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    Summary
    EudraCT Number:2017-003377-34
    Sponsor's Protocol Code Number:54767414ALL2005
    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:2018-08-29
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-003377-34
    A.3Full title of the trial
    An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    Uno studio in aperto, multicentrico, di fase 2 per valutare l'efficacia e la sicurezza di daratumumab in soggetti pediatrici e giovani adulti di età compresa tra 1 e 30 anni con Leucemia Linfoblastica Acuta o Linfoma Linfoblastico da precursori delle cellule B o T, di tipo recidivante o refrattario
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    Uno studio in aperto, multicentrico, di fase 2 per valutare l'efficacia e la sicurezza di daratumumab in soggetti pediatrici e giovani adulti di età compresa tra 1 e 30 anni con Leucemia Linfoblastica Acuta o Linfoma Linfoblastico da precursori delle cellule B o T, di tipo recidivante o refrattario
    A.4.1Sponsor's protocol code number54767414ALL2005
    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 SponsorJanssen-Cilag International N.V.
    B.1.3.4CountryBelgium
    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 supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportJANSSEN CILAG INTERNATIONAL NV
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportJANSSEN CILAG SPA
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International N.V.
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 715242166
    B.5.5Fax number+31 715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.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/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab
    D.3.2Product code HuMax-CD38
    D.3.4Pharmaceutical form 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 INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJNJ-54767414 (Daratumumab)
    D.3.9.3Other descriptive nameHUMAX-CD38
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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) 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 Yes
    D.3.11.13.1Other medicinal product typehuman monoclonal antibody
    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 Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    Leucemia Linfoblastica Acuta o Linfoma Linfoblastico da precursori delle cellule B o T, di tipo recidivante o refrattario
    E.1.1.1Medical condition in easily understood language
    Blood or bone cancer
    Tumore del sangue o delle ossa
    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 10066109
    E.1.2Term Precursor B-lymphoblastic leukemia acute
    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 10066110
    E.1.2Term T-cell 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
    The main objective is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in relapsed/refractory B-cell ALL and T-cell ALL as measured by the complete response (CR) rate.
    L'obiettivo primario è valutare l'efficacia di daratumumab in aggiunta alla chemioterapia standard nella leucemia linfoblastica acuta (ALL) a cellule B e nella leucemia linfoblastica acuta a cellule T, di tipo recidivante o refrattario, mediante misura del tasso di risposta completa (CR).
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of daratumumab, including overall response rate (ORR), relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in pediatric and young adult subjects with B-cell and T-cell acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LL), and minimal residual disease (MRD) negative rate in subjects with B-cell and T-cell ALL
    - To assess the safety and tolerability of daratumumab in pediatric and young adult subjects with B-cell and T-cell ALL/LL
    - To assess the pharmacokinetics (PK) of daratumumab in pediatric and young adult subjects with B-cell and T-cell ALL/LL
    - To assess daratumumab immunogenicity in pediatric and young adult subjects with B-cell ALL and T-cell ALL/LL
    - To assess daratumumab concentration in cerebrospinal fluid (CSF)
    - Valutare l'efficacia di daratumumab, compresi tasso di risposta globale (ORR), sopravvivenza senza recidiva (RFS), sopravvivenza libera da eventi (EFS) e sopravvivenza globale (OS) in soggetti pediatrici e giovani adulti affetti da leucemia linfoblastica acuta /linfoma linfloblastico (LL) a cellule B e T, nonché la percentuale di malattia minima residua in soggetti con leucemia linfoblastica acuta a cellule B e T
    - Valutare la sicurezza e la tollerabilità di daratumumab in soggetti pediatrici e giovani adulti con ALL/LL a cellule B e T
    - Valutare la farmacocinetica (PK) di daratumumab in soggetti pediatrici e giovani adulti con ALL/LL a cellule B e T
    - Valutare l'immunogenicità di daratumumab in soggetti pediatrici e giovani adulti con ALL/LL a cellule B e T
    - Valutare la concentrazione di daratumumab nel liquido cerebrospinale (CSF)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each potential subject must satisfy all the following criteria to be enrolled in the study:
    1. ≥1 and ≤30 years of age
    2. Documented ALL or LL as defined by the criteria below:
    a) B-cell cohort:
    Stage 1:
    - ALL in second or greater relapse or refractory to 2 prior induction
    regimens with ≥5% blasts in the bone marrow and aged 1 to <18 years
    Stage 2:
    - ALL in second or greater relapse or refractory to 2 prior induction
    regimens with ≥5% blasts in the bone marrow and aged 1 to 30 years
    - LL in second or greater relapse or refractory to 2 prior induction
    regimens and biopsy proven and with evidence of measurable disease
    by radiologic criteria and aged 1 to 30 years
    b) T-cell cohort:
    Stage 1:
    - ALL in first relapse or refractory to 1 prior induction/consolidation
    regimen with ≥5% blasts in the bone marrow and aged 1 to <18 years
    Stage 2:
    - ALL in first relapse or refractory to 1 prior induction/consolidation
    regimen with ≥5% blasts in the bone marrow and aged 1 to 30 years
    - LL in first relapse or refractory to 1 prior induction/consolidation
    regimen biopsy proven and with evidence of measurable disease by
    radiologic criteria and aged 1 to 30 years
    3. Performance status ≥70 by Lansky scale (for subjects <16 years of age) or Karnofsky scale (for subjects ≥16 years of age)
    4. Adequate hematology laboratory values at Cycle 1 Day 1 pre-dosing defined as follows:
    a. Hemoglobin ≥7.5 g/dL (≥5 mmol/L; prior red blood cell [RBC] transfusion is permitted)
    b. Platelet count ≥10 × 109/L (prior platelet transfusion is permitted)
    5. Adequate renal function defined as normal serum creatinine for the subject’s age or creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 mL/min/1.73 m^2 at Cycle 1 Day 1 pre-dosing
    6. Adequate liver function at Cycle 1 Day 1 pre-dosing defined as:
    a. Alanine aminotransferase level ≤2.5x the upper limit of normal (ULN)
    b. Aspartate aminotransferase level ≤2.5xULN, and
    c. Total bilirubin ≤2x ULN or direct bilirubin level ≤2.0xULN
    7. Female subjects of reproductive potential prior to initiation of the study or during the study (should reproductive potential change during the study) must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose interruptions, and for 6 months after the last dose of any component of the treatment regimen. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. Birth control methods must include one highly effective method of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants], or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy
    8. During the study and for 6 months after receiving the last dose of any component of the treatment regimen, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
    9. Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 6 months after discontinuing study treatment (even after a successful vasectomy)
    10. Male subjects of reproductive potential must not donate sperm during the study or for 6 months after the last dose of study treatment
    11. The informed consent form (ICF) must be signed by a legally authorized representative or by the subject if at legal age of consent indicating understanding of the purpose of, and procedures required for, the study and willingness to participate in the study. Assent is also required of children capable of understanding the nature of the study according to country-specific or site-specific standards
    12. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
    Per essere arruolati nello studio, i potenziali soggetti devono soddisfare tutti i criteri elencati di seguito:
    1. Età compresa fra ≥1 e ≤30 anni.
    2. ALL o LL documentati, secondo quanto definito dai criteri sotto:
    a) Coorte cellule B:
    Stadio 1:
    -ALL in seconda recidiva o più o refrattaria a 2 precedenti regimi di induzione con ≥5% blasti nel midollo osseo ed età compresa fra 1 e <18 anni.
    Stadio 2:
    -ALL in seconda recidiva o più o refrattaria a 2 precedenti regimi di induzione con ≥5% blasti nel midollo osseo ed età compresa fra 1 e 30 anni.
    -LL in seconda recidiva o più o refrattario a 2 precedenti regimi di induzione, biopsia comprovata e con evidenza di malattia misurabile tramite criteri radiologici ed età compresa fra 1 e 30 anni
    b) Coorte cellule T:
    Stadio 1:
    -ALL in prima recidiva o refrattaria a 1 precedente regime di induzione/consolidamento con ≥5% blasti nel midollo osseo ed età compresa fra 1 e <18 anni.
    Stadio 2:
    -ALL in prima recidiva o refrattaria a 1 precedente regime di induzione/consolidamento con ≥5% blasti nel midollo osseo ed età compresa fra 1 e 30 anni.
    -LL in prima recidiva o refrattario a 1 precedente regime di induzione/consolidamento, biopsia comprovata e con evidenza di malattia misurabile tramite criteri radiologici ed età compresa fra 1 e 30 anni
    3. Stato di performance ≥70 secondo la scala Lansky (per soggetti di età <16 anni) o scala Karnofsky (per soggetti di età ≥16 anni) 4. Valori ematologici adeguati al Ciclo 1 Giorno 1 pre-dose, definiti come segue:
    a. emoglobina ≥ 7,5 g/dl (≥5 mmol/l; precedente trasfusione di globuli rossi [RBC] permessa)
    b. conta piastrinica ≥10 × 109/l (precedente trasfusione di piastrine permessa)
    5. Funzione renale adeguata, definita come creatinina nel siero normale per l'età del soggetto (vedere Allegato 3) o clearance della creatinina o velocità di filtrazione glomerulare (GFR) misurata con radioisotopo 70 ml/min/1,73 m2 al Ciclo 1 Giorno 1 pre-dose.
    6. Funzione epatica adeguata al Ciclo 1 Giorno 1 pre-dose, definita come segue:
    a. livello di alanina aminotransaminasi ≤ 2,5 volte il limite superiore alla norma (ULN),
    b. livello di aspartato aminotransaminasi ≤ 2,5 volte ULN e
    c. bilirubina totale ≤2 volte ULN o livello di bilirubina diretta ≤2,0 volte ULN
    7. Le donne in grado di concepire un figlio, prima di iniziare lo studio o durante lo studio (nel caso il potenziale riproduttivo dovesse cambiare durante lo studio) devono impegnarsi ad astenersi in modo continuo dai rapporti eterosessuali o a usare 2 metodi contraccettivi efficaci in contemporanea durante il periodo di trattamento, durante una qualsiasi interruzione del dosaggio e per 6 mesi dopo l'ultima dose di un qualsiasi componente del regime di trattamento. L'astinenza sessuale è considerata un metodo altamente efficace solo se intesa come astensione da rapporti eterosessuali durante l'intero periodo di rischio associato al farmaco dello studio. I metodi contraccettivi devono comprendere una forma di contraccezione altamente efficace (legatura delle tube, dispositivo intrauterino, metodo ormonale [pillola contraccettiva, iniezioni, cerotti ormonali, anelli vaginali o impianti] oppure vasectomia del partner) e un ulteriore metodo contraccettivo efficace (preservativo maschile in lattice o sintetico, diaframma o cappuccio cervicale). La contraccezione deve iniziare 4 settimane prima della somministrazione. Una contraccezione affidabile è indicata anche in presenza di una storia di infertilità, tranne se dovuta a isterectomia.
    8. Durante lo studio e per i 6 mesi successivi all'ultima dose di un componente qualsiasi del regime di trattamento, le donne devono acconsentire a non donare ovuli (ovociti) a scopo di riproduzione assistita.
    9. Gli uomini in età fertile e sessualmente attivi con donne potenzialmente in grado di concepire devono utilizzare sempre un preservativo in lattice o sintetico durante lo studio e per i 6 mesi successivi all'interruzione del trattamento sperimentale (anche dopo una vasectomia effettuata con successo).
    10. Gli uomini potenzialmente in grado di concepire non devono donare lo sperma durante lo studio e per i 6 mesi successivi all'ultima dose di trattamento dello studio.
    11. Il modulo di consenso informato (ICF) deve essere firmato da un rappresentante legale autorizzato o dal soggetto, se maggiorenne, a indicare l'avvenuta comprensione dello scopo dello studio e delle procedure necessarie, nonché la volontà di partecipare allo studio. Per gli adolescenti in grado di comprendere la natura dello studio è necessario l'assenso secondo gli standard specifici per Paese o per centro sperimentale.
    12. Intenzione e capacità di conformarsi ai divieti e alle restrizioni specificati in questo protocollo.
    E.4Principal exclusion criteria
    Any potential subject who meets any of the following criteria will be excluded from participating in the study:
    1. Received an allogeneic hematopoietic transplant within 3 months of screening
    2 Active acute graft-versus-host disease of any grade or chronic graft-versus-host disease of Grade 2 or higher
    3. Received immunosuppression post hematopoietic transplant within 1 month of study entry.
    4. Philadelphia chromosome positive (Ph+) B-cell ALL eligible for tyrosine kinase inhibitor therapy
    5. Has either of the following:
    a. Evidence of dyspnea at rest or oxygen saturation ≤94%.
    b. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma may participate in the study
    6. Down syndrome, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
    7. Prior exposure to daratumumab or other anti-CD38 therapies
    8. Prior cancer immunotherapy (ie, CAR-T, inotuzumab) within 4 weeks prior to start of daratumumab treatment or blinatumomab within 2 weeks prior to the start of daratumumab treatment
    9. For subjects with T-cell ALL/LL only: prior cumulative anthracycline exposure must not exceed 400 mg/m^2 (each 10 mg/m^2 of idarubicin should be calculated as the equivalent of 30 mg/m^2 of doxorubicin)
    10. Subject is known to be seropositive for human immunodeficiency virus, hepatitis B (defined by a positive test for hepatitis B surface antigen or antibodies to hepatitis B surface and core antigens), or hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)
    11. Screening 12-lead electrocardiogram (ECG) showing a baseline QT interval >470 msec or Grade 3 or higher cardiac disorders (according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03)
    12. Known allergies, hypersensitivity, or intolerance to mannitol, glucocorticoid, doxorubicin, cytarabine, methotrexate, vincristine, cyclophosphamide, 6-mercaptopurine, mAb (IRR is not considered hypersensitivity) or human proteins, or their excipients, or known sensitivity to mammalian-derived products
    13. Received an investigational drug, was vaccinated with live attenuated vaccines, or used an invasive investigational medical device within 4 weeks before the planned first dose of study drug, or is currently being treated in an investigational study.
    14. Pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of any component of the treatment regimen
    15. Plans to father a child while enrolled in this study or within 6 months after the last dose of any component of the treatment regimen
    16. Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study
    17. Major surgery within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration
    Note: Subjects with planned surgical procedures to be conducted under local anesthesia may participate
    18. Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications listed in Section 8 of protocol.
    NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study.
    I potenziali soggetti in possesso di uno qualsiasi dei seguenti criteri saranno esclusi dalla partecipazione allo studio:
    1. Trapianto allogenico di cellule ematopoietiche effettuato entro 3 mesi dallo screening.
    2. Malattia acuta e attiva del trapianto contro l'ospite di qualsiasi grado o malattia cronica del trapianto contro l'ospite di grado 2 o superiore.
    3. Immunosoppressione successiva la trapianto ematopoietico entro 1 mese dall'ingresso nello studio.
    4. ALL a cellule B cromosoma Philadelphia positivo, idonea alla terapia con inibitore della tirosin-chinasi.
    5. Una delle seguenti condizioni:
    a. Evidenza di dispnea a riposo o saturazione dell'ossigeno ≤94%.
    b. Noto asma persistente moderato o grave negli ultimi 2 anni o asma incontrollato di qualsiasi classificazione. I soggetti che soffrono attualmente di asma intermittente controllato o asma persistente lieve controllato sono ammessi allo studio.
    6. Sindrome di Down, leucemia mielomonocitica giovanile, anemia di Fanconi, sindrome di Kostmann, sindrome di Shwachman o qualsiasi altra sindrome nota che interessi il midollo osseo.
    7. Precedente esposizione a daratumumab o ad altre terapie anti-CD38.
    8. Precedente immunoterapia per il cancro (ad es. CAR-T, inotuzumab) nelle 4 settimane precedenti l'inizio del trattamento con daratumumab o assunzione di blinatumomab nelle 2 settimane precedenti l'inizio del trattamento con daratumumab.
    9. Solo per i soggetti con ALL/LL a cellule T: una precedente esposizione cumulativa ad antraciclina non deve superare i 400 mg/m2 (ogni 10 mg/m2 di idarubicina da calcolare come equivalente di 30 mg/m2 di doxorubicina).
    10. Sieropositività nota al virus dell'immunodeficienza umana, all'epatite B (definita da un test positivo per l'antigene di superficie dell'epatite B o per gli anticorpi contro l'antigene core dell'epatite B) o all'epatite C (tranne in presenza di risposta virologica sostenuta (SVR), definita come aviremia almeno 12 settimane dopo il completamento della terapia antivirale).
    11. Elettrocardiogramma (ECG) a 12 derivazioni allo screening che mostra un intervallo QT al basale >470 msec o patologia cardiaca di grado 3 o superiore (secondo i criteri terminologici comuni per gli eventi avversi del National Cancer Institute [NCI CTCAE], versione 4.03).
    12. Allergie note, ipersensibilità o intolleranza a mannitolo, glucocorticoide, doxorubicina, citarabina, metotrexato, vincristina, ciclofosfamide, 6 mercaptopurina, anticorpi monoclonali (per reazioni correlate all’infusione (IRR) non si parla di ipersensibilità) o proteine umane o relativi eccipienti (fare riferimento ai rispettivi foglietti illustrativi e all’Investigator’s Brochure), oppure sensibilità nota a prodotti di derivazione mammifera.
    13. Assunzione di un farmaco sperimentale, vaccinazione con vaccini attenuati vivi o uso di un dispositivo medico sperimentale invasivo entro le 4 settimane precedenti alla prima somministrazione pianificata del farmaco sperimentale, o attualmente in trattamento in uno studio sperimentale.
    14. Gravidanza o allattamento al seno in atto oppure intenzione di iniziare una gravidanza durante l'arruolamento nello studio o nei 6 mesi successivi all'assunzione dell'ultima dose di un qualsiasi componente del regime di trattamento.
    15. Intenzione di concepire un figlio durante l'arruolamento nel presente studio o entro i 6 mesi successivi all'ultima dose di un qualsiasi componente del regime di trattamento.
    16. Condizione o patologia medica o psichiatrica concomitante (ad es., infezione sistemica attiva, diabete non controllato, pneumopatia infiltrativa diffusa acuta), incline ad interferire con le procedure o i risultati dello studio oppure che, secondo lo sperimentatore, potrebbe costituire un rischio per la partecipazione a questo studio.
    17. Intervento chirurgico maggiore nelle 2 settimane precedenti lo screening o mancata ripresa completa da un precedente intervento chirurgico oppure previsione di intervento chirurgico durante la partecipazione allo studio o nelle 2 settimane successive all'ultima somministrazione del farmaco sperimentale.
    Nota: i soggetti con procedure chirurgiche programmate da effettuarsi in anestesia locale possono partecipare.
    18. Nota o presunta incapacità del soggetto di attenersi al protocollo di sperimentazione (ad es. a causa di alcolismo, tossicodipendenza o disturbo psicologico). Qualsiasi condizione del soggetto per cui, secondo il giudizio dello sperimentatore, la partecipazione non sarebbe nel miglior interesse del soggetto (ad es. ne comprometterebbe il benessere) o potrebbe impedire, limitare o confondere le valutazioni richieste dal protocollo. Assunzione da parte del soggetto di farmaci vietati secondo la Sezione 8 del protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    1. Complete response (CR) rate
    misura del tasso di risposta completa (CR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Within 2 cycles of therapy for B-cell ALL and at the end of Cycle 1 for T-cell ALL
    entro 2 cicli di terapia per i soggetti con ALL a cellule B e alla fine del ciclo 1 per i soggetti con ALL a cellule T.
    E.5.2Secondary end point(s)
    1. Overall response rate (ORR)
    2. Event-free survival (EFS)
    3. Relapse-free survival (RFS)
    4. Overall survival (OS)
    5. Minimal residual disease (MRD) negative rate
    6. Proportion of subjects who receive an allogeneic Hematopoietic stem cell transplant (HSCT) after treatment with daratumumab
    7. PK of daratumumab in pediatric and young adult subjects (Cmax and Cmin)
    8. Daratumumab immunogenicity incidence in pediatric and young adult subjects with B-cell T-cell ALL/LL
    9. Concentration of daratumumab in Cerebrospinal fluid (CSF)
    1. Valutare il tasso di risposta globale (ORR)
    2. Valutare la sopravvivenza senza recidiva (RFS)
    3. Valutare la sopravvivenza libera da eventi (EFS)
    4. Valutare la sopravvivenza globale (OS)
    5. Valutare la percentuale di malattia minima residua
    6. Valutare la percentuale di soggetti che ricevono un trapianto allogenico di cellule staminali ematopoietiche (HSCT) dopo essere stati trattati con Daratumumab;
    7. Valutare la farmacocinetica (PK) in soggetti pediatrici e giovani adulti (Cmax e Cmin)
    8. Valutare l'immunogenicità di daratumumab in soggetti pediatrici e giovani adulti con ALL/LL a cellule B e T
    9.Concentrazione di daratumumab nel liquido cerebrospinale (CSF)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Time from date of first treatment to first documented treatment failure or date of relapse from CR or death due to any cause, whichever occurs first
    2.Time from CR to relapse from CR or death due to any cause, whichever
    occurs first
    3.Time from date of first treatment to date of death due to any cause
    4.End of both Cycle (C)1 &C2 for T-cell cohort and Day (D)28 of every other cycle from C4 until CR for B-ALL/LL
    5.End of both C1,2
    6.B-cell cohort-Predose & at end of infusion on D1 of C1,2,3,6,9, EoT, follow-up
    T-cell cohort-Predose and at end of infusion at C1D1, C2D1,22, EoT, follow-up
    7.B cohort-Predose on D1 of C1,2,6,9, EoT, follow-up
    T cohort-Predose on D1 of C1,2, EoT, follow-up
    8.B cohort-Predose on D1 of C1,2,3,4,6,9
    T cohort-Predose on C1D1,15, C2D2,15
    Periodo che intercorre tra:
    1.il primo trattamento e primo fallimento del trattamento o data di recidiva in seguito a CRo morte. 2.tra la CRe la recidiva in seguito aCRo alla morte. 3.tra data del 1 trattamento e data di morte. 4.A fine di entrambi i cicli C1eC2 per coorte a celluleT e al giorno28 a cicli alterni per ALL/LL a cellule B. 5. A fine di entrambi i clicli C1,C2. 6.Coorte a cellule B- al Predose e a fine infusione del G1 del ciclo C1,2,3,6,9, a fine trattamento, durante i follow-up
    Coorte a celluleT -al Predose e a fine infusione del C1G1, C2G1, G22, a fine trattamento, durante i follow-up. 7. Coorte a cellule B -al Predose del G1 del C1,2,6,9, a fine trattamento, durante i follow-up Coorte a cellule T-al Predose del G1 del C1,2, a fine del trattamento,durante i follow-up.
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity and Biomarker analyses
    analisi di immunogenicità e dei biomarcatori
    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.8.2.4Number of treatment arms in the trial2
    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 EEA28
    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
    Belgium
    Canada
    Germany
    Israel
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    United States
    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
    The study will end 1 year after the last subject has initiated treatment. A futility analysis will be performed after Stage 1 of the study and could result in the trial ending prior to this if specific, protocol-defined efficacy events are not met.
    lo studio terminerà un anno dopo l’inizio del trattamento da parte dell’ultimo paziente. Una prima analisi di futilità sarà compiuta alla fine dello stadio 1 dello studio e potrebbe risultare nella conclusione prematura dello studio se non si dovessero verificare specifici eventi di efficacia definiti dal protocollo.
    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 years3
    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: 54
    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: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    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
    Children aged 1 year -18 years
    bambini tra 1 e 18 anni
    F.3.3.7Others No
    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 28
    F.4.2.2In the whole clinical trial 69
    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)
    Standard of care treatment.
    Terapia standard
    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 Decision2018-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-21
    P. End of Trial
    P.End of Trial StatusOngoing
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