Clinical Trials /

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

NCT01195480

Description:

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).

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

CD19-CAR <span class="go-doc-concept go-doc-intervention">Immunotherapy</span> for Childhood <span class="go-doc-concept go-doc-disease">Acute Lymphoblastic Leukemia</span> (<span class="go-doc-concept go-doc-disease">ALL</span>)

Title

  • Brief Title: CD19-CAR Immunotherapy for Childhood Acute Lymphoblastic Leukemia (ALL)
  • Official Title: Immunotherapy With CD19 Gene-modified EBV-specific CTLs After Stem Cell Transplant in Children With High-risk Acute Lymphoblastic Leukaemia
  • Clinical Trial IDs

    NCT ID: NCT01195480

    ORG ID: UCL/09/0050

    NCI ID: 2007-007612-29

    Trial Conditions

    Acute Lymphoblastic Leukemia

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    The aim of this clinical trial is to evaluate the feasibility, safety and biological effect
    of adoptive transfer of CD19 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).

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Prophylaxis arm Experimental Patients 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.
    Pre-emptive arm Experimental In 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.

    Eligibility Criteria

    Inclusion Criteria Pre-emptive arm

    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

    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 CD19 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 CD19 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 CD19 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

    Exclusion Criteria

    - 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

    - 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

    Minimum Eligible Age: N/A

    Maximum Eligible Age: 18 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Toxicity attributable to transfer of CD19-zeta transduced CTL

    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

    Secondary Outcome Measures

    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.

    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

    Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19-transduced EBV-CTL

    Trial Keywords

    Immunotherapy

    Gene Therapy

    Paediatric

    B cell Acute Lymphoblastic Leukaemia