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

• Register: ClinicalTrials.gov
• Last refreshed on: 17 October 2012
• Main ID: NCT01195480
• Date of registration: 03/09/2010
• Primary sponsor: University College, London
• Public title: CD19-CAR Immunotherapy for Childhood Acute Lymphoblastic Leukemia (ALL) CD19TPALL
• Scientific title: Immunotherapy With CD19? Gene-modified EBV-specific CTLs After Stem Cell Transplant in Children With High-risk Acute Lymphoblastic Leukaemia
• Date of first enrolment: May 2012
• Target sample size: 30
• Recruitment status: Recruiting
• URL: http://clinicaltrials.gov/show/NCT01195480
• Study type: Interventional
• Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Countries of recruitment

Austria, France, Germany, Italy, United Kingdom

Contacts

• Name: Zahid Sattar

• Name: Persis Amrolia, Professor
• Affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust

Key inclusion & exclusion 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 prednisone poor response or not in molecular remission (BCR-ABL/ABL ratio
> 0.02%) pre-HSCT or

- Infant ALL age < 6 months at diagnosis with MLL gene rearrangement and either
presenting wcc >300 x 109/L or poor steroid early response (i.e circulating blast
count >1x109/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 UKALL2010

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) 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 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 (10/10) or a single
antigenic/allelic (9/10) mismatch with the recipient

- A life expectancy of at least 8 weeks

- Karnofsky score of >60% if >10 years old or Lansky performance score of greater than
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

- 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



Age minimum: N/A
Age maximum: 18 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Acute Lymphoblastic Leukemia

Intervention(s)

Biological: Irradiated donor-derived Lymphoblastoid Cell Line

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

Primary Outcome(s)

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]

Toxicity attributable to transfer of CD19-zeta transduced CTL [Time Frame: 1 year]

Secondary Outcome(s)

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]

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]

Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19?-transduced EBV-CTL [Time Frame: 2 years]

Secondary ID(s)

2007-007612-29

UCL/09/0050

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Children with Leukaemia

Department of Health, United Kingdom

European Union

JP Moulton Charitable Foundation

The Leukemia and Lymphoma Society