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    Summary
    EudraCT Number:2010-024264-18
    Sponsor's Protocol Code Number:MT103-205
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-08-01
    Trial results View 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 number2010-024264-18
    A.3Full title of the trial
    A Single-Arm Multicenter Phase II Study preceded by Dose Evaluation to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab (MT103) in Pediatric and Adolescent Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Combined Pharmacokinetic, Dose-Finding, Safety and Efficacy Study in Pediatric and Adolescent Patients with Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
    A.4.1Sponsor's protocol code numberMT103-205
    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 SponsorAmgen Research (Munich) GmbH
    B.1.3.4CountryGermany
    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 supportAmgen Research (Munich) GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointIHQ medical Info-Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstr. 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6300
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/650
    D.3 Description of the IMP
    D.3.1Product nameBlinatumomab
    D.3.2Product code MT103, AMG103
    D.3.4Pharmaceutical form Powder 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 codeMT103
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number33 (process 4) to 30.3 (process 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.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
    Pediatric and adolescent patients with B-precursor ALL in second or later bone marrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments.
    E.1.1.1Medical condition in easily understood language
    Acute lymphoblastic leukemia-a cancer of the blood and marrow
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    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
    The first part (Phase I) is to determine the recommended Phase II dose of blinatumomab. The Phase II Part is to assess the efficacy of blinatumomab.
    E.2.2Secondary objectives of the trial
    Phase I Part:
    - To assess the safety of different dose levels of blinatumomab in different age groups
    - To assess pharmacokinetics of different dose levels of blinatumomab in different age groups
    - To assess the anti-leukemia activity of blinatumomab
    - To assess the development of anti-drug antibodies (ADA) to blinatumomab
    - To describe changes in pharmacodynamic markers following treatment with blinatumomab at differing dose levels

    Phase II Part:
    - To assess the safety of blinatumomab
    - To assess the development of ADA to blinatumomab

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Morphologic and immunophenotypic evidence of B-precursor ALL (pro B-, pre B-, common ALL) with > 25% blasts in bone marrow (M3) at study enrolment.
    2. Age < 18 years at enrollment [only children age 2-17 will be enrolled prior to the identification of the recommended Phase II dose].
    3. Relapsed/refractory disease:
    • Second or later bone marrow relapse,
    • Any marrow relapse after allogeneic HSCT, or
    • Refractory to other treatments:
    --Patients in first relapse must have failed to achieve a CR following full standard reinduction chemotherapy regimen of at least 4 weeks duration
    --Patients who have not achieved a first remission must have failed a full standard induction regimen
    4. Karnofsky performance status ≥ 50% for patients ≥ 16 years and Lansky Performance Status (LPS) of ≥ 50% for patients < 16 years
    5. Organ function requirements: Patients must have
    a. Creatinine clearance ≥ 70 mL/min/1.73 m2 or a normal serum
    creatinine based on age/gender prior to day 1
    b. Adequate liver function defined as:
    -Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age OR direct bilirubin ≤ 1.5 mg/DL prior to day 1
    -ALT (SGPT) ≤ 135 IU/L at least once during screening
    6. Patient and/or his/her legal representative have reviewed the patient information/informed consent form and have had their questions answered and have given written informed consent
    E.4Principal exclusion criteria
    1. Active acute or extensive chronic GvHD
    2. Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment
    3. Evidence for current CNS involvement by ALL (CNS 2, CNS 3) or testicular involvement by ALL [patients with CNS relapse at the time of M3 relapse are not eligible for the Phase I part but are eligible for the Phase II part of the study, if CNS is successfully treated prior to enrollment]. Two successive CSF evaluations at least one week apart following completion of CNS therapy that are CNS1 are required
    4. History of relevant CNS pathology or current relevant CNS pathology (seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
    5. History of autoimmune disease with potential CNS involvement or current autoimmune disease
    6. Any HSCT within 3 months prior to blinatumomab treatment
    7. Cancer chemotherapy within 2 weeks prior to blinatumomab treatment (except for intrathecal chemotherapy and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids)
    8. Chemotherapy related toxicities that haven't resolved to ≤ Grade 2
    9. Radiotherapy within 2 weeks prior to blinatumomab treatment
    10. Immunotherapy (e.g. rituximab, alemtuzumab) within 6 weeks prior to blinatumomab treatment
    11. Any investigational product within 4 weeks prior to study entry
    12. Previous treatment with blinatumomab
    13. Known hypersensitivity to immune globulins or to any other component of the study drug formulation
    14. Presence of HAMA reactivity (in patients with prior exposure to murine antibodies or proteins)
    15. Active malignancy other than ALL
    16. Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
    17. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive)
    18. Pregnant or nursing female adolescent patients
    19. Post-menarchal female adolescent patients or male adolescent patients not willing to use an effective form of contraception during treatment phase of the study and at least 3 months thereafter
    20. Placed into an institution due to juridical or regulatory ruling
    E.5 End points
    E.5.1Primary end point(s)
    Phase I Part:
    - Maximal tolerable dose defined by ≤ 1 of 6 patients experiencing dose limiting toxicity (DLT) or maximal administered dose (MAD)

    Phase II Part:
    - Rate of complete remission (CR) within the first 2 cycles
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I Part:
    In the Phase I part of the study, safety will be assessed by the occurence of dose limiting toxicity (DLT) within the first 28 days of treatment (cycle 1).

    Phase II Part:
    In the Phase II part of the study, efficacy will be assessed by measurement of complete blood count (CBC) and evaluation of a bone marrow will be assessed at D15 of the first cycle and at the end of the infusion period (D29, can be delayed until Day 42) of every cycle.
    E.5.2Secondary end point(s)
    Phase I Part:
    1. Overall incidence and severity of adverse events
    2. Quantification and characterization of pharmacokinetic parameters over time
    3. Rate of complete remission (CR) within first 2 cycles
    4. Time to hematological relapse
    5. CR duration
    6. Overall survival (OS)
    7. Relapse free survival
    8. Proportion of patients who develop ADA at any time
    9. Quantification and characterization of cytokine serum concentrations

    Phase II Part:
    1. Overall incidence and severity of adverse events
    2. Proportion of patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with blinatumomab
    3. Time to hematological relapse
    4. CR duration
    5. Overall survival (OS)
    6. Relapse free survival
    7. Proportion of patients who develop ADA at any time

    Exploratory Endpoints (Phase I + II)
    1. Rate of MRD response
    2. Rate of complete MRD response
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I Part:
    1. Continously
    2. D1, 3, 8, 15, 22, 29 (cycle 1 + 2)
    3.-7. Efficacy will be assessed by measurement of complete blood count (CBC) and evaluation of a bone marrow aspiration at D15 of the first cycle and at the end of the infusion period (D29, can be delayed until Day 42) of each cycle.
    8. End of every cycle
    9. D1, 2, 3

    Phase II Part:
    1.-2. Continously
    3.-6. as for 3.-7. Phase I Part
    7. End of every cycle

    Exploratory Endpoints (Phase I + II)
    as for 3.-7. Phase I Part
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 use 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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Austria
    Canada
    France
    Germany
    Italy
    Netherlands
    Switzerland
    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
    The end of the trial is defined as the last protocol mandated evaluation for the last patient in the study.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    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: 70
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 31
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 33
    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
    Very young children.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 70
    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)
    No specific Treatment is planned after Trial Participation.
    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 Decision2011-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-09-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-05-24
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