CD19-CAR Immunotherapy for Childhood Acute Lymphoblastic Leukemia (ALL) (CD19TPALL)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University College, London
Sponsor:
Collaborators:
European Union Framework 6 Specific Targeted Research Project Initiative
The Leukemia and Lymphoma Society
Children with Leukaemia
Department of Health, United Kingdom
JP Moulton Charitable Foundation
Deutsche Krebshilfe
Information provided by (Responsible Party):
University College, London
ClinicalTrials.gov Identifier:
NCT01195480
First received: September 3, 2010
Last updated: August 7, 2013
Last verified: August 2013
  Purpose

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).


Condition Intervention Phase
Acute Lymphoblastic Leukemia
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
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Immunotherapy With CD19ζ Gene-modified EBV-specific CTLs After Stem Cell Transplant in Children With High-risk Acute Lymphoblastic Leukaemia

Resource links provided by NLM:


Further study details as provided by University College, London:

Primary Outcome Measures:
  • Toxicity attributable to transfer of CD19-zeta transduced CTL [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    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

  • 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 [ Time Frame: 1 year ] [ Designated as safety issue: No ]

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. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: May 2012
Estimated Study Completion Date: January 2021
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prophylaxis arm
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.
Genetic: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta
All patients will be treated at the same total dose level of 2 x 10^8/m2
Biological: Irradiated donor-derived Lymphoblastoid Cell Line

The initial cohort of 10 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 20 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 1, 4 and 8 weeks post-transduced CTL infusion.

Experimental: Pre-emptive arm
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.
Genetic: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta
All patients will be treated at the same total dose level of 2 x 10^8/m2
Biological: Irradiated donor-derived Lymphoblastoid Cell Line

The initial cohort of 10 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 20 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 1, 4 and 8 weeks post-transduced CTL infusion.


  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01195480

Contacts
Contact: Sneha Haria 02076799327 cd19@ctc.ucl.ac.uk
Contact: Laura Clifton-Hadley 0207 679 9138 cd19@ctc.ucl.ac.uk

Locations
France
Centre Hospitalier Universitaire Robert Debré, Service d'Hématologie Pédiatrique Not yet recruiting
Paris, France, 75019
Contact: Jean-Hughes Dalle, Dr    +33 140 032000    jean-hugues.dalle@rdb.aphp.fr   
Principal Investigator: Jean-Hughes Dalle, Dr         
Germany
Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Not yet recruiting
Essen, Germany, 45122
Contact: Bernhard Kremens, Dr    +49 201 723 2500    bernhard.kremens@uk-essen.de   
Principal Investigator: Bernhard Kremens, Dr         
Hospital for Children and Adolescents III, Goethe University Not yet recruiting
Frankfurt, Germany, 60590
Contact: Peter Bader, Dr    +49 696 301 7542    peter.bader@kgu.de   
Principal Investigator: Peter Bader, Dr         
Medizinische Hochschule Not yet recruiting
Hannover, Germany, 30625
Contact: Martin Sauer, Dr    +49 511 519 6705    sauer.martin@mh-hannover.de   
Principal Investigator: Martin Sauer, Dr         
University Children's Hospital Not yet recruiting
Münster, Germany, 48149
Contact: Claudia Rossig, Dr    +49 251 835 2813    rossig@uni-muenster.de   
Principal Investigator: Claudia Rossig, Dr         
Italy
Ospedale S.Gerardo dei Tintori Not yet recruiting
Monza, Italy, 20052
Contact: Ettore Biagi, Dr    +39 039 233 2232    ettore.biagi@pediatriamonza.it   
Principal Investigator: Ettore Biagi, Dr         
United Kingdom
Bristol Children's Hospital Recruiting
Bristol, United Kingdom, BS2 8BJ
Contact: Michelle Cummins, Dr    +44 117 342 8752    Michelle.Cummins@ubht.nhs.uk   
Principal Investigator: Michelle Cummins, Dr         
Great Ormond Street Hospital for Children Recruiting
London, United Kingdom, WC1N 3JH
Contact: Persis Amrolia, Professor    +44 207 405 9200 ext 8434    Persis.Amrolia@gosh.nhs.uk   
Principal Investigator: Persis Amrolia, Prof         
Sub-Investigator: Nicholaus Goulden, Dr         
Sub-Investigator: Paul Veys, Dr         
Sponsors and Collaborators
University College, London
European Union Framework 6 Specific Targeted Research Project Initiative
The Leukemia and Lymphoma Society
Children with Leukaemia
Department of Health, United Kingdom
JP Moulton Charitable Foundation
Deutsche Krebshilfe
Investigators
Study Chair: Persis Amrolia, Professor Great Ormond Street Hospital for Children NHS Foundation Trust
  More Information

No publications provided

Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT01195480     History of Changes
Other Study ID Numbers: UCL/09/0050, 2007-007612-29
Study First Received: September 3, 2010
Last Updated: August 7, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
Germany: Paul-Ehrlich-Institut
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by University College, London:
Immunotherapy
Gene Therapy
Paediatric
B cell Acute Lymphoblastic Leukaemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on July 23, 2014