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Acute Lymphoblastic LeukemiaPhase 1/2CD19TPALLNCT01195480

CD19-CAR Immunotherapy for Childhood Acute Lymphoblastic Leukemia (ALL)

A Phase 1/2 study testing donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta and Irradiated donor-derived Lymphoblastoid Cell Line in people with Acute Lymphoblastic Leukemia, run by University College, London at 7 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The aim of this clinical trial is to evaluate the feasibility, safety and biological effect of adoptive transfer of CD19ζ chimaeric receptor transduced donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTL) in patients with high-risk or relapsed B cell precursor ALL after allogeneic Haematopoietic Stem Cell… Read more about this study

Who is it for?
Ages Up to 18 years
Conditions the study is for
Acute Lymphoblastic Leukemia
What is being tested?
donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta and Irradiated donor-derived Lymphoblastoid Cell Line
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
7 sitesin 2 countries
Study dates
May 2012to Nov 2015
Phase
Phase 1/2
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 Up to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Children (18 years or younger) with CD19+ precursor B cell ALL fulfilling one of the following criteria who are undergoing an allogeneic stem cell transplant from an EBV-seropositive donor:
  • In first remission, if at least one of the following criteria are met:
  • t(9;22) and MRD positive (BCR-ABL/ABL ratio > 0.01%) after HR3 block of EsPhALL or pre-HSCT or
  • Infant ALL age < 6 months at diagnosis with MLL gene rearrangement and either presenting wcc >300 x 10^9/L or poor steroid early response (i.e circulating blast count >1x10^9/L following 7 day steroid pre-phase of Interfant 06) or
  • Resistant disease (> 30% blasts at end of induction treatment day 28-33) in subsequent morphological CR or
  • High level bone marrow MRD (> 1 in 1000) at week 12 ALL-BFM 2000/AIEOP BFM ALL 2009/EORTC 58951 protocols, week 12-15 of FRALLE A or at week 14 of UKALL2011
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  • Relapsed patients if at least one of the following criteria are met:
  • Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse in second CR or
  • Early (within 6 months of finishing therapy) isolated bone marrow relapse with bone marrow MRD > 1 in 100 at day 35 of reinduction in second CR or
  • Early (within 6 months of finishing therapy) bone marrow or combined relapse with high level bone marrow MRD (> 1 in 1000) at the end of consolidation therapy (week 12-13 UKALL R3/INTREALL and COOPRALL protocols, prior to protocol M in BFM relapse protocol (ALL-REZ BFM 2002) and after Protocol II-IDA in AIEOP LLA Rec 2003)or
  • Any relapse of infant or Philadelphia-positive ALL in morphological complete remission
  • Any patient being transplanted in 3rd or greater CR
  • These patients have a high (> 50%) risk of relapse and will be monitored for evidence of MRD in bone marrow aspirates (monthly for months 1-6, 6 weekly months 7.5-12 post HSCT) for the first year post-transplant. Patients who become MRD +ve in the marrow at a level minimum 5 x 10-4 (or BCR-ABL/ABL ratio 0.05% in Ph+ve ALL patients with no IgH MRD marker) but are in morphological remission (<5% blasts in BM) will be eligible to be treated pre-emptively with CD19ζ transduced CTL
  • Prophylaxis arm
  • Additionally, any patient (≤ 18 years) with ALL relapsing in the bone marrow (isolated or combined) after myeloablative allogeneic HSCT who achieves morphological remission after re-induction and who is a candidate for second HSCT at one of the participating centres is eligible to receive CD19ζ transduced CTL prophylactically
  • Stem cell donors must be EBV sero-positive and HLA-matched (8/8 HLA A,B,C and DR at medium resolution typing) or a single antigenic/allelic (7/8) mismatch with the recipient
  • A life expectancy of at least 12 weeks
  • Karnofsky score of >60% if >10 years old or Lansky performance score of >60 if ≤ 10 years old
  • Patients must have transduced donor-derived EBV-specific CTLs with 15% or higher expression of CD19ζ determined by flow-cytometry which meet the specified release criteria
  • Informed written consent indicating that patients are aware this is a research study and have been told of its possible benefits and toxic side effects

Who cannot join

  • Patients with CD19 negative precursor B cell ALL
  • EBV seronegative or > single antigenic/allelic HLA-mismatched donor
  • Active acute GVHD overall Grade 2 or higher or significant chronic GVHD requiring systemic steroids at the time of scheduled infusion of transduced CTL will be excluded until the patient is GVHD-free and off steroids
  • Pre-existing severe lung disease (FEV1 or FVC < 50% predicted) pre-HSCT or an oxygen requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray at the time scheduled for transduced CTL infusion
  • Serum bilirubin >3 times the upper limit of normal or an AST or ALT > 5 times the upper limit of normal
  • Serum creatinine >3 times upper limit of normal
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  • Active severe intercurrent infection at the time of transduced CTL infusion (if present consult with Chief investigator).
  • Patients in whom transduced donor-derived EBV-specific CTLs don't meet release criteria
  • Serologically positive for Hepatitis B, C or HIV pre-HSCT
  • Females of childbearing age with a positive pregnancy test
  • Known allergy to DMSO

Trial locations and contacts

7 sites in 2 countries.

7 sites in 2 countries

Germany4 sites

  • Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum

    Essen, 45122

  • Hospital for Children and Adolescents III, Goethe University

    Frankfurt, 60590

  • Medizinische Hochschule

    Hanover, 30625

  • University Children's Hospital

    Münster, 48149

Other trials in Germany

United Kingdom3 sites

  • Bristol Children's Hospital

    Bristol, BS2 8BJ

  • Great Ormond Street Hospital for Children

    London, WC1N 3JH

  • University College London Hospital

    London

Other trials in United Kingdom

About this study

Official title: Immunotherapy With CD19ζ Gene-modified EBV-specific CTLs After Stem Cell Transplant in Children With High-risk Acute Lymphoblastic Leukaemia

The aim of this clinical trial is to evaluate the feasibility, safety and biological effect of adoptive transfer of CD19ζ chimaeric receptor transduced donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTL) in patients with high-risk or relapsed B cell precursor ALL after allogeneic Haematopoietic Stem Cell Transplantation (HSCT).

Being tested
donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta, Irradiated donor-derived Lymphoblastoid Cell Line
Keywords
Immunotherapy, Gene Therapy, Paediatric, B cell Acute Lymphoblastic Leukaemia
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Burkitt Lymphoma

What participants receive

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

  • donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zetaGenetic

    All patients will be treated at the same total dose level of 2 x 10^8/m2

  • Irradiated donor-derived Lymphoblastoid Cell LineBiological

    The initial cohort of 5 patients (regardless of arm of study) will be treated as described. If transduced CTL infusion is safe in this initial cohort and real-time DNA PCR studies demonstrate that transduced CTL are undetectable in > 50% of patients by 2 months post-infusion, the remaining 25 patients (in either arm of the study) will be treated as above but with an additional vaccination of CD19-zeta-transduced EBV-LCL infusion.

    Vaccination will consist of 3 doses of 5 x 10^6 irradiated (70Gy) donor-derived EBV-lymphoblastoid cell line used to generate CTL and will be administered subcutaneously into the thigh (volume 0.3 ml) at day -2, week 4 and 8 post-transduced CTL infusion.

Study groups in NCT01195480
Study groupRoleWhat they receive
Prophylaxis armExperimentalPatients who have relapsed in the bone marrow after previous myeloablative HSCT and achieve remission after chemotherapy will be treated prophylactically with CD19-specific gene-engineered T cells after a second HSCT with reduced intensity conditioning.
Receives: Genetic: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta; Biological: Irradiated donor-derived Lymphoblastoid Cell Line
Pre-emptive armExperimentalIn this arm, patients identified at high (> 50%) risk of relapse will be eligible for generation of donor-derived EBV CTL immediately prior to HSCT. These patients will be monitored for evidence of MRD in regular bone marrow aspirates for the first year post-HSCT. MRD positivity post-HSCT is highly predictive of subsequent relapse. In those patients who become MRD+ in the marrow at a level of minimum 5 x 10-4, cryopreserved CTL that have been transduced with a retroviral vector carrying the CD19-zeta transgene will be thawed and administered to the patient pre-emptively.
Receives: Genetic: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta; Biological: Irradiated donor-derived Lymphoblastoid Cell Line

What is being measured

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

  1. Toxicity attributable to transfer of CD19-zeta transduced CTL

    1. Incidence of grade 3-5 toxicity attributable to transfer of CD19-zeta transduced CTL within 12 weeks of infusion.
    2. Incidence of significant (Grade II-IV) and severe (Grade III-IV) acute GVHD before day 100 and limited/extensive chronic GVHD between day 100-365.
    3. Incidence of hypogammaglobulinaemia after CD19-zeta CTL transfer at day 100, 6 months and 1 year post-HSCT

    Measured: 1 year

  2. Biological efficacy as assessed by effect of CD19-zeta transduced CTL on Minimal Residual Disease levels in the bone marrow in the first year post- transduced CTL infusion

    Measured: 1 year

Secondary outcomes (3)

  1. Persistence and frequency of circulating CD19-zeta transduced CTL in the peripheral blood of recipients after adoptive transfer as assessed by flow cytometry and quantitative real-time PCR.

    Measured: 1 year

  2. In vitro anti-leukaemic response of circulating PBMC post adoptive transfer of CD19-zeta transduced CTL using interferon-gamma ELISPOT assays after stimulation with CD19+ve targets

    Measured: 1 year

  3. Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL

    Measured: 2 years

Timeline

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

  1. First posted6 Sep 2010 (estimated)
  2. Study startMay 2012
  3. Primary completionNov 2015
  4. Study completionNov 2015

Why it stopped: Due to lack of biological efficacy and CD19 CAR CTL persistence

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 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01195480
Sponsor's protocol ID
UCL/09/0050
Other IDs
2007-007612-29
Acronym
CD19TPALL
Status last verified
May 2018
First submitted
3 Sep 2010
Last updated
17 May 2018
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta and Irradiated donor-derived Lymphoblastoid Cell Line in people with Acute Lymphoblastic Leukemia, run by University College, London at 7 sites in 2 countries.

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 20 inclusion and 11 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: stopped early, as of the sponsor's last update on 17 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Germany, 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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 was stopped early (reason given: Due to lack of biological efficacy and CD19 CAR CTL persistence). Results are not available in the source record.

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?

Toxicity attributable to transfer of CD19-zeta transduced CTL (time frame: 1 year). The study lists 2 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 NCT01195480.

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 17 May 2018; AzTrials last refreshed its copy on 6 Nov 2026.

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