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    The EU Clinical Trials Register currently displays   42157   clinical trials with a EudraCT protocol, of which   6934   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2016-004674-17
    Sponsor's Protocol Code Number:NL59901.078.17
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-07
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-004674-17
    A.3Full title of the trial
    A pilot study to test the feasibility, safety and efficacy of the addition of the BiTE antibody Blinatumomab to the Interfant-06 backbone in infants with MLL-rearranged acute lympfoblastic leukemia
    Studio pilota per valutare la fattibilità, la sicurezza e l’efficacia dell’aggiunta dell’anticorpo BiTE Blinatumomab alla chemioterapia del protocollo Interfant-06 in pazienti con Leucemia Linfoblastica Acuta MLL-riarrangiata di età inferiore a 1 anno.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Blinatumomab in patients (age<1 years) with acute lympfoblastic leukemia; study to test safety and efficacy of Blinatumomab
    Blinatumomab in pazienti affetti da Leucemia Linfoblastica Acuta di età inferiore a 1 anno: studio per valutare la sicurezza e l’efficacia del farmaco Blinatumomab
    A.3.2Name or abbreviated title of the trial where available
    Blinatumomab in Infant ALL
    Blinatumomab in Infant ALL
    A.4.1Sponsor's protocol code numberNL59901.078.17
    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 SponsorPrinses Maxima Centrum voor kinderoncologie
    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
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAIEOP
    B.5.2Functional name of contact pointCoodinatore Nazionale Italia
    B.5.3 Address:
    B.5.3.1Street AddressVia Massarenti 9
    B.5.3.2Town/ cityBologna
    B.5.3.3Post code40138
    B.5.4Telephone number0512144667
    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. name Blincyto
    D. of the Marketing Authorisation holderAmgen
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.1Product nameBlincyto
    D.3.2Product code [AMG103]
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    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.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    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. cell therapy medicinal product Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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. medicinal product typeImmunoterapia
    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
    Leucemia Linfoblastica Acuta
    E.1.1.1Medical condition in easily understood language
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety of 1 course of blinatumomab added to the Interfant- 06 backbone in infants with newly diagnosed ALL.
    Valutare la sicurezza di 1 ciclo di blinatumomab aggiunto a terapia Interfant-06 nei neonati con ALL di nuova diagnosi.
    E.2.2Secondary objectives of the trial
    to assess the feasibility of adding 1 course of blinatumomab to the Interfant-06 backbone - to define the preliminary response rate of this regimen — to assess pharmacokinetics of blinatumomab in infants
    valutare la fattibilità dell'aggiunta di 1 ciclo di blinatumomab alla terapia Interfant-06 - definire il tasso di risposta preliminare di questo regime - valutare la farmacocinetica di blinatumomab nei neonati
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patients must be treated according to Interfant-06 backbone
    2.Patients must have newly diagnosed, CD19 positive, B-precursor acute lymphoblastic leukemia
    3.Morphologica verification of the diagnosis, confirmed with immunophenotyping
    4. =365 days of age at time of diagnosis of ALL
    5.> 28 days of age at start of blinatumomab administration
    6.MR and HR patients according to risk stratification of the Interfant- 06 protocol , thus including all MLL-rearranged and MLL not evaluable patients (these latter are stratified and treated according to MR)
    7.M1 or M2 bone marrow after induction (~day 33). If the peripheral blood shows pancytopenia at day 33 it is justified to postpone the bone marrow puncture according to the Interfant-06 protocol. If the bone marrow at day 33 is hypocellular and one is therefore unable to determine M1 or M2 status, then the bone marrow puncture should be repeated.
    8.Written informed consent from parents or guardians
    1. I pazienti devono essere trattati secondo Interfant-06
    2. I pazienti devono presentare una nuova diagnosi di leucemia linfoblastica acuta, positiva per CD19, B-precursor
    3. Verifica morfologica della diagnosi, confermata con immunofenotipizzazione
    4.= 365 giorni di età al momento della diagnosi di ALL
    5.> 28 giorni di età all'inizio della somministrazione di blinatumomab
    6. pazienti MR e HR in base alla stratificazione del rischio del protocollo Interfant-06, compresi quindi tutti i pazienti con MLL riarrangiati e MLL non valutabili (questi ultimi sono stratificati e trattati in base alla MR).
    7. midollo osseo M1 o M2 dopo induzione (~ giorno 33). Se il sangue periferico mostra pancitopenia al giorno 33, è giustificato posticipare la puntura del midollo osseo secondo il protocollo Interfant-06. Se il midollo osseo al giorno 33 è ipocellulare e quindi non si è in grado di determinare lo stato M1 o M2, è necessario ripetere la puntura del midollo osseo.
    8. Consenso informato scritto da parte di genitori o tutore.
    E.4Principal exclusion criteria
    1.Biphenotypic ALL 2.Mature B-ALL 3.Presence of t(9;22) (q34;q11) or BCR-ABL fusion transcript 4.M3 marrow after induction 5.Patients with Down syndrome (because of increased toxicity of conventional chemotherapy) 6.ClinicaIly relevant CNS pathology requiring treatment (eg unstable epilepsy) 7.Evidence of CNS involvement of ALL (CNS2 or CNS3) at the end of induction. Subjects with CNS disease at the time of diagnosis are eligible if a CNS1 status is obtained prior to enrolment (lumbar puncture at ~day 29 of induction, see definitions CNS status in Appendix D) 8.Known infection with human immunode¿ciency virus (HIV) 9.Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing

    Exclusion criteria before start (-d3) of blinatumomab:
    1.Peripheral neutrophils <0.5 x 109/I and WBC <2 109/I (for M1 marrow only, with a maximum delay of 2 weeks. Patients with M2 bone marrow will not recover their blood counts and can start as soon as the other inclusion criteria are met) 2.Peripheral platelets < 50 x 109/L (for M1 marrow only with a maximum delay of 2 weeks. Patients with M2 bone marrow will not recover their blood counts and can start as soon as the other inclusion criteria are met) 3.Creatinine > 1.5 X ULN, based on the normal ranges for age and gender of the local laboratories 4.Total bilirubin > 3 x ULN unless the patient has documented Gilbert Syndrome 5.Chemotherapy related toxicities that have not resolved to S grade 2 6.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
    1 ALL bifenotipico
    2-ALL a cellule B Mature
    3- Presenza di t (9; 22) (q34; q11) o BCR-ABL
    trascritti di fusione
    4 Midollo M3 dopo induzione
    5 pazienti con sindrome di Down (a causa della maggiore tossicità della chemioterapia convenzionale)
    6 Patologia del SNC clinicamente rilevante che richiede un trattamento (ad es. Epilessia instabile)
    7- evidenza del coinvolgimento del SNC in ALL (CNS2 o CNS3) alla fine dell'induzione. I soggetti con malattia del sistema nervoso centrale al momento della diagnosi sono ammissibili se si ottiene uno stato CNS1 prima dell'arruolamento (puntura lombare al giorno 29 dell'induzione)
    8- infezione nota con virus dell'immunodeficienza umana (HIV)
    9- Ipersensibilità nota alle immunoglobuline o ad uno qualsiasi dei prodotti o componenti da somministrare

    Criteri di esclusione prima dell'inizio (-d3) di blinatumomab:
    1- neutrofili periferici <0,5x109 / l e globuli bianchi <2 109 / l (solo per midollo M1, con ritardo massimo di 2 settimane. I pazienti con midollo osseo M2 non recuperano la conta ematica e possono iniziare non appena gli altri criteri di inclusione sono soddisfatti)
    2- Piastrine periferiche <50x 109 / L (solo per midollo M1 con un ritardo massimo di 2 settimane. I pazienti con midollo osseo M2 non recuperano la conta ematica e possono iniziare non appena sono soddisfatti gli altri criteri di inclusione)
    3- creatinina> 1,5 XULN, in base ai normal ranges per età e sesso dei laboratori locali
    4- bilirubina totale> 3 X ULN a meno che il paziente non abbia sindrome di Gilbert documentata
    5- Tossicità correlate alla chemioterapia che non si sono risolte a <= grado 2
    6- Sintomi e / o segni clinici e / o segni radiologici e / o ecografici che indicano un'infezione acuta o cronica incontrollata, qualsiasi altra malattia concomitante o condizione medica che potrebbe essere esacerbata dal trattamento o complicherebbe seriamente il rispetto del protocollo
    E.5 End points
    E.5.1Primary end point(s)
    Incidence of clinically relevant toxicities defined as any toxicity that is possibly or definitely attributable to blinatumomab AND results in permanent discontinuation of blinatumomab OR death.
    Incidenza della tossicità clinicamente rilevante definita come qualsiasi tossicità eventualmente o sicuramente attribuibile a blinatumomab E che provochi l'interruzione permanente di blinatumomab O morte.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Continuously through treatment and safety follow-up
    Continuamente attraverso il trattamento e il follow-up di sicurezza
    E.5.2Secondary end point(s)
    1.Incidence and severity of (serious) adverse events, independently to relationship with blinatumomab 2.Number of treatment interruptions due to toxicity occurring during blinatumomab 3. Proportion of patients that receive a full course (4 weeks) of blinatumomab 4.Incidence and severity of key safety parameters till start of maintenance and during long-term follow-up; Activity/ Efficacy:
    1.MRD response at the following time points TP2 d33 (end of induction), TPblina1 d15 (after initial 15 days of blinatumomab) and TPblina2 d29 (after the complete course of blmatumomab)
    2.MRD response at the following time points TP2 d33 (end of induction) and TP4 (end of Protocol IB)
    3.Proportion of MR patients with MRD = 5x10- 4 before OCTADAD (indication for SCT)
    4.cCR/CR and 6 months post—induction EFS and the long-term EFS and OS Pharmacokinetics:; Pharmacokinetics: Steady state concentration of blinatumomab (Css)
    Tossicità / fattibilità:
    1.Incidenza e gravità di eventi avversi (gravi), indipendentemente dalla relazione con blinatumomab
    2.Numero di interruzioni del trattamento dovute alla tossicità che si verificano durante blinatumomab
    3. Proporzione di pazienti che ricevono un ciclo completo (4 settimane) di blinatumomab
    4 Incidenza e gravità dei parametri chiave di sicurezza fino all'inizio del mantenimento e durante il follow-up a lungo termine; Attività / Efficacia:
    1.Risposta MRD ai seguenti punti temporali TP2 d33 (fine dell'induzione), TPblina1 d15 (dopo 15 giorni dall’inizio di blinatumomab) e TPblina2 d29 (dopo il ciclo completo di blimatumomab)
    2. Risposta MRD ai seguenti punti temporali TP2 d33 ( fine dell'induzione) e TP4 (fine del protocollo IB)
    3. Proporzione di pazienti MR con MRD = 5x10- 4 prima di OCTADAD (indicazione per SCT)
    4.cCR / CR e EFS 6 mesi post-induzione e EFS a lungo termine e OS; Farmacocinetica: Concentrazione di blinatumomab (Css)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Continuously through treatment and safety follow-up; Continuously through treatment and safety follow-up; Continuously through treatment and safety follow-up
    Continuamente attraverso il trattamento e il follow-up di sicurezza; Continuamente attraverso il trattamento e il follow-up di sicurezza; Continuamente attraverso il trattamento e il follow-up di sicurezza
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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. 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 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.8.2.4Number of treatment arms in the trial1
    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 EEA17
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Czech Republic
    United Kingdom
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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.1.1.1In 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. of subjects for this age range: 5
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    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 No
    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 Yes
    F. of other specific vulnerable populations
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 30
    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)
    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 Decision2020-07-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-24
    P. End of Trial
    P.End of Trial StatusOngoing
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