Clinical trial NCT01195480: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Acute Lymphoblastic Leukemia
Keywords: Immunotherapy
Gene Therapy
Paediatric
B cell Acute Lymphoblastic Leukaemia
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: European Union
name: The Leukemia and Lymphoma Society
name: Children with Leukaemia
name: Department of Health, United Kingdom
name: JP Moulton Charitable Foundation
name: Deutsche Krebshilfe e.V., Bonn (Germany)
First posted: 2010-09-06
Enrollment: 29
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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

Primary outcomes:
measure: Toxicity attributable to transfer of CD19-zeta transduced CTL
timeFrame: 1 year
measure: 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
timeFrame: 1 year
Secondary outcomes:
measure: 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.
timeFrame: 1 year
measure: 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
timeFrame: 1 year
measure: Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL
timeFrame: 2 years
Other outcomes:
Locations:
city: Essen
country: Germany
facility: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum
city: Frankfurt
country: Germany
facility: Hospital for Children and Adolescents III, Goethe University
city: Hannover
country: Germany
facility: Medizinische Hochschule
city: Münster
country: Germany
facility: University Children's Hospital
city: Bristol
country: United Kingdom
facility: Bristol Children's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: London
country: United Kingdom
facility: University College London Hospital
Study officials:
affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust
name: Persis Amrolia, Professor
role: STUDY_CHAIR
References: