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    Summary
    EudraCT Number:2011-001514-34
    Sponsor's Protocol Code Number:ILNK15-01
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-01-08
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2011-001514-34
    A.3Full title of the trial
    Infusion of IL-15 activated NK cells after allogeneic stem cell transplantation in children transplanted for relapsed/refractory leukemia: a feasibility study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Infusion of activated donor-derived NK cells after stem cell transplantation in children transplanted with high-risk leukemia
    A.3.2Name or abbreviated title of the trial where available
    IL-15 activated NK cell infusion after alloSCT in pediatric high-risk hematological malignancies
    A.4.1Sponsor's protocol code numberILNK15-01
    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 SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    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 supportMiltenyi Biotec GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointDepartement Pediatrics
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2300 RC
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31715264131
    B.5.5Fax number71715248198
    B.5.6E-maila.lankester@lumc.nl
    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 nameIL15 activated NK cells
    D.3.2Product code IL15 activated NK cells
    D.3.4Pharmaceutical form Injection
    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 INNIL15 activated human NK cells
    D.3.10 Strength
    D.3.10.3Concentration number10x10e6 cells/kg
    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) 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 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
    Children with high-risk and recurrent acute leukemia are eligible for allogeneic hematopoietic stem cell transplantation (HSCT). However, leukemia relapse and viral infections after HSCT remain main reasons for treatment failure.
    E.1.1.1Medical condition in easily understood language
    Stem cell transplantation is a accepted treatment for children with high-risk acute leukemia. However, leukemia relapse and viral infections remain main reasons for treatment failure.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10023685
    E.1.2Term LAK cell therapy
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of the present study is to administer purified and ex vivo IL-15 activated donor-derived NK cells early after alloHSCT in children transplanted for high-risk acute leukemia.

    Primary objective:
    To document the feasibility to generate sufficient numbers of IL-15 activated NK cells from HSCT donors in the actual donorpatient combination of the alloHSCT setting, i.e. the Investigational Medicinal Product (IMP), meeting the release criteria, the safety of infusion and tolerability of the IMP post SCT in children transplanted because of refractory/ relapsed acute leukemia.
    E.2.2Secondary objectives of the trial
    To study and document in children receiving the IMP:
    1. Anti-leukemic/cytolytic reactivity and cytokine producing potential, e.g. IFN-γ, of NK cells ex vivo prior to and after NK infusion (intra-individual control).
    2. Reconstitution of lymphocyte populations with focus on analysis of activating and inhibitory receptors on NK cell subpopulations and investigation of NK cell function ex vivo. The latter will also be analyzed for NK cells present in donor leukapheresis material and the IMP.
    3. Disseminated (viral) infections after HSCT.
    4. Incidence and severity of acute and chronic GvHD
    5. Relapse of leukemia after HSCT
    6. Survival adter HSCT
    7. The relevance of mismatched KIR ligands (HLA types) and KIR
    genotype/phenotype of donor/recipient pairs for observed biological effects.

    Historical acute leukemia patients transplanted with unrelated or mismatched family donors in our unit between 2005-2012 will be used as controls.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patient inclusion criteria:
    1. Aged between 1-18 years at the time of HSCT;
    2. Undergoing HSCT for ALL or AML according to existing indications as defined in
    protocols/guidelines Dutch Childhood Oncolgy Group;
    3. Receiving a stem cell graft from a mismatched family (MMFD) or volunteer unrelated (MUD) donor;
    4. Life expectancy > 3 months.
    5. Availability of a stem cell donor willing to donate white blood cells by means of a non-mobilized leukapheresis procedure.

    E.4Principal exclusion criteria
    Patient exclusion criteria:
    1. Progressive leukemia after HSCT but before or at the day of NK cell infusion, defined as overt leukemia relapse, i.e., ≥ 25% blasts in the marrow and/or 5% circulating blasts in the peripheral blood or progressive extra-medullary disease;
    2. Lack of evidence for donor myeloid engraftment at the day of infusion (< 0.5 x 106
    neutrophils/L);
    3. Active acute GvHD ≥ grade II;
    4. Administration of steroids >1 mg/kg/day for any indication at the day of infusion;
    5. Any medical condition, which in the opinion of the treating physician, would interfere
    with the adequate evaluation of the patient (e.g. end-stage irreversible multi-system
    organ failure).
    6. Cord blood as stem cells donor
    E.5 End points
    E.5.1Primary end point(s)
    In addition to the standard evaluation following HSCT of children treated for leukemia, the following investigations will be performed in the context of the investigational NK cell infusion:
    - Feasibility of obtaining donor leukapheresis material, isolating required numbers of viable NK cells, generating IL-15 activated NK cells with adequate activation status and purity.
    - Tolerability and safety of IL-15 activated NK cell infusion. Registration of
    post infusion status of the patient, fever, nausea, chills, rash, erythema, and all
    serious adverse events, potentially linked to infusion.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients will be included during a two year period.
    An interim report on the primary objective will be provided 6-8 weeks after treatment of the first five patients or 12 months after start of the study. The report will be made by the principle and coordinating investigators.
    E.5.2Secondary end point(s)
    1. To document anti-leukemic/cytolytic reactivity and cytokine producing potential,
    e.g. IFN-γ, of NK cells ex vivo prior to and after NK infusion (intra-individual
    control).
    2. To document immune reconstitution after NK cell infusion. Apart from detailed
    investigation of T- and B-lymphocyte recovery, the focus will be on analysis of
    the surface expression patterns of activating and inhibitory receptors on NK cell
    subpopulations. The latter will also be investigated on NK cells present in the
    donor HSCT graft (if not CD34+ enriched), donor leukapheresis material and the
    IMP.
    Historical acute leukemia patients transplanted with unrelated or mismatched family donors in our unit between 2005-2011 will be used as controls for the functional and phenotypical studies indicated above.
    3. To document disseminated (viral) infections in children undergoing NK cell
    infusions post HSCT compared to aforementioned controls
    4. To document occurrence and severity of acute and chronic GvHD in NK cell
    recipients compared to aforementioned controls
    5. To document relapse of hematological malignancies in children undergoing NK
    cell infusions post HSCT compared to controls.
    6. To document survival in children undergoing NK cell infusions post HSCT
    compared to controls.
    7. To study the relevance of mismatching KIR ligands (HLA types) and KIR
    genotype/phenotype of donor/recipient pairs for observed biological effects.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be included during a two year period.
    An interim report on the primary objective will be provided 6-8 weeks after treatment of the first five patients or 12 months after start of the study. The report will be made by the principle and coordinating investigators.
    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 No
    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 No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    First feasibility study with IL-15 activated allogeneic NK cells infusion in children
    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 Yes
    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 Yes
    E.8.2.3.1Comparator description
    historical leukemia patients transplanted with unrelated or mismatched family donor
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    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 trial will end 1 year after inclusion of the final patient; i.e. all patients will be followed at least one year. All patients will be followed thereafter for regular follow-up in the out-patient SCT clinic of the department of Pediatrics.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 12
    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: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 5
    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 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
    Children with high-risk acute leukemia undergoing allogeneic stem cell transplantation.
    The informed consent procedure for participation in the current study includes both the parents/legal guardians and the patients.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    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)
    The treatment and follow-up of the study patients after end of participation in the trial will be identical compared to stem cell transplantation patients not included in the current study. Patients will be followed routinely in the stem cell transplantation outpatient clinic of the department of pediatrics.
    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 Decision2012-03-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-03
    P. End of Trial
    P.End of Trial StatusOngoing
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