Immunotherapy with CD19? chimeric antigen receptor gene-modified EBV-specific CTLs after stem cell transplant in children with high-risk acute lymphoblastic leukaemia - CD19-CAR Immunotherapy for Childhood A

Phase 1

• Conditions: The medical condition under investigation is childhood precursor B acute lymphoblastic leukaemia (ALL).; MedDRA version: 14.0Level: LLTClassification code 10000844Term: Acute lymphoblastic leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2007-007612-29-GB
• Lead Sponsor: niversity College London

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2011-09-28
• Study Completion: 2018-12-10
• Last Update Posted: 20 July 2020

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 29

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 at one of the participating centers will be eligible for entry into the trial and EBV CTL generation:
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 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 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 = 5 x 10-4 but are in haematological remission will be eligible to be treated pre-emptively with CD19zeta transduced CTL.

Prophylaxis arm

Any patient (= 18 years) with precursor B-ALL relapsing in the bone marrow (either 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 sites is eligible to receive CD19zeta 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.
- Patients must have a life expectancy of at least 12 weeks.
- Patients must have Karnofsky score of >60% if = 10 years old or Lansky performance score of greater than 60 if < 10 years old (see Appendix 2 of protocol).
- Patients must have transduced donor-derived EBV-specific CTLs with =15% expression of CD19? determined by flow-cytometry which meet the specified release criteria.
- Patients or legal guardians must sign an informed consent indicating that they are aware this is a research trial and have been told of its possible benefits and toxic side effects.

Are the trial subjects under 18? yes
Number of subjects for this age range: 30
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

Patients with CD19 negative precursor B cell ALL

Patients transplanted from an EBV seronegative or > single antigenic/allelic HLA-mismatched donor.

Patients with active acute GVHD overall Grade =2 (Seattle criteria) or significant chronic GVHD requiring systemic steroids at the time of scheduled infusion of transduced CTL will be excluded from infusion of transduced CTL until the patient is GVHD-free and off steroids.

Patients with 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 will be excluded.

Patients with a serum bilirubin greater than 3 times the upper limit of normal or an AST or ALT greater than 5 times the upper limit of normal will be excluded.

Patients with a serum creatinine greater than 3 times upper limit of normal will be excluded.

Patients with an active severe intercurrent infection at the time of transduced CTL infusion may be excluded (if present consult with Chief investigator).

Patients in whom transduced donor-derived EBV-specific CTLs do not meet release criteria will be excluded from receiving transduced CTL.

Patients who are serologically positive for Hepatitis B, C or HIV pre-HSCT will be excluded.

Female patients of childbearing age with a positive pregnancy test.

In addition, patients with severe allergy to gentamicin will be excluded from receiving vaccination with irradiated donor-derived BLCL.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified