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    Summary
    EudraCT Number:2017-003778-15
    Sponsor's Protocol Code Number:20130265
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-11-08
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2017-003778-15
    A.3Full title of the trial
    A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study of Blinatumomab in Japanese Subjects with Acute Lymphoblastic Leukemia that did not respond to previous therapy or that relapsed after initially successful previous therapy
    A.4.1Sponsor's protocol code number20130265
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02412306
    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 Inc.
    B.1.3.4CountryUnited States
    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 Inc.
    B.4.2CountryUnited States
    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 AddressDammstrasse 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 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 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 codeAMG 103
    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.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
    relapsed/refractory B-precursor Acute Lymphoblastic Leukemia
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10066109
    E.1.2Term Precursor B-lymphoblastic leukemia 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
    Phase 1b: To determine the maximum tolerated dose (MTD) of blinatumomab in adult and pediatric subjects with R/R B-precursor ALL.
    Phase 2 Part: To evaluate the rate of CR/CRh* in adult subjects with R/R B-precursor ALL who receive blinatumomab
    E.2.2Secondary objectives of the trial
    Phase 1b: To evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of blinatumomab in adult and pediatric subjects with R/R B-precursor ALL.
    Phase 2 Part: To evaluate other measures of efficacy, safety and PK in adult subjects with R/R B-precursor ALL at the blinatumomab regimen selected based on the Phase 1b data
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Adult Subjects:
    * Subjects with Philadelphia-negative B-precursor ALL, with any of the following:
    • Relapsed or refractory after first line therapy with first remission duration ≤ 12 months; or
    • Relapsed or refractory after first salvage therapy; or
    • Relapsed or refractory within 12 months of alloHSCT
    * Greater than 5% blasts in bone marrow
    * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
    * Age ≥ 18 years-old at enrollment

    Pediatric Subjects:
    * Age < 18 years-old at enrollment
    * Subjects with relapsed/refractory B-precursor ALL, defined as one of the following:
    • second or later bone marrow relapse;
    • any marrow relapse after alloHSCT; or
    • Refractory to other treatments:
    o For subjects in first relapse: failure to achieve a CR following a full standard reinduction chemotherapy regimen
    o For subjects who have not achieved a first remission: failure to achieve remission following a full standard induction regimen
    * Greater than 5% blasts in bone marrow
    * Karnofsky performance status ≥ 50% for subjects ≥ 16 years
    * Lansky performance status ≥ 50% for subjects < 16 years
    E.4Principal exclusion criteria
    * History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:
    − Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician
    − 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 in situ without evidence of disease
    − Adequately treated mucosal gastric cancer or mucosal colorectal cancer without evidence of disease
    * Diagnosis of Burkitt’s Leukemia according to WHO classification
    * History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, psychosis
    − With the exception of CNS leukemia that is well controlled with intrathecal therapy
    * Active ALL in the CNS (confirmed by cerebrospinal fluid [CSF analysis]) or testes
    * Isolated extramedullary disease
    * Current autoimmune disease or history of autoimmune disease with potential CNS involvement
    * Autologous HSCT within 6 weeks prior to start of blinatumomab treatment
    * AlloHSCT within 12 weeks prior to start of blinatumomab treatment
    * Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria, or active chronic GvHD requiring systemic treatment
    * Any systemic therapy against GvHD within 2 weeks prior to start of blinatumomab treatment
    * Cancer chemotherapy within 2 weeks prior to start of blinatumomab treatment (Intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab treatment. Pediatric subjects only: Tyrosine kinase inhibitors and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids, intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab)
    * Radiotherapy within 2 weeks prior to start of blinatumomab treatment
    * Immunotherapy (eg, rituximab) within 6 weeks prior to start of blinatumomab treatment
    * Subject received prior anti-CD19 therapy
    * Eligibility for alloHSCT at the time of enrollment (as defined by disease status, performance status and availability of donor)
    * Abnormal screening laboratory values as defined below:
    − AST (SGOT) and/or ALT (SGPT) and/or ALP ≥ 5 x upper limit of normal (ULN)
    − Total bilirubin ≥ 1.5 x ULN (unless related to Gilbert´s or Meulengracht disease)
    − Creatinine ≥ 1.5 ULN for age, or creatinine clearance < 60 mL/min
    * Known infection with HIV or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive)
    * Currently receiving treatment in another investigational device or drug study, or less than 4 weeks since ending treatment on another investigational device or drug study(s). Other investigational procedures while participating in this study are excluded.
    * Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing
    * Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject’s and investigator’s knowledge
    * Previous treatment with blinatumomab
    * Chemotherapy related toxicities (excluding hematologic) that have not resolved to ≤ grade 2
    * 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
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b: Incidence of Dose limiting toxicities (DLTs)
    Phase 2: CR/CRh* within 2 cycles of treatment with blinatumomab
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1b: at the end of the DLT period
    Phase 2: after 2 treatment cycles; The primary analysis will be triggered when all enrolled subjects complete induction treatment during the Phase 2 part of the study.
    E.5.2Secondary end point(s)
    Phase 1b
    • Incidence and severity of adverse events
    • Complete remission (CR)/complete remission with partial hematological recovery (CRh*) within first 2 cycles of treatment with blinatumomab for adult subjects and M1 remission within the first 2 cycles of treatment with blinatumomab for pediatric subjects
    • Time to hematological relapse (TTHR)
    • Relapse free survival (RFS)
    • Overall survival (OS)
    • Blinatumomab PK parameters (eg, steady state concentration [Css] and clearance of blinatumomab)
    • Serum cytokine concentrations
    • Incidence of anti-blinatumomab antibody formation

    Phase 2:
    • TTHR
    • RFS
    • Allogeneic HSCT (alloHSCT) treatment with blinatumomab
    • Best overall response within 2 cycles of treatment with blinatumomab
    • OS
    • Incidence and severity of adverse events
    • 100-day mortality after alloHSCT
    • Blinatumomab PK parameters (eg, steady state concentration [Css] and clearance of blinatumomab)
    • Serum cytokine concentrations
    • Incidence of anti-blinatumomab antibody formation
    E.5.2.1Timepoint(s) of evaluation of this end point
    The primary analysis (CR/CRh* rate within 2 treatment cycles) will be triggered when all enrolled subjects complete induction treatment during the Phase 2 part of the study. A final analysis will be conducted when all enrolled subjects complete the long-term follow-up period of the protocol.
    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
    Phase 1b/2 study in Japanese subjects
    E.7.2Therapeutic exploratory (Phase II) No
    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 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Japan
    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
    Primary Completion: when the last subject is assessed or receives an intervention for the purposes of final collection of data for the primary endpoint, whether the study concluded as planned or was terminated early.
    End of Trial: Phase 1b/2: when the last subject is assessed or receives an intervention for evaluation in the study, which corresponds to the 24 month long-term follow-up visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years4
    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: 30
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 17
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 13
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 85
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    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
    children under 18 years of age
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 122
    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
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: Japan
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