of B cell compartment. The percentage reduction from baseline. Absolute B cell numbers measured by flow of PBMC (cells/ul) .

    Measured: 1 year

  3. Cytokine profile

    1. 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).

    Measured: 1 year

  4. Clinical complete response

    1. Clinical response evaluated using standard PET-CT criteria at day 28 compared to baseline scan. Proportion of patients with complete response will be calculated.

    Measured: 1 month

  5. Eligibility to allogeneic transplantation

    1. 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.

    Measured: 1-3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 May 2015 (estimated)
  2. Study startJun 2016
  3. Primary completion2 Feb 2020
  4. Study completion21 Mar 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02431988
Sponsor's protocol ID
UCL/14/0385
Other IDs
2015-000348-40, 2015
Acronym
COBALT
Status last verified
Apr 2023
First submitted
23 Mar 2015
Last updated
28 Apr 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 34515338

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Leukapheresis, Cyclophosphamide and Fludarabine in people with Diffuse Large B-Cell Lymphoma, run by University College, London at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Feasibility of adequate leucapheresis collection and generation of CAR19 T cells. (time frame: 1 month). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02431988, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2023.

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