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    Summary
    EudraCT Number:2019-000473-23
    Sponsor's Protocol Code Number:74494550AML2001
    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:2021-06-17
    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 number2019-000473-23
    A.3Full title of the trial
    A Phase 2 Study of Cusatuzumab Plus Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia who are not Candidates for Intensive Chemotherapy
    Uno studio di fase 2 su cusatuzumab in associazione con azacitidina in pazienti con leucemia mieloide acuta di nuova diagnosi che non sono candidati alla chemioterapia intensiva
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study of Cusatuzumab Plus Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia who are not Candidates for Intensive Chemotherapy
    Uno studio clinico su cusatuzumab in associazione con azacitidina in pazienti con leucemia mieloide acuta di nuova diagnosi che non sono candidati alla chemioterapia intensiva
    A.3.2Name or abbreviated title of the trial where available
    CULMINATE
    CULMINATE
    A.4.1Sponsor's protocol code number74494550AML2001
    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 NV
    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 Cilag International NV
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportJanssen Cilag SpA
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International NV
    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 number0031715242166
    B.5.5Fax number0031715242110
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCusatuzumab
    D.3.2Product code [JNJ-74494550]
    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 INNCusatuzumab
    D.3.9.1CAS number 1864871-20-4
    D.3.9.2Current sponsor codeJNJ-74494550
    D.3.9.4EV Substance CodeSUB195527
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 20
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee 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 No
    D.IMP: 2
    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 VIDAZA
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene US, Celgene BV
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAzacitidina
    D.3.2Product code [Azacitidina]
    D.3.4Pharmaceutical form Powder and solvent for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINA
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor codeAzacitidina
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee 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 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 No
    D.IMP: 3
    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 Vidaza
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene 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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAzacitidina
    D.3.2Product code [Azacitidina]
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    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 INNAZACITIDINA
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor codeAzacitidina
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee 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 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 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
    Acute Myeloid Leukemia
    Leucemia Mieloide Acuta
    E.1.1.1Medical condition in easily understood language
    Blood cancer
    Tumore del Sangue
    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 10000886
    E.1.2Term Acute myeloid 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 determine the efficacy of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy
    Determinare l'efficacia di cusatuzumab in associazione con azacitidina in pazienti con leucemia mieloide acuta (AML) non trattata precedentemente e che non sono candidati alla chemioterapia intensiva
    E.2.2Secondary objectives of the trial
    1) To determine the below responses
    a) Complete response (CR)
    b) CR with incomplete recovery (CRi)
    c) CR with partial hematological revovery (CRh)
    d) CR without MRD (CRMRD-)
    e) Morphologic leukemia-free state (MLFS)
    f) Partial response (PR)
    g) Stable disease
    h) Relapse after CR, CRi, CRh
    i) Progressive Disease
    2) To assess time to response and duration of response
    3) To assess the safety profile of cusatuzumab in combination with azacitidine
    4) To assess the pharmacokinetics of cusatuzumab alone and in combination with azacitidine
    5) To assess the immunogenicity of cusatuzumab alone and in combination with azacitidine
    1) Determinare i seguenti tipi di risposte:
    a) Risposta Completa (CR)
    b) Risposta Completa con recupero incompleto (CRi)
    c) Risposta Completa con recupero ematologico parziale (CRh)
    d) Risposta Completa senza Malattia Minima Residua (MRD) (CRMRD-)
    e) Stato di Assenza di Leucemia Morfologica (MLFS)
    f) Risposta Parziale (PR)
    g) Malattia Stabile
    h) Ricaduta dopo CR, CRi, CRh
    i) Progressione di Malattia
    2) Valutare il tempo e la durata della risposta
    3) Valutare il profilo di sicurezza di cusatuzumab in associazione con azacitidina
    4) Valutare la farmacocinetica di cusatuzumab da solo e in associazione con azacitidina
    5) Valutare l'immunogenicità di cusatuzumab da solo e in associazione con azacitidina
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. =18 years of age
    MODIFIED
    2.1. AML according to WHO 2016 criteria and fulfilling all of the following criteria that defines those who are "not candidates for intensive chemotherapy":d procedures required for, the study and is willing to participate in the study
    ¿ =75 years of age or
    ¿ <75 years of age with of at least one of the following comorbidities:
    o Eastern Cooperative Oncology Group (ECOG) Performance Status of 2
    o Severe cardiac comorbidity defined as congestive heart failure or ejection fraction =50%
    o Severe pulmonary comorbidity defined as documented pulmonary disease with lung diffusing capacity for carbon monoxide (DLCO) =65%
    of expected, or forced expiratory volume in 1 second (FEV1) =65% of expected or dyspnea at rest requiring oxygen
    o Moderate hepatic impairment defined according to National Cancer Institute (NCI) organ dysfunction classification criteria (total bilirubin = 1.5 up to 3 times upper limit of normal [ULN])
    o Creatinine clearance <45 mL/ min/1.73 m² (by MDRD formula)
    o Comorbidity that, in the Investigator's opinion, makes the patient unsuitable for intensive chemotherapy and must be documented and approved by the Sponsor before randomization
    MODIFIED
    3.1. De novo or secondary AML
    MODIFIED
    4.1. Previously untreated AML (except: emergency leukapheresis, hydroxyurea, and/or 1 dose of cytarabine [eg, 1-2g/m^2] during the screening phase to control hyperleukocytosis. These treatments must be discontinued =24 hours prior to start of study drug). Empiric all trans retinoic acid (ATRA) treatment for presumed acute promyelocytic leukemia (APL) is permitted but APL must be ruled out and ATRA must be discontinued =24 hours prior to the start of study drug;
    MODIFIED
    5.1. Not eligible for an allogeneic hematopoietic stem cell transplantation.
    MODIFIED
    6.1. ECOG Performance Status score of 0, 1 or 2.
    MODIFIED
    7.1. The following clinical laboratory values at screening:
    ¿ AST or ALT <3 times ULN; for participants with leukemic infiltration of the liver, AST and ALT <5 times ULN is permitted
    ¿ Total bilirubin = 3 times ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin or in case of liver infiltration by AML
    (documented by biopsy or imaging) serum total bilirubin <5 times ULN
    ¿ Creatinine Clearance >30 mL/min (by MDRD formula)
    MODIFIED
    8.1. A woman must be either:
    ¿ Not of childbearing potential: postmenopausal (amenorrhea for at least 12 months);
    ¿ Of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for participants in the clinical study while receiving study treatment and for at least 3 months after the last dose of study treatment A woman of childbearing potential must have a negative highly-sensitive serum ß-hCG or urine pregnancy test at screening.
    A woman of childbearing potential must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study treatment and for 3 months after the last dose of study treatment.
    MODIFIED
    9.1. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth
    control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal
    foam/gel/film/cream/suppository for at least 3 months after last study treatment.
    ¿ Must agree to not donate sperm during the study treatment and for 3 months after the last dose of study treatment.
    ¿ Not plan to father a child during the study treatment and for 3 months
    after the last dose of study treatment.
    MODIFIED
    10.1. Must sign an informed consent form (ICF) indicating that he or she (or their legally acceptable representative) understands the purpose of,
    and procedures required for, the study and is willing to participate in the study.
    1)=18anni
    2) MODIFICATO AML secondo i criteri WHO2016 e corrispondente ai criteri che definiscono I PAZIENTI “non candidati alla chemioterapia intensiva”:
    ->=75anni o
    -<75 ANNI E Comorbidità con almeno1delle seguenti COMORBIDITA':
    ECOG PS 2
    comorbidità cardiaca definita come insufficienza cardiaca congestizia o frazione di eiezione=50%
    comorbidità polmonare definita come pneumopatia documentata con capacità di DLCO=65%del valore atteso o FEV1=65% del valore atteso o dispnea a riposo che richiede ossigeno
    Insufficienza epatica moderata definita secondo i criteri NCI di classificazione delle disfunzioni degli organi (bilirubina totale=1,5 fino a 3 volte il limite superiore della norma [ULN])
    Clearance della creatinina<45 mL/min/1,73 m² (formula MDRD)
    Comorbidità che, secondo il giudizio dello sperimentatore, rende il pz inadatto alla chemioterapia intensiva e che deve essere documentata e approvata dallo sponsor prima della randomizzazione
    3)N° MODIFICATO
    •AML de novo o secondaria
    4) N° MODIFICATO
    •AML non trattata in precedenza(eccezioni:leucaferesi, 1 dose di citarabina e/o idrossiurea durante lo screening per controllare l’iperleucocitosi interrotta almeno 24H prima dell’inizio DEL TRATTAMENTO DI STUDIO).Il trattamento con ATRA per una presunta APL è consentito ma deve essere interrotto almeno1gg prima l’inizio DEL FARMACO DI STUDIO E L'APL DEVE ESSERE DEBELLATA
    5) N° MODIFICATO
    Soggetti non idonei al trapianto allogenico di cellule staminali ematopoietiche
    6) N° MODIFICATO
    ECOG PS 0,1,2
    7) N° MODIFICATO
    I seguenti valori clinici di lab allo screening:
    •AST o ALT<3volte l’ULN; per i pz con infiltrazione leucemica del fegato(documentata da imaging o biopsia) sono ammessi AST e ALT<5 volte l’ULN
    •Bilirubina tot=3vlt l’ULN tranne nel caso in cui l’aumento della bilirubina sia dovuto alla sindrome di Gilbert o non abbia un’origine epatica o in caso di infiltrazione epatica dell’AML(documentata da imaging o biopsia) bilirubina tot nel siero<5vlt l’ULN
    •Clearance creatinina>30mL/min (formula MDRD)
    8) N° MODIFICATO
    Le donne devono soddisfare una delle seguenti condizioni:
    •Donne non fertili:post-menopausa (>45anni con amenorrea da almeno12mesi)
    •Donne potenzialmente fertili che praticano1metodo contraccettivo altamente efficace in linea con i regolam locali in materia di metodi contraccettivi DURANTE TUTTO IL PERIODO DI TRATTAMENTO E ALMENO 3MESI DOPO TALE PERIODO
    Le donne potenzialmente fertili devono presentare1test di gravidanza sul siero altamente sensibile(beta-hCG) o sulle urine negativo allo screening
    UNA DONNA IN ETA FERTILE DEVE ACCONSNETIRE A NON DONARE OVOCITI AI FINI DELLA RIPRODUZIONE ASSISTITA DURANTE TUTTO IL PERIODO DI TRATTAMENTO E ALMENO 3MESI DOPO TALE PERIODO
    Nota: in caso di variazione della situazione di fertilità dopo l’inizio dello studio (ad es. una donna non eterosessualmente attiva diventa attiva o a una donna premenarcale compare la prima mestruazione), la donna dovrà cominciare ad utilizzare un metodo contraccettivo altamente efficace, come precedentemente descritto.
    6)Gli uomini sessualmente attivi con donne potenzialmente fertili e che non sono stati sottoposti a vasectomia devono acconsentire a usare un metodo contraccettivo a barriera, DURANTE TUTTO IL PERIODO DI TRATTAMENTO E ALMENO 3MESI DOPO TALE PERIODO
    DEVONO ACCONSENTIRE A NON DONARE SPERMA DURANTE TUTTO IL PERIODO DI TRATTAMENTO E ALMENO 3MESI DOPO TALE PERIODO
    NON DEVONO PIANIFICARE DI DIVENTARE PADRI DURANTE TUTTO IL PERIODO DI TRATTAMENTO E ALMENO 3MESI DOPO TALE PERIODO
    7)Firma del ICF indicante che il pz O IL SUO LEGALE RAPPRESENTANTE ha compreso lo scopo dello studio e le relative procedure e che intende prendervi parte
    E.4Principal exclusion criteria
    Any potential participant who meets any of the following criteria will be excluded from participating in the study:
    1. Criterion modified per Amendment 1
    1.1. Acute promyelocytic leukemia
    2. Leukemic involvement or clinical symptoms of leukemic involvement of the central nervous system.
    3. Criterion modified per Amendment 1
    3.1. Use of immune suppressive agents for the past 4 weeks before the first administration of cusatuzumab on Cycle 1 Day 3. For regular use of
    systemic corticosteroids, participants may only be included if free of systemic corticosteroids for a minimum of 5 days before the first administration of cusatuzumab. Treatment of adrenal insufficiency with physiologic replacement doses of corticosteroids are allowed.
    4. Prior treatment with a hypomethylating agent for treatment of AML or MDS
    5. Criterion modified per Amendment 1
    5.1. Active malignancies (ie, progressing or requiring treatment in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:
    ¿ Non-melanoma skin cancer treated within the last 24 months that is considered completely cured
    ¿ Adequately treated breast lobular carcinoma in situ and breast ductal carcinoma in situ
    ¿ Adequately treated cervical carcinoma in situ without evidence of disease
    ¿ History of localized breast cancer and receiving antihormonal agents, or history of localized prostate cancer (N0M0) and receiving androgen deprivation therapy
    ¿ Malignancy that is considered cured with minimal risk of recurrence
    6. Criterion modified per Amendment 1
    6.1. Any active systemic infection
    7. Criterion modified per Amendment 1
    7.1. A history of human immunodeficiency virus (HIV) antibody positive or tests positive for HIV at screening
    8. Criterion modified per Amendment 1
    8.1. Active hepatitis B or C infection or other clinically active liver disease Seropositive for hepatitis B: defined by a positive test for hepatitis B
    surface antigen [HBsAg]. Participants with resolved infection (ie, participants who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screened using real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti- HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR.
    Known Hepatitis C infection or positive serologic testing for Hepatitis C (anti-HCV antibody)
    9. New York Heart Association Class IV heart failure or ongoing unstablE angina
    10. Known allergies, hypersensitivity, or intolerance to cusatuzumab or azacitidine or its excipients (ie, mannitol, an excipient of azacitidine).
    11. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or physical limitations that could prevent, limit, or confound the protocol-specified assessments.
    12. Criterion modified per Amendment 1
    12.1. Major surgery, (eg, requiring general anesthesia) within 4 weeks prior to initiation of the study.
    13. Women who are breastfeeding.
    14. Received a live, attenuated vaccine within 4 weeks prior to initiation of study treatment.
    NOTE: Investigators should ensure that all study enrollment (inclusion/exclusion) criteria have been met at screening and prior to the first dose of study intervention. If a participant's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study intervention is given such that he or she no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.
    1 MODIFICATO
    1.Leucemia promielocitica acuta
    2.Coinvolgimento leucemico o sintomi clinici di coinvolgimento leucemico del sistema nervoso centrale
    3.MODIFICATO Utilizzo di agenti immunosoppressivi nelle 4 settimane precedenti alla prima somministrazione di cusatuzumab il Giorno 1 del Ciclo 1. Per l’utilizzo regolare di corticosteroidi sistemici, i partecipanti possono essere inclusi soltanto se liberi da corticosteroidi sistemici da almeno 5 giorni prima della somministrazione di cusatuzumab. TRATTAMENTI PER INSUFFICIENZA ADRENERGICA CON SOSTITUTI FISIOLOGICI DEI CORTICOSTEROIDI SONO PERMESSI.
    4.Precedente trattamento con un agente ipometilante per il trattamento della AML o della MDS
    5.MODIFICATO Diagnosi di altra neoplasia maligna (DE NOVO O PROGRESSIONE RICHIEDENTE TRATTAMENTO non chirurgico concomitante OLTRE AL FARMACO DI STUDIO:
    ECCEZIONI::
    TUMORE ALLA PELLE TRATTATO E DEBELLATO NEGLI ULTIMI 24 MESI
    CARCINOMA LOBULARE O DUTTALE AL SENO DEBITAMENTE TRATTATO NEGLI ULTIMI 24 MESI
    CARCINOMA ALLA CERVICE UTERINA TRATTATO NON PRESENTANTE SEGNI DI PATOLOGIA
    STORIA DI CANCRO AL SENO LOCALIZZATO TRATTATO CON AGENTI ANTIORMONALI
    STORIA DI CANCRO ALLA PROSTATA TRATTATO CON ANTIANDROGENI
    TUMORI MALIGNI CONSIDERATI CURATI CON MINIMO RISCHIO DIRIACUTIZZAZIONE
    6.MODIFICATO Qualsiasi infezione sistemica attiva
    7 MODIFICATO.Precedete positività all’anticorpo anti-virus dell’immunodeficienza umana (HIV) o risultato positivo del test per l’HIV
    8 MODIFICATO.InfeINFEZIONE DA EPATITE B O C ATTIVA, O ALTRE PATOLOGIE EPATICHE:
    PAZIENTI SIEROPOSITIVI PER EPATITE B:DEFINITI COME POSITIVI AL TEST HBsAG I PARTECIPANTI CON INFEZIONE RISOLTA DEVONO RICEVERE ALLO SCREENING UN TEST RT-PCR PER MISURARE I LIVELLI DI DNA VIRALE; I CASI POSITIVI AL TEST DEVONO ESSERE ESCLUSI.
    I PARTECIPANTI CON EVIDENZE SEROLOGICHE DI VACCINAZIONE E VACCINAZIONE NOTA NON DEVONO FARE IL TEST TRAMITE RT-PCR.
    INFEZIONE NOTA DI EPATITE C O TEST SEROLOGICO POSITIO PER EPATITE C

    9 Insufficienza cardiaca di classe IV secondo la New York Heart Association o angina instabile in corso (vedere la Sezione 10.7 Appendice 7)

    10.Allergie, ipersensibilità o intolleranza note a cusatuzumab o azacitidina o ai relativi eccipienti (ovvero il mannitolo, un eccipiente di azacitidina)

    11.Qualsiasi condizione per cui, secondo il giudizio dello sperimentatore, la partecipazione non sarebbe nel miglior interesse del partecipante (ad es., ne comprometterebbe il benessere) o qualsiasi limitazione fisica che potrebbe impedire, limitare o confondere le valutazioni specificate dal protocollo

    12.MODIFICATO Soggetti sottoposti a un intervento chirurgico maggiore (ad es. con anestesia generale) PRIMA DELL'INIZIO DELLO STUDIO
    Nota: i partecipanti con procedure chirurgiche programmate da effettuarsi in anestesia locale possono partecipare. In tal caso, lo sperimentatore deve informare lo sponsor prima della randomizzazione

    13.MODIFICATO: DONNE CHE ALLATTANO AL SENO

    14.MODIFICATO SOMMINISTRAZIONE DI UN VACCINO VIVO ATTENUATO NELLE 4 SETTIMANE PRECEDENTI L'INIZIO DEL TRATTAMENTO

    GLI SPERIMENTATORI DEVONO GARANTIRE CHE SIANO RISPETTATI TUTTI I CRITERI DI INCLUSIONE/ESCLUSIONE ALLO SCREENING E PRIMA DELLA PRIMA SOMMINISTRAZIONE DI FARMACO;SE LO STATO DEL PAZIENTE CAMBIA DOPO LO SCREENING MA PRIMA DELLA PRIMA SOMMINISTRAZIONE DI FARMACO, TALE PAZIENTE DEVE ESSERE ESCLUSO DALLA SPERIMENTAZIONE.
    E.5 End points
    E.5.1Primary end point(s)
    Complete response (CR) rate per ELN 2017 (Dohner 2017)
    Tasso di Risposta Completa (CR) secondo il sistema prognostico secondo ELN 2017 (Dohner 2017)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 2 cycles (approximately every 2 months)
    Ogni 2 cicli (approssimativamente ogni 2 mesi)
    E.5.2Secondary end point(s)
    1. Rate of CRh
    2. Rate of CR + CRh
    3. Rate of CRi
    4. Overall response rate (ORR) = Rate of CR+ CRh+ CRi
    5. Rate of CR without MRD
    6. Rate of MRD negativity among participants achieving CR, CRh, CRi, or MLFS ; defined as less than 1 blast or leukemic stem cell in 1,000
    leukocytes (MRD level <10^-3)
    7. Time to response, defined as time from randomization in Part 1 or enrollment in Part 2 to achieving the first response of CR, CRh, or CRi;
    duration of response, defined as time from achieving the first response of CR, CRh, or CRi to disease relapse or death from any cause.
    8. Transfusion independence (RBC or platelets) is defined as a period of at least 56 consecutive days with no transfusion between first dose of
    study drug and the last dose of study drug + 30 days.
    9. Safety profile of Adverse Events (AE) and Serious Adverse Events (SAE)
    10. Pharmacokinetics
    11. Immunogenicity / anti-drug antibody testing
    1. Tasso di CRh
    2. Tasso di CR + CRh
    3. Tasso di CRi
    4. Tasso di risposta totale (ORR) = Tasso di CR+ CRh+ CRi
    5. Tasso di CR senza MRD
    6. Tasso di MRD negativa tra i partecipanti che raggiungono CR, CRh, CRi, o MLFS; definita come presenza di meno di un blasto o cellula staminale leucemica in 1,000 leucociti (livello di MRD<10^-3)
    7. Tempo di risposta, definito come il tempo intercorrente tra la randomizzazione NELLA PARTE 1 E AL TRATTAMENTO NELLA PARTE 2 e il raggiungimento della PRIMA RISPOSTA DI CR CRh E CRi; durata della risposta, definita come il tempo intercorrente tra il raggiungimento della PRIMA RISPOSTA DI CR CRh E CRi; e la ricaduta di malattia;
    8. L'INDIPENDEnZA DaLLA TRASFUSIONE è DEFINITO COME UN PERIODO DI ALMENO 56 SETTIMANE CONSECUTIVE TRA LA PRIMA DOSE DI FARMACO DI STUDIO E L'ULTIMA DOSE + 30GG
    9. Farmacocinetica
    10. Immunogenicità / test sugli anticorpi contro il farmaco
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 to 7. Every 2 cycles (approximately every 2 months)
    8. Throughout the study
    9. Cycle (C) 1 Day (D) 1, C1D3, C1D4, C1D7, C1D10, C1D17, Cycle =2 D3,
    Cycle =2 D17, C3D21 to C4D1, C5D21 to C6D1, and EOT (end of
    treatment)
    10. C1D3, C1D17, Cycle =2 D3, and EOT
    1-7. Ogni 2 cicli (approssimativamente ogni 2 mesi)
    8. Nel corso di tutto lo studio
    9. Ciclo(C)1 Giorno(D)1, C1D3, C1D4, C1D7, C1D10, C1D17, Cycle =2 D3, Ciclo =2 D17, C3D21 to C4D1, C5D21 to C6D1, e EOT (fine del trattamento)
    10. C1D3, C1D17, Ciclo =2 D3, e EOT
    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 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
    Tolerability and Biomarker evaluations
    Tollerabilità e valutazione 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 Yes
    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 Yes
    E.8.2.3.1Comparator description
    NAp
    NAp
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Australia
    Brazil
    France
    Israel
    Italy
    Russian Federation
    Spain
    Switzerland
    Turkey
    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 end of study (study completion) is defined as the time at which 50% of participants have died
    La fine dello studio (completamento dello studio) è definita come il momento in cui il 50% dei partecipanti è deceduto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    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 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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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
    Refer to protocol and informed consent form
    FARE RIFERIMENTO AL PROTOCOLLO E AL CONSENSO INFORMATO
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 49
    F.4.2.2In the whole clinical trial 150
    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)
    Participants who are continuing to derive benefit from treatment with cusatuzumab, azacitidine or both agents as assessed by their investigator at the end of the study may continue to receive these medications.
    I pazienti che al termine dello studio continueranno a trarre beneficio dal trattamento con cusatuzumab, azacitidina o entrambi i farmaci secondo giudizio dello Sperimentatore, potranno continuare a ricevere tale trattamento
    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 Decision2019-09-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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