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

NCT ID: NCT01195480

Last Updated: 2018-05-17

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-31
• Study Completion Date: 2015-11-30

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).

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

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

Intervention Type: GENETIC

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

Irradiated donor-derived Lymphoblastoid Cell Line

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

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

Intervention Type: GENETIC

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

Irradiated donor-derived Lymphoblastoid Cell Line

Intervention Type: BIOLOGICAL

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.

Interventions

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

Intervention Type: GENETIC

Irradiated donor-derived Lymphoblastoid Cell Line

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.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

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

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Union

OTHER

Sponsor Role: collaborator

The Leukemia and Lymphoma Society

OTHER

Sponsor Role: collaborator

Children with Leukaemia

UNKNOWN

Sponsor Role: collaborator

Department of Health, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

JP Moulton Charitable Foundation

OTHER

Sponsor Role: collaborator

Deutsche Krebshilfe e.V., Bonn (Germany)

OTHER

Sponsor Role: collaborator

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Persis Amrolia, Professor

Role: STUDY_CHAIR

Great Ormond Street Hospital for Children NHS Foundation Trust

Locations

Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum

Essen, , Germany

Hospital for Children and Adolescents III, Goethe University

Frankfurt, , Germany

Medizinische Hochschule

Hanover, , Germany

University Children's Hospital

Münster, , Germany

Bristol Children's Hospital

Bristol, , United Kingdom

Great Ormond Street Hospital for Children

London, , United Kingdom

University College London Hospital

London, , United Kingdom

Countries

Germany; United Kingdom

Related Links

http://www.nature.com/leu/journal/vaop/ncurrent/full/leu201739a.html

Final Publication

Other Identifiers

2007-007612-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

UCL/09/0050

Identifier Type: -

Identifier Source: org_study_id