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    Summary
    EudraCT Number:2018-003006-32
    Sponsor's Protocol Code Number:ALL2418
    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:2020-12-16
    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 number2018-003006-32
    A.3Full title of the trial
    "A Phase IIA Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin (IO) in Adult Patients with B-Cell Acute Lymphoblastic Leukemia with positive Minimal Residual Disease before any Hematopoietics Stem Cell Transplantation"
    “Studio di fase IIA sulla fattibilità e l’efficacia di Inotuzumab Ozogamicin (IO) in pazienti adulti con leucemia linfoblastica acuta a cellule B con malattia minima residua positiva, prima di un trapianto di cellule staminali ematopoietiche”
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial aimed at examinate the functionality and effectiveness of the drug "IO" in adult patients with a rare form of cancer that affect the cells from which the white blood cells (cells present in the blood) originate before being subjected to a medical procedure used in hematology known as transplantation, which leads to the replacement of the cells from which the blood originates.
    Studio in cui si vuole studiare la funzionalità e l'efficacia del farmaco "IO" in pazienti adulti affetti da una forma rara di tumore che colpisce le cellule dalle quali hanno origine i globuli bianchi ( cellule presenti nel sangue) prima di essere sottoposti ad una procedura medica utilizzata in ematologia nota come trapianto , che porta alla sostituzione delle cellule da cui originano quelle del sangue.
    A.3.2Name or abbreviated title of the trial where available
    ALL2418
    ALL2418
    A.4.1Sponsor's protocol code numberALL2418
    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 SponsorFONDAZIONE GIMEMA (GRUPPO ITALIANO MALATTIE EMATOLOGICHE DELL' ADULTO) FRANCO MANDELLI ONLUS
    B.1.3.4CountryItaly
    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 supportPfizer S.R.L.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione GIMEMA Franco Mandelli ONLUS
    B.5.2Functional name of contact pointCentro Dati GIMEMA
    B.5.3 Address:
    B.5.3.1Street Addressvia Casilina, 5
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00182
    B.5.3.4CountryItaly
    B.5.4Telephone number0670390526
    B.5.5Fax number0670390540
    B.5.6E-mailgimema@gimema.it
    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.2.1.1.1Trade name NA
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER EUROPE MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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/3/13/1127
    D.3 Description of the IMP
    D.3.1Product nameInotuzumab Ozogamicina (IO)
    D.3.2Product code [PF-05208773]
    D.3.4Pharmaceutical form 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 INNInotuzumab Ozogamicin (IO)
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameInotuzumab Ozogamicin (IO)
    D.3.10 Strength
    D.3.10.1Concentration unit µg/m2 microgram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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) 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 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 typeAnticorpo monoclonale IgG4 anti - CD22 umanizzato coniugato con calicheamicina
    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 Purinethol
    D.2.1.1.2Name of the Marketing Authorisation holderAspen Pharma Trading Limited
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 name6-Mercaptopurina
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMERCAPTOPURINA
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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) 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 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 typeagente antineoplastico - antimetabolita
    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 NA
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences Distribution B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 namePonatinib
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNImatinib
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    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) 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 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 typeAgente antineoplastico- inibitore delle protein-chinasi
    D.IMP: 4
    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.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameCiclofosfoammide
    D.3.2Product code [NA]
    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 INNCICLOFOSFAMIDE
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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) 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 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 typeAntineoplastico - agente alchilante
    D.IMP: 5
    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.2.1.2Country 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 nameMetotrexato
    D.3.2Product code [NA]
    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 INNMETOTREXATO
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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) 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 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 typeAntineoplastico - antimetabolita
    D.IMP: 6
    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.2.1.2Country 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 nameVincristina
    D.3.2Product code [na]
    D.3.4Pharmaceutical form Concentrate 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 INNVINCRISTINA
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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) 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 No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product Yes
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeAntineoplastico e alcaloide ottenuto dalla pianta pervinca Vinca rosea L.
    D.IMP: 7
    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.2.5The 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 namePrednisone
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPREDNISONE
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Yes
    D.3.11.13.1Other medicinal product typeCorticosteroide sistemico
    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 B-cell Lymphoblastic Leukemia with minimal residual positive disease prior to haematopoietic stem cell transplantation in adult patients
    Leucemia Linfoblastica Acuta a cellule B con malattia minima residua positiva, prima di un trapianto di cellule staminali ematopoietiche in pazienti adulti
    E.1.1.1Medical condition in easily understood language
    Disease caused by the abnormal growth of some bone marrow cells (soft tissue present within some bones) progenitors of lymphocytes, cells found in the blood.
    Malattia causata dalla crescita abnorme di alcune cellule del midollo osseo (tessuto molle presente all'interno di alcune ossa) progenitrici dei linfociti, cellule che si trovano nel 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 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 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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to determine effectiveness of Inotuzumab in obtaining MRD negativity in MRD positive ALL patients.
    L' obiettivo primario dello studio è quello di determinare l'efficacia di Inotuzumab nell'ottenimento della negatività della Malattia Minima residua (MRD) nei pazienti affetti da Leucemia Linfoblastica Acuta (LAL) MRD positivi.
    E.2.2Secondary objectives of the trial
    The study aim is to:
    - Establish survival of the treatment population;
    - Define treatment safety and incidence of adverse events in MRD positive population;
    - Define the number of patient that will have a bridge to transplant with Inotuzumab (considering only patients that could be transplanted).
    Lo scopo dello studio è di:
    - Stabilire la sopravvivenza della popolazione in trattamento;
    - Definire la sicurezza del trattamento e l'incidenza degli eventi avversi nella popolazione MRD positiva;
    - Definire il numero di pazienti che avranno con Inotuzumab un "ponte" per il trapianto (considerando solo pazienti che potrebbero essere trapiantati).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenetics
    Version: 1.0
    Date: 20/07/2018
    Title: Pharmacogenomic parameters
    Objectives: Evaluation of the expression profile of genes involved in DNA repair and DNA damage response genes as ATM, ATR, BLM etc.

    Pharmacogenomics
    Version: 1.0
    Date: 20/07/2018
    Title: Translational Research
    Objectives: Flow-cytometry analysis of CD22 expression

    Farmacogenetica
    Versione: 1.0
    Data: 20/07/2018
    Titolo: Parametri farmacogenomici
    Obiettivi: Valutazione del profilo di espressione dei geni coinvolti nella riparazione del DNA e dei geni di risposta al danno del DNA come ATM, ATR, BLM ecc.

    Farmacogenomica
    Versione: 1.0
    Data: 20/07/2018
    Titolo: Ricerca Traslazionale
    Obiettivi: Analisi dell'espressione di CD22 tramite citometria a flusso
    E.3Principal inclusion criteria
    All patients must meet all the following criteria for study entry:
    1. To be classified as having ALL according to WHO classification of haematological neoplasms, patients must have >20% blasts in bone marrow at the time of diagnosis;
    2. Blasts at the diagnosis or in any timepoint had to be CD22+;
    3. To have a measurable BCR-ABL1 fusion transcript (cohort 1) or a measurable IG/TCR specific rearrangement (cohort 2);
    4. To have any measurable MRD positivity after at least:
    a. 3 months of therapy for Ph+ ALL, or the failure of at least 2nd line TKI (cohort 1)
    b. 2 courses of therapy for Ph- ALL (cohort 2);
    5. and to not have more than 5% of bone marrow blasts. Patients has to be in 1st or 2nd complete remission;
    6. Patients = 18 years old with no upper age limit;
    7. Patients with a life expectancy >12 weeks;
    8. Adequate hepatic function as defined by the following criteria:
    a. total serum bilirubin =1.5 x upper limit of normal (ULN), unless due to Gilbert’s syndrome
    b. alanine aminotransferase (ALT) =2.5 × ULN
    c. aspartate aminotransferase (AST) =2.5 × ULN;
    9. Adequate pancreatic function as defined by the following criterion:
    a. serum lipase and amylase =1.5 × ULN;
    10. For females of childbearing potential, a negative pregnancy test must be documented at Screening;
    11. Female and male patients who are fertile should use an effective form of contraception with their sexual partners from screening through 4 months after the end of treatment. As a precautionary measure, breast-feeding should be discontinued during treatment with Inotuzumab and should not be restarted after discontinuation of Inotuzumab. Male patients must agree to refrain from sperm donation, from initial treatment administration until 12 months after the last dose of study drug.
    12. Signed written informed consent according to ICH/EU/GCP and national local laws.
    Tutti i pazienti devono soddisfare i seguenti criteri per l'ingresso nello studio:
    1. I pazienti devono avere al momento della diagnosi una percentuale di blasti nel midollo osseo >20%, per avere la diagnosi di LAL in base alla classificazione WHO relativa alle neoplasie ematologiche;
    2. I blasti alla diagnosi o ad ogni controllo nel corso dello studio devono essere CD22+;
    3. Deve essere misurabile il gene di fusione BCR-ABL trascritto (gruppo 1) oppure deve essere misurabile uno specifico riarrangiamento IG/TCR (gruppo 2);
    4. Deve essere misurabile la positività della MRD dopo almeno:
    a) 3 mesi di terapia per la LAL Ph+, o il fallimento di almeno un trattamento di seconda linea con un TKI (gruppo 1);
    b) 2 cicli di terapia per la LAL Ph- (gruppo 2);
    5. Non devono avere più del 5% dei blasti nel midollo osseo. I pazienti devono trovarsi in prima o seconda remissione completa;
    6. Pazienti di età = 18 anni, senza limite superiore di età;
    7. Pazienti con un’aspettativa di vita > 12 settimane;
    8. Adeguata funzionalità epatica come stabilito dai seguenti criteri:
    a) bilirubina sierica totale =1.5 superiore al limite di normalità (ULN), tranne che non sia dovuta alla Sindrome di Gilbert;
    b) alanina aminotransferasi (ALT) =2.5 superiore al limite di normalità;
    c) aspartato aminotransferasi (AST) =2.5 superiore al limite di normalità;
    9. Adeguata funzionalità pancreatica come stabilito dai seguenti criteri:
    a) Lipasi ed amilasi sieriche =1.5 superiori al limite di normalità;
    10. Per le donne potenzialmente fertili, deve essere documentato allo Screening un test di gravidanza negativo;
    11. Pazienti uomini e donne fertili dovrebbero assolutamente accettare di utilizzare una forma efficace di contraccezione con i loro partner sessuali dallo screening fino a 4 mesi dopo la fine del trattamento. Come misura precauzionale, l'allattamento deve essere interrotto durante il trattamento con Inotuzumab e non deve essere ripreso dopo l'interruzione di Inotuzumab. I pazienti di sesso maschile devono accettare di astenersi dalla donazione di sperma, dalla somministrazione iniziale del trattamento fino a 12 mesi dopo l'ultima dose del farmaco in studio;
    12. Consenso informato firmato scritto nel rispetto dei principi ICH/EU/GCP e delle normative nazionali applicabili.
    E.4Principal exclusion criteria
    1. More than 5% of BM blasts;
    2. WHO performance status = 50% (Karnofsky) or = 3 (ECOG);
    3. Active HBV or HCV hepatitis, or AST/ALT = 2.5 x ULN and bilirubine = 1.5 x ULN;
    4. Evidence of liver fibrosis, portal hypertension or other clinically relevant liver abnormalities at screening liver ultrasonography;
    5. History of alcohol abuse;
    6. Burkitt lymphoma and active CNS leukemia. Patients with previuos neurological toxicitiy as well comorbidity will be carefully evaluated for enrolment;
    7. Ongoing or active infections.
    8. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
    9. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
    a. any history of myocardial infarction, stroke, or revascularization
    b. unstable angina or transient ischemic attack within 6 months prior to enrollment
    c. congestive heart failure within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards within 6 months prior to enrollment
    d. history of clinically significant (as determined by the treating physician) atrial arrhythmia
    e. any history of ventricular arrhythmia
    f. any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism;
    10. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control;
    11. Creatinine level > 2.5mg/dl or Glomerular Filtration Rate (GFR) < 20 ml/min or proteinuria > 3.5 g/day;
    12. Documented inherited protrombotic disorders;
    13. Patients who have received any investigational drug = 4 weeks;
    14. Patients who have undergone major surgery = 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy;
    15. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention or with a life expectancy due to other malignancy <6 months;
    16. Patients that have received Inotuzumab or Anti CD22 directed therapies before
    17. Patients with known hereditary coagulopathy;
    18. Patient that received during their life diagnosis of VOD or had ongoing VOD;
    19.Patients with hypersensitivity to the active substance or to any of the excipients (Sucrose, Polysorbate 80, Sodium chloride, tromethamine);
    20. Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of induction therapy). Post menopausal women must be amenorrhoic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 4 months following discontinuation of study drugs. Fertile patients will be advised to adopt contraceptive methods while on treatment;
    21. Patients unwilling or unable to comply with the protocol.
    1. Più del 5% di blasti nel midollo osseo;
    2. Performance status = 50% (Karnofsky) o = 3 (ECOG) secondo i criteri diagnostici WHO;
    3. Epatite HCV o HBV attive, o AST/ALT = 2.5 superiore al limite di normalità e bilirubina = 1.5 superiore al limite di normalità (ULN);
    4. Evidenza di fibrosi epatica, ipertensione portale o altre patologie epatiche clinicamente rilevanti, emerse nel corso dell’ecografia del fegato effettuata allo screening;
    5. Storia di abuso di alcol; 6. Linfoma di Burkitt e Leucemia attiva nel SNC. I pazienti con precedente tossicità neurologica come anche comorbidità saranno attentamente valutati per l'arruolamento;
    7. Infezioni attive o in corso;
    8. Ipertrigliceridemia non trattata (trigliceridi > 450 mg/dl);
    9. Disordine cardiovascolare clinicamente significativo, non controllato o attivo che comprenda in modo specifico, ma non sia limitato a:
    a) una storia di infarto del miocardio, ictus o rivascolarizzazione;
    b) angina instabile o attacco ischemico transitorio nei sei mesi antecedenti l’arruolamento;
    c) nei sei mesi antecedenti l’arruolamento insufficienza cardiaca congestizia oppure frazione di eiezione ventricolare sinistra (LVEF) al di sotto del limite inferiore di normalità dei range di laboratorio di riferimento;
    d) storia di aritmia atriale clinicamente significativa (come diagnosticato dal medico curante);
    e) storia di aritmia ventricolare;
    f) storia di tromboembolia venosa incluse la trombosi venosa profonda o l’embolia polmonare;
    10. Ipertensione non controllata (pressione sanguigna diastolica >90 mm Hg; sistolica > 140 mm Hg). Pazienti con ipertensione dovrebbero essere in trattamento nel momento in cui entrano nello studio, per mantenere sotto controllo la pressione sanguigna;
    11. Livelli di creatinina > 2.5 mg/dl o Tasso di Filtrazione Glomerulare (GFR) < 20 ml/min o proteinuria > 3.5 g/die;
    12. Disturbi protrombotici ereditari documentati;
    13. Pazienti che abbiano assunto farmaci sperimentali nelle 4 settimane precedenti;
    14. Pazienti che siano stati sottoposti ad interventi chirurgici importanti nelle 2 settimane antecedenti l’inizio della somministrazione del farmaco in studio o che non si siano ripresi dagli effetti collaterali della terapia; 15. Pazienti con una storia di un’altra neoplasia primaria al momento clinicamente significativa o che richieda un intervento attivo o con un’aspettativa di vita < 6 mesi a causa di un’altra neoplasia;
    16. Pazienti che abbiano ricevuto precedentemente Inotuzumab o terapie dirette Anti CD22;
    17. Pazienti con coagulopatia ereditaria nota;
    18. Pazienti che abbiano ricevuto nel corso della vita una diagnosi di Malattia Veno-Occlusiva (VOD) o abbiano una VOD in corso;
    19.Pazienti con ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti (saccarosio, polisorbato 80, cloruro di sodio, trometamina).
    20. Pazienti che sono in gravidanza o allattamento e adulti potenzialmente fertili che non stiano utilizzando un metodo contraccettivo efficace (donne potenzialmente fertili devono avere un test sierico di gravidanza effettuato nelle 48 ore antecedenti la somministrazione della terapia di induzione). Le donne in post-menopausa devono essere amenorroiche da almeno 12 mesi per essere considerate non potenzialmente fertili. Pazienti donne e uomini devono acconsentire ad utilizzare un metodo anticoncezionale di barriera efficace durante lo studio e nei 4 mesi successivi all'interruzione dell’assunzione dei farmaci in studio. Ai pazienti fertili sarà consigliato di adottare metodi contraccettivi durante il trattamento;
    21. Pazienti che non acconsentano o non siano in grado di rispettare il protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Primary end point is % of MRD negativity after course 2 (or course 1 if will be performed only course1).
    L' End point primario è la % della negatività MRD dopo il ciclo di induzione 2 (o il ciclo di induzione 1 se verrà eseguito solo il ciclo 1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    From enrollment until the end of course 2 (or course 1 if only course 1 is run).
    Dall'arruolamento fino al termine del ciclo di induzione 2 (o ciclo di induzione 1 se verrà eseguito solo il ciclo 1).
    E.5.2Secondary end point(s)
    - Molecular Disease Progression: defined as the rise of more than 2 log in MRD from any previous
    determination
    - Disease Progression: this is also equivalent to Treatment Failure, Lack of Efficacy, or No
    Response.
    - Overall Survival (OS), defined as the number of days between the first study drug administration and
    death from any cause or lost to follow up.
    - Event Free Survival (EFS), defined as the number of days between the first study drug administration
    and any event including disease progressionor death.
    - DFS (Disease Free Survival), defined as the interval between the date of response achievement and the date of death, relapse or last follow-up.
    - Incidence time and nature of any adverse event.
    - Severe effect related to treatment safety is defined as an adverse event occurring within the first cycle, judged to be related to treatment and meeting any of the following criteria:
    o Grade 3 non-hematological toxicity lasting more than 7 days.
    o Grade 4 non-hematological toxicity.
    - Incidence, severity, seriousness and treatment-causality of Treatment Emergent Signs and Symptoms.
    - Frequency of clinically significant abnormalities in physical examination, safety laboratory tests, vital signs and 12-Lead ECG.
    - VOD occurred during or after protocol or transplant procedures for up to 2 years.
    - Progressione della malattia molecolare: definita come l'aumento di più di 2 log in MRD da qualsiasi precedente determinazione
    - Progressione della malattia: equivale anche al fallimento del trattamento, alla mancanza di efficacia o alla mancata risposta.
    - Sopravvivenza generale (OS), definita come il numero di giorni tra la prima somministrazione del farmaco in studio e la morte per qualsiasi causa o persi al follow up.
    - Event Free Survival (EFS), definito come il numero di giorni tra la prima somministrazione del farmaco in studio e qualsiasi evento che includa la progressione della malattia o la morte.
    - DFS (Survival senza malattia), definito come l'intervallo tra la data di raggiungimento della risposta e la data di morte, recidiva o ultimo follow-up.
    - Tempo di incidenza e natura di qualsiasi evento avverso.
    - L'effetto grave correlato alla sicurezza del trattamento è definito come un evento avverso che si verifica entro il primo ciclo, giudicato correlato al trattamento e che soddisfa uno dei seguenti criteri:
    o tossicità non ematologica di grado 3 che dura più di 7 giorni.
    o tossicità non ematologica di grado 4
    - Incidenza, gravità, gravità e trattamento-causalità del trattamento Segni e sintomi emergenti.
    - Frequenza di anomalie clinicamente significative nell'esame obiettivo, test di laboratorio di sicurezza, segni vitali e ECG a 12 derivazioni.
    - VOD si è verificato durante o dopo le procedure di protocollo o di trapianto fino a 2 anni.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Estimations will be provided with Kaplan Meyer model.
    Safety will be reported with descriptive statistics.
    The detection time is approximately three years.
    Le stime saranno fornite con il modello Kaplan Meier.
    La sicurezza verrà riportata con statistiche descrittive.
    Il tempo di rilevazione è all'incirca di tre anni.
    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 No
    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
    Feasibility
    Fattibilità
    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 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) Yes
    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 concerned33
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    Last Visit Last Subject
    Ultima Visita dell'Ultimo Soggetto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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: 76
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 76
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state76
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 76
    F.4.2.2In the whole clinical trial 76
    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)
    Patients will continue to be followed according to the normal care provided by good clinical practice.
    I Pazienti continueranno ad essere seguiti secondo la normale attività assistenziale prevista dalla buona pratica clinica.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Fondazione GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Franco Mandelli ONLUS
    G.4.3.4Network Country Italy
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-07-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-13
    P. End of Trial
    P.End of Trial StatusOngoing
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