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

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Brief Title

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

Official Title

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

Brief 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 Transplantation (HSCT).
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Toxicity attributable to transfer of CD19-zeta transduced CTL

Secondary Outcome

 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.

Condition

Acute Lymphoblastic Leukemia

Intervention

donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta

Study Arms / Comparison Groups

 Prophylaxis arm
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Genetic

Estimated Enrollment

29

Start Date

May 2012

Completion Date

November 2015

Primary Completion Date

November 2015

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 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

        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
      

Gender

All

Ages

N/A - 18 Years

Accepts Healthy Volunteers

No

Contacts

Persis Amrolia, Professor, , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT01195480

Organization ID

UCL/09/0050

Secondary IDs

2007-007612-29

Responsible Party

Sponsor

Study Sponsor

University College, London

Collaborators

 European Union

Study Sponsor

Persis Amrolia, Professor, Study Chair, Great Ormond Street Hospital for Children NHS Foundation Trust


Verification Date

May 2018