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

Acute Lymphoblastic Leukemia Clinical Trial

— CD19TPALL  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01195480
• Other study ID #: UCL/09/0050
• Secondary ID: 2007-007612-29
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: May 2012
• Est. completion date: November 2015

Study information

• Verified date: May 2018
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 29
• Est. completion date: November 2015
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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 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.

Locations

Country	Name	City	State
Germany	Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum	Essen
Germany	Hospital for Children and Adolescents III, Goethe University	Frankfurt
Germany	Medizinische Hochschule	Hannover
Germany	University Children's Hospital	Münster
United Kingdom	Bristol Children's Hospital	Bristol
United Kingdom	Great Ormond Street Hospital for Children	London
United Kingdom	University College London Hospital	London

Sponsors (7)

Lead Sponsor	Collaborator
University College, London	Children with Leukaemia, Department of Health, United Kingdom, Deutsche Krebshilfe e.V., Bonn (Germany), European Union, JP Moulton Charitable Foundation, The Leukemia and Lymphoma Society

Countries where clinical trial is conducted

Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Toxicity attributable to transfer of CD19-zeta transduced CTL	Incidence of grade 3-5 toxicity attributable to transfer of CD19-zeta transduced CTL within 12 weeks of infusion.; 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.; Incidence of hypogammaglobulinaemia after CD19-zeta CTL transfer at day 100, 6 months and 1 year post-HSCT	1 year
Primary	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		1 year
Secondary	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.		1 year
Secondary	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		1 year
Secondary	Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19?-transduced EBV-CTL		2 years

External Links

•   Final Publication