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    Summary
    EudraCT Number:2015-000733-76
    Sponsor's Protocol Code Number:GMALL-MOLACT1-BLINA
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-03-02
    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 number2015-000733-76
    A.3Full title of the trial
    A multicenter, single-arm study to assess the efficacy, safety, and tolerability of the BiTE® antibody blinatumomab in adult patients with minimal residual disease (MRD) of B-precursor acute lympho-blastic leukemia (Blast Successor Trial)
    Eine multizentrische, einarmige Studie zur Bestimmung der Wirksamkeit, Sicherheit und Verträglichkeit des BiTE® Antikörpers Blinatumomab bei erwachsenen Patienten mit minimaler Resterkrankung (MRD) einer B-Vorläufer akuten lymphatischen Leukämie („Blast“ Nachfolge Studie)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to about blinatumomab for patients with minimal residual disease (MRD) of acute lymphoblastic leukemia
    Eine Studie über Blinatumomab für Patienten mit minimaler Resterkrakung von Akuter Lymphatischer Leukämie
    A.4.1Sponsor's protocol code numberGMALL-MOLACT1-BLINA
    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 SponsorGoethe-Universität Frankfurt, Universitätsklinikum, Med. Klinik II
    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 Limited
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportAmgen BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinik Frankfurt, Med. Klinik II
    B.5.2Functional name of contact pointGMALL-Studienzentrale
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Stern-Kai 7
    B.5.3.2Town/ cityFrankfurt
    B.5.3.3Post code60590
    B.5.3.4CountryGermany
    B.5.4Telephone number+49(0)6963016365
    B.5.5Fax number+49(0)6963017463
    B.5.6E-mailgmall@em.uni-frankfurt.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.3.1Product nameBlinatumomab
    D.3.4Pharmaceutical form Powder and solvent for concentrate 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 Yes
    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.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
    Patients with minimal residual disease (MRD) positive B-precursor ALL with and without prior SCT documented after an interval of at least 8 days from last systemic chemo-therapy
    • at a level of ≥10-4 - <10-3 (molecular failure or molecular relapse) in an assay with a minimum sensitivity of 10-4 OR
    • at levels below 10-4 :
    o Positive <10-4, non quantifiable (MolNE1) OR
    o Positive <10-4 (MolNE2) OR
    • Presence of minimal residual disease (MRD), non quantifiable (MolNE3).
    E.1.1.1Medical condition in easily understood language
    Patients with minimal residual disease of Acute Lymphoblastic Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066104
    E.1.2Term Precursor B-lymphoblastic leukaemia 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 efficacy of blinatumomab to induce complete MRD response in patients regardless of prior SCT
    E.2.2Secondary objectives of the trial
    -Remission duration, relapse-free survival and overall survival
    -Relapse localisation and relapse characteristics
    -Efficacy of Blinatumomab in patients with our without prior SCT
    -Effect of Blinatumomab on MRD response
    -Safety and tolerability of blinatumomab in patients with or without prior SCT
    -Effect of blinatumomab on duration of MRD response and complete MRD response
    -Effect of blinatumomab on the kinetics of MRD response
    -Effect of blinatumomab on GvHD in patients with relapse after SCT
    -Outcome of SCT after blinatumomab including mortality rate
    -Outcome of patients without SCT after blinatumomab
    -Patient’s quality of life during and after therapy
    -Effect of pre-defined dose reductions, recommendations and local handling practices, on safety, tolerability and treatment realisation of blinatumomab
    -Resource utilization and practical treatment organisation
    -To assess potential biologic predictors of response to blinatumomab and relapse risk after blinatumomab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with CD19 positive B–precursor ALL in complete hematological remission defined as less than 5% blasts in bone marrow after at least three intense chemotherapy blocks (e.g., GMALL induction I-II/consolidation I).
    2. Presence of minimal residual disease (MRD) after an interval of at least 8 days from last systemic chemo-therapy
    • at a level of ≥10-4 - <10-3 (molecular failure or molecular relapse) in an assay with a minimum sensitivity of 10-4 OR
    • at levels below 10-4 :
    o Positive <10-4, non quantifiable (MolNE1) OR
    o Positive <10-4 (MolNE2) OR
    • Presence of minimal residual disease (MRD), non quantifiable (MolNE3).
    3. For evaluation of MRD patients must have at least one molecular marker based on individual rearrange-ments of immunoglobulin, TCR-genes or other suitable genes evaluated by the reference laborabory of the trial
    4. Bone marrow function as defined below:
    - ANC (Neutrophils) >/= 1,000/µL
    - Platelets >/= 50,000/µL (transfusion permitted)
    - HB level >/= 9g/dl (transfusion permitted)
    5. Renal and hepatic function as defined below:
    - AST (GOT), ALT (GPT), and AP < 5 x upper limit of normal (ULN)
    - Total bilirubin < 1.5 x ULN (unless related to Gilbert's Meulen-gracht disease)
    - Creatinine < 1.5x ULN
    - Creatinine clearance >/= 60 mL/min (e.g. calculated according Cockroft & Gault)
    6. Negative HIV test, negative hepatitis B (HbsAg) and hepatitis C virus (anti-HCV) test
    7. Negative pregnancy test in women of childbearing potential
    8. ECOG Performance Status 0 or 1
    9. Age min. 18 years
    10. Ability to understand and willingness to sign a written informed consent
    11. Signed and dated written informed consent is available
    12. Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)
    E.4Principal exclusion criteria
    1. Ph/BCR-ABL positive ALL
    2. Presence of circulating blasts or current extramedullary involvement by ALL
    3. History or presence of clinically relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome or psychosis)
    4. Current detection of ALL blast cells in cerebrospinal fluid
    5. History of or active relevant autoimmune disease
    6. Systemic cancer chemotherapy within 2 weeks prior to study treatment (except for intrathecal prophylaxis)
    7. Radiotherapy within 4 weeks prior to study treatment
    8. Live vaccination within 2 weeks before the start of study treatment
    9. Autologous hematopoietic stem cell transplantation (SCT) within six weeks prior to study treatment
    10. Allogeneic SCT within 12 weeks before the start of study treatment
    11. Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
    12. Any systemic therapy against GvHD within 2 weeks before start of study treatment
    13. Therapy with monoclonal antibodies (rituximab, alemtuzumab) within 4 weeks prior to study treatment
    14. Treatment with any investigational product within four weeks prior to study treatment
    15. Previous treatment with blinatumomab or other anti-CD19-therapy
    16. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
    17. History of malignancy other than ALL diagnosed within 5 years prior to start of protocol-specified therapy with the exception of:
    - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    - Adequately treated cervical carcinoma in situ without evidence of disease
    - Adequately treated breast ductal carcinoma in situ without evidence of disease
    - Prostatic intraepithelial neoplasia without evidence of prostate cancer
    18. Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator
    19. Nursing women
    20. Woman of childbearing potential and is not willing to use a highly effective method of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment.
    21. Male who has a female partner of childbearing potential, and is not willing to use a highly effective form of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients who achieve complete MRD response after one cycle of treatment with blinatumomab in patients with and without prior SCT
    E.5.1.1Timepoint(s) of evaluation of this end point
    After one cycle of treatment (4 weeks of treatment),
    E.5.2Secondary end point(s)
    Secondary endpoints
    • Probability of continuous complete remission (remission duration) at 18 months following initiation of blinatumomab
    • Probability of hematological relapse-free survival rate at 18 months following initiation of blinatumomab
    • Probability of overall survival at 18 months following initiation of blinatumomab
    • Frequency of different relapse localisations in proportion to total hematological relapses
    • Biological evaluation of hematological and extramedullary relapses including CD19 expression
    • Overall incidence and severity of adverse events in patients with and without prior SCT (CTC-AE 4.0)
    • Proportion of patients who achieve MRD response after one or two cycles of treatment with Blinatumomab
    • Proportion of patients who achieve complete MRD response after two cycles of treatment with blinatumomab in patients with and without prior SCT
    • Probability of continuous MRD response and complete MRD response and duration of MRD response at 18 months following initiation of blinatumomab
    • Time to MRD response measured by time-point of first achievement
    • Evaluation of GvHD as part of AE documentation and according to Glucksberg Criteria, grade and localisa-tion.
    • Evaluation of overall survival, remission duration, relapse-free survival and treatment related mortality (at day 100 and later) in patients with SCT in complete remission after blinatumomab
    • Evaluation of overall survival, remission duration, relapse-free survival and treatment related mortality in patients without SCT in complete remission after blinatumomab
    • Measurement of Quality of Life with EORTC instruments (EORTC QLQ C30 and EQ-5D) at different time-points during treatment
    • Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD

    Exploratory endpoints
    • Incidence of dose reductions, incidence of treatment interruptions, days of interruption, withdrawals, total delivered dose, total days of treatment and realisation rate calculated as scheduled total dose/delivered total dose
    • Realisation of different prevention and management strategies in terms of frequencies and effect on AE duration and grade
    • Hospitalisation days, utilisation of infusion pumps and ambulatory care services
    • Evaluation of biological markers at different time-points during first treatment cycle, in primary materials and in comparison of primary material and relapse material
    E.5.2.1Timepoint(s) of evaluation of this end point
    18 months following initiation of blinatumomab (end of follow-up-period)
    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 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 concerned22
    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 No
    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
    Prerequiste for termination of the trial is LVLS (i.e. End of Follow-up-period for the last patient) and completed data collection
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 48
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state60
    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)
    according to standard of care; retreatment if possible according to protocol
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-04-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-28
    P. End of Trial
    P.End of Trial StatusOngoing
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