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    Summary
    EudraCT Number:2007-007612-29
    Sponsor's Protocol Code Number:UCL/09/0050
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-09-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2007-007612-29
    A.3Full title of the trial
    Immunotherapy with CD19ζ chimeric antigen receptor gene-modified EBV-specific CTLs after stem cell transplant in children with high-risk acute lymphoblastic leukaemia
    A.3.2Name or abbreviated title of the trial where available
    CD19-CAR Immunotherapy for Childhood ALL
    A.4.1Sponsor's protocol code numberUCL/09/0050
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01195480
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Union Framework 6 Specific Targeted Research Project Initiative
    B.4.2CountryEuropean Union
    B.4.1Name of organisation providing supportThe UK Leukaemia & LymphomaResearch Fund
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportChildren with Leukaemia
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportUK Department of Health
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportMoulton Charitable Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London
    B.5.2Functional name of contact pointAdvanced Therapy Trial Manager
    B.5.3 Address:
    B.5.3.1Street AddressCR-UK & UCL Cancer Trials Centre, 90 Tottenham Court Road
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW1T 4TJ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number44207679 9327
    B.5.6E-mailCD19@ctc.ucl.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCD19 T Cell Receptor (TCR) gene modified donor EBV-specific Cytotoxic T Lymphocytes (EBV-CTL)
    D.3.2Product code CD19 transduced EBV-CTL
    D.3.4Pharmaceutical form Suspension for infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.3.11.13.1Other medicinal product typeNote for D.3.11.11.1: CD19 transduced EBV-CTLs has been granted GMO classification and approval by HCB, AFSSAPS for the 2 participating sites in France and the French manufacturer UTCG.
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIrradiated donor-derived EBV-Lymphoblastoid cell line (LCL)
    D.3.2Product code irradiated EBV-LCL
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The medical condition under investigation is childhood precursor B acute lymphoblastic leukaemia (ALL).
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10000844
    E.1.2Term Acute lymphoblastic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To evaluate the feasibility and safety 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 acute lymphoblastic leukaemia (BCP-ALL) after allogeneic HSCT.

    2. To determine the biological effect of infusion of CD19ζ-transduced EBV-CTL on residual leukaemia as assessed by MRD quantification in the bone marrow.
    E.2.2Secondary objectives of the trial
    3. To determine the survival of CD19ζ-transduced EBV-CTL in vivo.

    4. To determine the in vitro activity of circulating T cells after adoptive immunotherapy against CD19+ve targets.

    5. To determine if vaccination with irradiated EBV-specific LCL post immunotherapy improves in vivo survival and expansion of CD19ζ-transduced EBV-CTL.

    6. To determine relapse rate and disease-free survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 CD19ζ 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary end point(s)
    1. Toxicity attributable to transfer of CD19-zeta transduced CTL:
    (a) Incidence of grade 3-5 toxicity (graded by the NCI Common Terminology Criteria for Adverse Events, v4.0) attributable to transfer of CD19-zeta transduced CTL within 12 weeks of infusion.
    (b) Incidence of significant (Grade II-IV) and severe (Grade III-IV) acute GVHD before day 100 (graded by Seattle criteria) and limited/extensive chronic GVHD between day 100-365.
    (c) Incidence of hypogammaglobulinaemia after CD19-zeta CTL transfer at day 100, 6 months and 1 year post-HSCT
    2. 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
    E.5.2Secondary end point(s)
    3. Persistence and frequency of circulating CD19ζ transduced CTL in the peripheral blood of recipients after adoptive transfer as assessed by flow cytometry and quantitative real-time PCR.

    4. In vitro anti-leukaemic response of circulating PBMC post adoptive transfer of CD19ζ transduced CTL using interferon-γ ELISPOT assays after stimulation with CD19+ve targets

    5. Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial will be 10 years after last patient receives infusion of CD19ζ transduced EBV-CTL, at which point ‘declaration of end of trial’ form will be submitted to participating regulatory authorities and ethical committees, as required.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years12
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years12
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Our study will include patients under 16 years of age and therefore will require a parent/legal guardian to sign an informed consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 30
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-09-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-08-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-03-18
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