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    Summary
    EudraCT Number:2016-001935-12
    Sponsor's Protocol Code Number:AIEOPBFMALL2017
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-23
    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 ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2016-001935-12
    A.3Full title of the trial
    AIEOP-BFM ALL 2017 - International collaborative treatment protocol for children and adolescents with acute lymphoblastic leukemia
    AIEOP-BFM ALL 2017 - Medzinárodný liečebný protokol pre deti a adolescentov s akútnou lymfoblastovou leukémiou
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    International collaborative treatment protocol for children and adolescents with acute lymphoblastic leukemia
    Medzinárodný liečebný protokol pre deti a adolescentov s akútnou lymfoblastovou leukémiou
    A.3.2Name or abbreviated title of the trial where available
    AIEOP-BFM ALL 2017
    AIEOP-BFM-ALL-2017
    A.4.1Sponsor's protocol code numberAIEOPBFMALL2017
    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 SponsorUniversitätsklinikum Schleswig-Holstein, Campus Kiel
    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 supportDeutsche Krebshilfe
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinikum Schleswig-Holstein, Campus Kiel
    B.5.2Functional name of contact pointStudy Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressArnold-Heller-Str. 3, Haus U 18
    B.5.3.2Town/ cityKiel
    B.5.3.3Post code24105
    B.5.3.4CountryGermany
    B.5.6E-mailall-bfm-studie@pediatrics.uni-kiel.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
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate for solution for 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 INNBLINATUMOMAB
    D.3.9.1CAS number 853426-35-4
    D.3.9.2Current sponsor codeBLINATUMOMAB
    D.3.9.3Other descriptive nameBLINATUMOMAB
    D.3.9.4EV Substance CodeSUB35403
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38.5
    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 No
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form
    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 INNBORTEZOMIB
    D.3.9.1CAS number 179324-69-7
    D.3.9.4EV Substance CodeSUB20020
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) 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) 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
    acute lymphoblastic leukemia in children and adolescents <18 years
    of age
    Akútna lymfoblastová leukémia detí a adolescentov pod 18 rokov
    E.1.1.1Medical condition in easily understood language
    acute lymphoblastic leukemia in children and adolescents <18 years
    of age
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - Randomization R-eHR: Early high-risk (early HR) pB-ALL defined by genetics and/or inadequate treatment response over the course of induction: Can the pEFS from time of randomization be improved by additional therapy with the proteasome inhibitor Bortezomib during an extended consolidation treatment phase compared to standard extended consolidation?
    - Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or inadequate treatment response by the end of consolidation: Can the pEFS from time of randomization be improved by a treatment concept including two cycles of post-consolidation immunotherapy with Blinatumomab (15 µg/m²/d for 28 days per cycle) plus 4 doses intrathecal Methotrexate compared to two conventional highly intensive chemotherapy courses?
    (continued in field for another language)
    - Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics and intermediate MRD response: Can the probability of disease-free survival (pDFS) from time of randomization be improved by additional therapy with one cycle of post-reintensification immunotherapy with Blinatomomab (15 µg/m²/d for 28 days)?
    - Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients defined by treatment response over the course of induction: Can the pEFS from time of randomization be improved by the extension of the standard of care consolidation phase by 14 days with an increase of the consolidation cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by 50%?
    E.2.2Secondary objectives of the trial
    - All randomizations: Can the overall survival be improved by the treatment in the experimental arm?
    - All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm?
    - Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with Bortezomib?
    - Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with Blinatumomab?
    (continued in field for another language)
    - Randomization R-HR: What is the proportion of patients with insufficient MRD response to Blinatumomab as defined in the protocol (section 3.1.7) as compared to the MRD response after the HR-2’ block in the control arm?
    - Randomization R-HR: Can the MRD load after the first treatment cycle (HR-2’/Blinatumomab) and the second cycle (HR-3’/Blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy?
    - Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the Blina cycle compared to 4 weeks of standard maintenance therapy?
    - Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase?
    - Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009?
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Characterization of mechanisms of response and resistance and identification of therapeutic targets.
    2. Pre-clinical models including patient-derived xenografts (PDX) to investigate mechanisms of response and resistance, identify new biomarkers and therapeutic strategies
    3. Evaluation of drug response profiles (DRP) by screening diagnostic samples from HR-ALL patients to identify alternative therapeutic strategies
    4. Activity-based profiling of proteasome components and ex-vivo drug profiling of diagnostic samples from Patients with Early High Risk B-cell precursor ALL and matched controls to establish predictive markers of response to Bortezomib in ALL
    5. Genetic predisposition to ALL and influence of germline genetic variants on treatment response and toxicity
    6. Molecular characterization of leukemia occurring in patients that had a prior neoplasia (observation patients)
    7. Influence of host immune system for outcome of targeted immunotherapy: immunological studies for patients treated with Blinatumomab
    8. Effect of host commensal microorganisms for leukemia development and toxicity
    9. Integrated genomic platform – merging clinical, diagnostic and research information for better outcomes
    10. Novel approaches for diagnostics and treatment of CNS-involvement
    11. Identification of new markers for detection of clinically relevant subgroups in ALL by flow cytometry and to improve detection of minimal residual disease
    12. Development of next generation diagnostics for the detection of minimal residual disease
    13. Metabolomic profiling at onset and in different treatment phases
    14. Characterization of genetic signatures in childhood Down-Syndrome ALL
    E.3Principal inclusion criteria
    - newly diagnosed acute lymphoblastic leukemia, from 1st September 2023 onwards only acute lymphoblastic leukemia with T-cell phenotype or
    - newly diagnosed mixed phenotype acute leukemia (MPAL) meeting one of the following criteria:
    • biphenotypic with a dominant T or B lineage assignment,from 1st September 2023 onwards only those with a dominant T lineage assignment,
    •bilineal either with a dominant lymphoblastic (from 1st September 2023 onwards only T lymphoblastic) population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen
    - newly diagnosed acute undifferentiated leukemia
    - age < 18 years (up to 17 years and 365 days) at the day of diagnosis
    - patient enrolled in a participating center
    - written informed consent to trial participation and transfer and processing of data
    E.4Principal exclusion criteria
    - Ph+ (BCR-ABL1 or t(9;22)-positive) ALL
    - bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset
    - pre-treatment with cytostatic drugs
    - glucocorticoid pre-treatment with ≥ 1 mg/kg/d Prednisolone equivalent for more than two weeks during the last month before diagnosis
    - treatment started according to another protocol
    - underlying diseases that does not allow treatment according to the protocol
    - ALL diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
    - evidence of pregnancy or lactation period
    - Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
    - participation in another clinical trial that interferes with the protocol
    - other condition (either pre-existing or related to leukemia biology as present at diagnosis) or circumstances that significantly conflict with the treatment according to the protocol
    E.5 End points
    E.5.1Primary end point(s)
    For the randomized study questions, the primary endpoint will be the time from randomization until the first event defined as follows:
    Randomization R-eHR, R-HR and R-T: Cytomorphological or molecular non-response (resistance to protocol treatment, considered as event at day zero), relapse, second malignancy or death from any cause. This will be called EFS time.
    Randomization R-MR: Relapse, second malignancy or death from any cause. This will be called DFS time.
    E.5.1.1Timepoint(s) of evaluation of this end point
    EFS and DFS time: end of study
    E.5.2Secondary end point(s)
    - Survival starting at the same time point as the EFS/DFS
    - Frequency and incidence of treatment-related mortality in induction or CCR
    - Frequency and incidence of AE of interest and SAE in specific protocol phases, randomized arms and overall during follow-up
    - MRD load after the randomized treatment phases (R-eHR, R-HR, R-MR and R-T)
    - MRD load after the first/second cycle of Blinatumomab or after the HR 2’/HR 3’ block (R-HR)
    - Proportion of patients with poor MRD response to the first Blinatumomab cycle (“Blinatumomab Poor-Response”) (R HR)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Survival, treatment-related mortality, AE and SAE: end of study
    MRD related endpoints: after the repective MRD evaluation of the last patient in study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial14
    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 concerned51
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA104
    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
    Switzerland
    Australia
    Israel
    Austria
    Czechia
    Germany
    Italy
    Slovakia
    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 years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months0
    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: 5000
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 1
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 9
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 493
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 3565
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 932
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2019-01-23. Yes
    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
    recruitment of young children
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1910
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 4400
    F.4.2.2In the whole clinical trial 5000
    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 except for routine follow-up according to clinical standard of 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 Decision2019-02-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-21
    P. End of Trial
    P.End of Trial StatusOngoing
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