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    Summary
    EudraCT Number:2017-002314-31
    Sponsor's Protocol Code Number:DLI-TARGET
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-05-03
    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 ConcernedGermany - PEI
    A.2EudraCT number2017-002314-31
    A.3Full title of the trial
    Phase 2 Study Evaluating the Safety, Tolerability and Efficacy of Allogeneic Donor Lymphocyte Infusions Combined with Blinatumomab in Patients with Treatment-Resistant Mixed Chimerism or Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia after Allogeneic Stem Cell Transplantation
    Phase 2 Studie zur Evaluation der Sicherheit, Tolerabilität und Effektivität der allogenen Spender-Lymphozyten-Infusion in Kombination mit Blinatumomab in Patienten mit therapierefraktärem gemischtem Chimärismus oder minimaler Resterkrankung der B-Vorläufer Akuten Lymphatischen Leukämie nach allogener Stammzelltransplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Allogeneic Donor Lymphocyte Infusions Combined with Blinatumomab
    Allogene Spender-Lymphozyten-Infusion in Kombination mit Blinatumomab
    A.3.2Name or abbreviated title of the trial where available
    DLI-TARGET
    DLI-TARGET
    A.4.1Sponsor's protocol code numberDLI-TARGET
    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 SponsorKlinikum der Universität München
    B.1.3.4CountryGermany
    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 supportAmgen Ltd
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Universität München
    B.5.2Functional name of contact pointStudienzentrale Hämatologie
    B.5.3 Address:
    B.5.3.1Street AddressMarchioninistraße 15
    B.5.3.2Town/ cityMünchen
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number004989440077907
    B.5.5Fax number00498944001977907
    B.5.6E-mailChristian_Schmidt@med.uni-muenchen.de
    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 Yes
    D.2.1.1.1Trade name BLINCYTO
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/650
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate and solution for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    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 Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal bispecific antibody
    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
    Subjects with treatment-resistant mixed chimerism or MRD of CD19+ B-precursor ALL after allogeneic SCT
    E.1.1.1Medical condition in easily understood language
    Subjects after allogeneic stem cell transplantation who have achieved a complete morphologic remission but are in very high risk for relapse because of mixed chimerim or MRD.
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10063621
    E.1.2Term Acute lymphoblastic leukaemia recurrent
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10063625
    E.1.2Term Acute lymphoblastic leukemia recurrent
    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 and tolerability of combined DLI and blinatumomab treatment in subjects with treatment-resistant MC or MRD of CD19+ B-precursor ALL after allogeneic SCT.
    E.2.2Secondary objectives of the trial
    1) To evaluate the efficacy of a combined treatment of DLI and blinatumomab to induce a complete MRD/chimerism response.
    2) To evaluate the duration of the response and survival
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Patients with CD19+ B–precursor ALL (as determined by immunophenotyping) in hCR (defined as having less than 5% blasts in bone marrow) after allogeneic SCT.
    2) One, or a combination of the following documented after an interval of at least 2 weeks since cessation of the most recent leukemia-targeting therapy (i.e. chemotherapy, immunotherapy or cellular therapy, except for intrathecal prophylaxis):
    - Positivity for CD19+ MRD (molecular failure or molecular relapse), defined as presence of MRD at a level of ≥10-4 according to an assay with a minimum sensitivity of 10-4.
    - Donor chimerism <90%, as determined by analysis of host and donor STRs in bone marrow sample engraftment analysis.
    3) At least one previous line of treatment for MRD-positivity and/or reduced donor chimerism (i.e. blinatumomab, DLI, TKI or other agents) after allogeneic SCT.
    4) For those with BCR/ABL-positive B-precursor ALL only: persistence of MRD and/or MC following at least one ≥ second generation TKI (dasatinib, nilotinib, bosutinib, ponatinib) OR intolerance to second generation TKI and intolerance to or persistence of MRD and/or MC following imatinib mesylate.
    5) Availability of allogeneic donor lymphocytes from the subject’s donor (at least 2 x 108 T cells/kg).
    6) Subject (or subject's legally acceptable representative when the subject is legally too young to provide informed consent) has provided written informed consent prior to initiation of any study-specific activities/procedures.
    7) Subject (or Subject’s legally acceptable representative when the subject is legally too young to provide informed consent) has provided informed consent to be followed up in the GMALL-Registry.
    8) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
    9) Renal function as follows: serum creatinine < 2.0 mg/dL and estimated glomerular filtration rate > 30 mL/min.
    10) Hepatic function as follows:
    - Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN)
    - Alkaline phosphatase (ALP) < 3.0 x ULN
    - Bilirubin ≤ 2.0 x ULN (unless considered due to Gilbert's syndrome or hemolysis)
    E.4Principal exclusion criteria
    1) Eligibility for treatment with blinatumomab ALONE or other antibody-based treatment approaches (e.g. inotuzumab ozogamicin), as considered by the treating physician.
    2) Eligibility for standard chemotherapy, as considered by the treating physician.
    3) Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent) within 14 days or 5 half-lives (whichever is longer) prior to baseline MRD and/or chimerism assessment.
    4) Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment.
    5) Any grade of GvHD currently requiring treatment.
    6) Clinically relevant central nervous system (CNS) pathology requiring treatment (e.g., unstable epilepsy).
    7) Evidence of current CNS involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully controlled prior to enrollment.
    E.5 End points
    E.5.1Primary end point(s)
    Subject incidence and grade of AEs including GvHD
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety in terms of AE incidence will be evaluated after the first patient received at least one dose with blinatumomab until LVLS.
    E.5.2Secondary end point(s)
    1) For MRD-positive patients: MRD response.
    Efficacy parameters: complete MRD response rate (patients achieving MolCR, defined as MRD which is not detectable by molecular probes with a sensitivity of ≥10−4), duration of complete MRD response, and time to complete MRD response.
    2) For patients with MC: chimerism response.
    Efficacy parameters: CC/low-level MC response rate (defined as patients with ≥90% donor STRs present in bone marrow DNA sample at engraftment analysis), duration of CC/low-level MC response, and time to CC/low-level MC response.
    3) Progression-free survival and overall survival.

    Exploratory Endpoints:
    1) Expansion of Donor Lymphocytes as measured by T cell chimerism.
    2) Lymphocyte counts as well as T cell activation (including T cell subsets). Other immune subsets may also be examined.
    3) Changes in serum cytokine levels.
    4) CD19 expression levels on the ALL cell surface.
    5) Number of blood products transfused during the study period.
    6) Days of antibiotic treatment for infection during the study period
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy analysis will be performed on all subjects who received a minimum of 4 days blinatumomab. Endpoints will be analysed by use of appropriate descriptive techniques after the EOCS visit has been completed by all subjects.
    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) No
    E.7.1.1First administration to humans No
    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 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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 No
    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) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 No
    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)
    None specified. Patients will be treated according to the local standard care.
    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 Decision2018-08-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-07-06
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