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    Summary
    EudraCT Number:2015-004293-15
    Sponsor's Protocol Code Number:UCART19_02(CL1-68587-001)
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-04-06
    Trial 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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-004293-15
    A.3Full title of the trial
    A phase 1, open label, non-comparative, study to evaluate the safety and the ability of UCART19 to induce molecular remission in paediatric patients with relapsed /refractory B-cell acute lymphoblastic leukaemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the safety and efficacy of UCART19 in children with B cell lymphoblastic leukaemia that has relapsed or not responded to other treatments
    A.3.2Name or abbreviated title of the trial where available
    UCART19_PALL
    A.4.1Sponsor's protocol code numberUCART19_02(CL1-68587-001)
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02808442
    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 SponsorInstitut de Recherches Internationales Servier (I.R.I.S)
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportADIR
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitut de Recherches Internationales Servier
    B.5.2Functional name of contact pointClinical Studies Department
    B.5.3 Address:
    B.5.3.1Street Address50 rue Carnot
    B.5.3.2Town/ citySuresnes
    B.5.3.3Post code92284
    B.5.3.4CountryFrance
    B.5.4Telephone number+3315572 4366
    B.5.5Fax number+3315572 5412
    B.5.6E-mailclinicaltrials@servier.com
    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 nameUCART19
    D.3.2Product code S68587
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCD19CAR/RQR8+_TCRαβ–_T-cells
    D.3.9.2Current sponsor codeS68587
    D.3.9.3Other descriptive nameUCART19
    D.3.9.4EV Substance CodeSUB180949
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2x10^7
    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) No
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberGene therapy medicinal product EMA/132648/2014
    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.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
    Paediatric relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia
    E.1.1.1Medical condition in easily understood language
    Children with B-cell lymphoblastic leukaemia that has relapsed or for whom previous treatment has not worked.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10060390
    E.1.2Term Leukaemia lymphoblastic acute
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety of UCART19 in paediatric patients with relapsed or refractory B-ALL.
    E.2.2Secondary objectives of the trial
    To determine the ability of UCART19 to achieve molecular remission at D28 after the first UCART19 infusion
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients

    2a. Age ranging from birth to <18 years

    3a. Patients with relapsed or refractory CD19-positive B-acute lymphoblastic leukemia (B-ALL) (National Comprehensive Cancer Network (NCCN), 2017),
    - Morphologically confirmed with ≥ 5% leukemic blasts in the bone marrow
    - or presenting a quantifiable MRD load of 1x10-3 (by multiparameter flow cytometry and/or quantitative polymerase chain reaction) at the end of the last induction treatment
    - Who have exhausted alternative treatment options

    Relapsed disease is defined as:
    - second or subsequent bone marrow relapse or,
    - any bone marrow relapse after allo-SCT.

    Refractory disease is defined by not achieving an initial complete response (CR) after 2 cycles of a standard chemotherapy regimen (primary refractory). Subjects who were refractory to subsequent chemotherapy regimens after an initial remission were considered chemo-refractory

    Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated.

    4. Estimated life expectancy ≥ 12 weeks (according to investigator’s judgement)

    6a. Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 50

    35. Adequate organ function defined as:
    a. Creatinine clearance ≥ 30 mL/min (as calculated using the method standard for the institution). In equivocal cases, a 24-hour urine collection test can be used to estimate the creatinine clearance more accurately.
    b. Serum ALT/AST ≤ 3 x ULN
    c. Total bilirubin ≤ 1.5 x ULN (unless the patient has a history of Gilbert’s Syndrome, in which case, total bilirubin must be ≤ 2.5 ULN)
    d. Left Ventricular Ejection Fraction (LVEF) ≥ 45% and no clinically significant ECG findings

    44. Availability of a donor for potential allo-HSCT in the event of persistent marrow aplasia without evidence of residual leukemia

    7. Written informed consent from parent(s) or legal representative and or written assent from patient when applicable obtained prior any study-specific procedure of the protocol

    60 No detectable anti-CD19 CAR transgene copies in blood, by qPCR, in patients previously treated with CAR-T cell therapy.
    E.4Principal exclusion criteria
    34. Patients unwilling to undergo a safety follow-up for 15 years

    9. Foreseeable poor compliance to the study procedures

    10a. Previous treatment with gene or gene-modified cell therapy medicine products (except autologous CAR-T cell therapy).

    11a. Use of previous anti-leukemic therapy (including approved therapies and other investigational products) within 5 half-lives prior to UCART 19 administration. Inotuzumab ozogamicin must be stopped at least 28 days prior to UCART19 administration. Participation in non-interventional registries or epidemiological studies is allowed

    12. CD19-negative B-cell leukaemia

    15. Burkitt cell acute leukaemia (L3 ALL)

    45a. Clinically suspected extramedullary involvement (except CNS and isolated skin involvement)

    37a. Evidence of disease progression after cytoreduction, if administered (e.g., significant increase in peripheral blast count)

    17a. Active CNS leukemia (CNS-3)

    28. Clinically active significant CNS dysfunction

    29a. Known history of irreversible severe neurological toxicity related to previous antileukemic treatment leading to organic central nervous system lesions

    30. Primary immunodeficiency or bone marrow failure syndrome

    14. Weight< 8.8 kgs

    16b. Allogeneic HSCT within 3 months prior to screening; any donor lymphocyte infusions must be completed > 6 weeks prior to Screening


    31. Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS involvement) prior to Inclusion

    18. Use of rituximab and other anti CD20 antibodies known to have the same epitope as rituximab or anti CD20 for which the epitope is unknown within 3 months prior to UCART19 infusion

    19. Presence of donor-specific anti-HLA antibodies directed against UCART19

    20b. Active, acute or chronic graft versus host disease (GvHD) requiring systemic treatment within 4 weeks of UCART19 infusion

    21a. Patients with autoimmune disease requiring systemic immunosuppression that cannot be stopped

    22. A known hypersensitivity to any of the test materials or related compounds including murine and bovine products

    24. Active systemic bacterial, fungal, protozoal or viral infection not controlled by adequate treatment, and presence of positive blood cultures within 7 days before Inclusion

    33. Patients tested positive for human immunodeficiency virus (HIV) and/or or human T-lymphotropic
    virus (HTLV)

    25a. Abnormal findings during the screening period, any other medical condition(s) or laboratory findings that in the opinion of the investigator, might jeopardize the patient’s safety

    26. Any planned medical/surgical treatment that might interfere with the ability to comply with the study requirements

    27a. Risk of pregnancy or non compliance with contraception (if applicable) .Girls of childbearing potential must have been tested negative in a pregnancy test within 7 days prior to inclusion. Within the frame of this study, female participants of childbearing potential and male participants with partners of childbearing potential must use an effective method of birth control, as well as their partners, from the screening period up to 12 months after the last dose of Investigational Medicinal Product (IMP) administration.

    36. Any known contraindication to any of the drugs that will be used for the lymphodepletion (fludarabine, cyclophosphamide) or other drugs proposed for safety issues (including tocilizumab, rituximab).

    59. Corticosteriods (topical, inhaled or nasal corticosteroids are permitted) within 5 days before administration of UCART19

    61. Known history of CRS grade 4 related to previous CAR-T cell therapy.

    ELIGIBILITY CRITERIA FOR UCART19 ADMINISTRATION (WITHIN 24 HOURS PRIOR TO INFUSION)

    38a. Adequate organ functions including renal and hepatic function based on the last assessment performed within the lymphodepletion period, defined as:
    - Creatinine clearance ≥ 30 mL/min (as calculated using the method standard for the institution. In equivocal cases, a 24-hour urine collection test can be used to estimate the creatinine clearance more accurately.
    - Serum ALT/AST ≤ 3 x ULN
    - Total bilirubin ≤ 1.5 x ULN (unless the patient has a history of Gilbert’s Syndrome, in which case, total bilirubin must be ≤ 2.5 ULN)

    39. No clinical signs of cardiac failure

    40. No active systemic bacterial, fungal, protozoal or viral infection not controlled by adequate treatment, and absence of positive blood cultures within 7 days before UCART19 administration

    41a. No evidence of disease progression after lymphodepletion (e.g., significant increase in peripheral blast count)

    42. Baseline oxygen saturation level > 92% in room air

    43a. No Abnormal findings during the lymphodepletion period, neither any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the patient’s safety
    E.5 End points
    E.5.1Primary end point(s)
    - Adverse events graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI-CTCAE) version V4.3 June 14, 2010, throughout the study, except CRS, TLS and acute GvHD events that will be graded according to the grading systems of Lee, Cairo and Harris, respectively ;

    - Clinical examination and cardiac evaluation (ECG, echocardiography) ;

    - Vital signs (blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation level),

    - Laboratory data assessments: haematology, biochemistry, coagulation parameters ;

    - Viral / bacterial / protozoal infection monitoring,
    E.5.1.1Timepoint(s) of evaluation of this end point
    safety will be evaluated on an on-going basis throughout the trial
    E.5.2Secondary end point(s)
    1- The activity of UCART19 will include a careful examination and valuation of the blood and the marrow if indicated.
    2- MRD evaluation by multiparameter flow cytometry and/or qPCR
    E.5.2.1Timepoint(s) of evaluation of this end point
    1: Day 28 after the first UCART19 infusion
    2: During the screening period, at D-1, (D14), D28, D56, D84, M4, M6, M9, M12
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Analysis of safety and/or efficacy biomarkers
    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) No
    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 Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    Spain
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days13
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    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: 18
    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.1.1.4.1Number of subjects for this age range: 3
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    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 No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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
    minors subjects
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 13
    F.4.2.2In the whole clinical trial 18
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the discontinuation of the study, the participant will access to an appropriate medical care by his doctor.
    After completion of the study or at time of premature discontinuation, patients will be rolled-over to a separate long-term follow-up study and will be followed for 15 years.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-31
    P. End of Trial
    P.End of Trial StatusOngoing
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