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    Summary
    EudraCT Number:2020-006048-15
    Sponsor's Protocol Code Number:ALL2820
    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:2021-06-07
    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 number2020-006048-15
    A.3Full title of the trial
    Newly Diagnosed Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL). Sequential Treatment with Ponatinib and the Bispecific Monoclonal Antibody Blinatumomab vs Chemotherapy and Imatinib.
    Leucemia acuta linfoblastica Philadelphia-positiva dell’adulto alla diagnosi. Trattamento sequenziale con il ponatinib e l’anticorpo monoclonale bispecifico blinatumomab vs chemioterapia e imatinib.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The study aims to verify the greater efficacy of the treatment of Acute Lymphoblastic Leukemia Ph + through the combination of Ponatinib and Blinatumomab, a specific monoclonal antibody, in adult patients, compared to the administration of chemotherapy and Imatinib.
    Lo studio ha lo scopo di verificare la maggiore efficacia del trattamento della Leucemia Linfoblastica Acuta Ph+ tramite la combinazione di Ponatinib e Blinatumomab, un anticorpo monoclonale specifico, in pazienti adulti, rispetto alla somministrazione di chemioterapia ed Imatinib.
    A.3.2Name or abbreviated title of the trial where available
    ALL2820
    ALL2820
    A.4.1Sponsor's protocol code numberALL2820
    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 supportFondazione GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Franco Mandelli Onlus
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportAmgen S.r.l. via E. Tazzoli, 6 - 20154 - Milano
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportIncyte Biosciences International Sàrl, Rue Docteur-Yersin 10, 1110 Morges, Switzerland
    B.4.2CountrySwitzerland
    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
    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 Yes
    D.2.1.1.1Trade name Iclusig 15 mg compresse rivestite con film
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/715
    D.3 Description of the IMP
    D.3.1Product nameIclusig
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Film-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 INNPonatinib
    D.3.9.1CAS number 943319-70-8
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive namePonatinib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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) 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: 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 BLINCYTO - 38,5 MICROGRAMMI - POLVERE PER CONCENTRATO E SOLUZIONE PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - POLVERE:FLACONCINO (VETRO) 38,5MCG - SOLUZIONE: 10 ML FLACONCINO (VETRO) - 1 FLACONCINO + 1 FLACONCINO
    D.2.1.1.2Name of the Marketing Authorisation holderAMGEN EUROPE B.V.
    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 nameBlinatumomab
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBlinatumomab
    D.3.9.1CAS number 853426-35-4
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameBlinatumomab
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number28
    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 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 Iclusig 15 mg compresse rivestite con film
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/715
    D.3 Description of the IMP
    D.3.1Product nameIclusig
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Film-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 INNPonatinib
    D.3.9.1CAS number 943319-70-8
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive namePonatinib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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) 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
    Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.
    Leucemia acuta linfoblastica Philadelphia-positiva dell'adulto.
    E.1.1.1Medical condition in easily understood language
    Acute lymphoblastic leukemia, a blood cancer that begins when the lymphocytes undergo neoplastic transformation in the marrow, with uncontrolled multiplication and progressive accumulation.
    Leucemia linfoblastica acuta, malattia tumorale del sangue che inizia quando i linfociti subiscono trasformazione neoplastica nel midollo, con moltiplicazione incontrollata e progressivo accumulo.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    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
    To explore the efficacy of a front-line chemo-free strategy based on the administration of Ponatinib plus steroids as induction treatment, followed by the infusion of Blinatumomab as consolidation in adult Ph+ ALL (=18 years, no upper age limit), and to compare it with a chemotherapy scheme combined with Imatinib (control arm), in terms of event-free survival (EFS), a composite endpoint, with events defined as: non achievement of MRD negativity (CMR or PNQ), deaths for any reason, toxicity and resistance (due or not to an ABL1 mutation development) in adult Ph+ ALL (=18 years, no upper age limit).
    Esplorare l’efficacia di una strategia terapeutica di prima linea con induzione/consolidamento chemo-free basata sulla somministrazione di ponatinib più steroidi come trattamento di induzione, seguita dall’infusione di blinatumomab come consolidamento in pazienti adulti (=18 anni, senza limite massimo di età) affetti da LAL Ph+, e di confrontarla con uno schema chemioterapico in combinazione con Imatinib (braccio di controllo), in termini di sopravvivenza libera da eventi (event-free survival, EFS), un endpoint composito con gli eventi definiti come: mancata negativizzazione della malattia minima residua (MMR) - intendendo per negativi sia i CMR che i positivi non quantificabili (PNQ) -, morte per ogni causa, tossicità e resistenza (dovuta o no a mutazioni del gene ABL1) nei pazienti adulti (=18 anni, senza limite massimo di età) affetti da LAL Ph+.
    E.2.2Secondary objectives of the trial
    1. The key secondary objective is represented by the feasibility of patients’ stratification to allo-SCT allocation on the basis of a refined MRD evaluation and on the presence/absence of additional genetic lesions (namely IKZF1 plus CDKN2A/B and/or PAX5).
    2. Capability of Blinatumomab to further reduce the MRD levels after Ponatinib induction.
    3. CMR or positive not-quantifiable (PNQ) duration.
    4. DFS at 1 and 3 years.
    5. OS at 1 and 3 years.
    6. Cumulative incidence of relapse (CIR).
    7. Safety profile.
    8. Comparison of patients’ quality of life (QoL) profiles over time by randomization arms.
    9. CMR (or PNQ) achievement, duration of CMR, OS and DFS according to the clinical, biological and molecular characteristics at baseline, including type of fusion protein (p190 vs p210) and presence of additional genomic lesions.
    10 & 11 please see the Protocol.
    1. Fattibilità della stratificazione dei pazienti all’assegnazione ad allo-SCT sulla base di una valutazione accurata della MMR e sulla presenza/assenza di ulteriori lesioni genetiche (chiamate IKZF1 plus CDKN2A/B e/o PAX5)
    2. Capacità del blinatumomab di ridurre ulteriormente i livelli di MMR dopo l’induzione con Ponatinib
    3. Durata della CMR o del PNQ
    4. DFS ad 1 e 3 anni
    5. OS ad 1 e 3 anni
    6. CIR
    7. Profilo di sicurezza
    8. Confronto dei profili di qualità della vita dei pazienti nel tempo in base ai bracci di randomizzazione
    9. Raggiungimento di CMR (o PNQ), durata della CMR, OS e DFS in accordo alle caratteristiche cliniche, biologiche e molecolari al baseline, inclusi il tipo di proteina di fusione (p190 vs p210) e la presenza di ulteriori lesioni genomiche
    10 e 11 si veda Protocollo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenomics
    Version: 1.0
    Date: 28/02/2020
    Title: Traslational Research
    Objectives: 1. Confronto di GUS over ABL1 as a control gene and comparison of data interpretation. 2. In CMR and PNQ cases, analysis of MRD levels by digital droplet PCR (ddPCR). 3. MRD assessment by IG/TCR (immunoglobulin/T-cell receptor) gene screening. 4. Screening of ABL1 mutations by both Sanger and ddPCR. 5. Flow cytometric evaluation of the spinal fluid at diagnosis 6. Analysis of the TREG compartment (for the experimental arm only).

    Farmacogenomica
    Versione: 1.0
    Data: 28/02/2020
    Titolo: Ricerca Traslazioinale
    Obiettivi: 1. Confronto di GUS over ABL1 as a control gene and comparison of data interpretation. 2. In CMR and PNQ cases, analysis of MRD levels by digital droplet PCR (ddPCR). 3. MRD assessment by IG/TCR (immunoglobulin/T-cell receptor) gene screening. 4. Screening of ABL1 mutations by both Sanger and ddPCR. 5. Flow cytometric evaluation of the spinal fluid at diagnosis 6. Analysis of the TREG compartment (for the experimental arm only).
    E.3Principal inclusion criteria
    1. Signed written informed consent according to ICH/EU/GCP and national local laws.
    2. Newly diagnosed adult B-precursor Ph+ ALL patients.
    3. WHO performance status less or equal to 2.
    4. Age greater or equal to18 years, with no upper age limit.
    5. Renal and hepatic function as defined below:
    - AST (GOT), ALT (GPT), and AP <2 x upper limit of normal (ULN).
    - Total bilirubin <1.5 x ULN.
    - Creatinine clearance equal or greater than 50 mL/min.
    6. Pancreatic function as defined below:
    - Serum amylase less or equal to 1.5 x ULN and serum lipase less or equal to1.5 x ULN.
    7. Normal cardiac function.
    8. No evidence of CNS leukemia at blinatumomab start.
    9. Negative HIV test, negative hepatitis B (HBsAg) and hepatitis C virus (anti-HCV) test.
    10. Negative pregnancy test in women of childbearing potential.
    11. Bone marrow specimen from primary diagnosis available.
    1. Firma del Consenso Informato scritto in accordo alle normative ICH/EU/GCP e le leggi nazionali.
    2. Pazienti adulti affetti da LAL B Ph+ di nuova diagnosi.
    3. WHO performance status = 2.
    4. Età = 18 anni, senza limite massimo.
    5. Funzionalità renale ed epatica come di seguito definite:
    - AST (GOT), ALT (GPT), e AP <2 x ULN;
    - bilirubina totale <1.5 x ULN;
    - Clearance della creatinine uguale o maggiore di 50 mL/min.
    6. Funzionalità pancreatica come definite dal seguente criterio:
    - amilasi e lipasi sierica = 1.5 x ULN.
    7. Funzionalità cardiaca normale.
    8. Nessuna evidenza di leucemia del SNC all’inizio del trattamento con blinatumomab.
    9. Test HIV negativo, test per epatiti HBV (HBsAg) ed HCV (anti-HCV) negativo.
    10. Test di gravidanza negativo per le donne potenzialmente fertili.
    11. Campione di midollo osseo dalla diagnosi primaria disponibile.
    E.4Principal exclusion criteria
    • History of or current relevant CNS pathology (ongoing grade =2 epilepsy, seizure, paresis, aphasia, clinically relevant apoplexia, severe brain injuries, dementia, Parkinson’s disease, organic brain syndrome, psychosis).
    • Impaired cardiac function, including any one of the following:
    - LVEF <45% as determined by MUGA scan or echocardiogram.
    - Complete left bundle branch block.
    - Use of a cardiac pacemaker.
    - ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads.
    - Congenital long QT syndrome.
    - History of or presence of significant ventricular or atrial arrhythmia.
    - Clinically significant resting bradycardia (<50 beats per minute).
    - QTc >450 msec on screening ECG (using the QTcF formula).
    - Right bundle branch block plus left anterior hemiblock, bifascicular block.
    - Myocardial infarction within 3 months prior to starting Ponatinib.
    - Angina pectoris.
    • Other clinically significant vascular and heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Ponatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
    • Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
    • Taking medications that are known to be associated with Torsades de Pointes and medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib.
    • History of or current autoimmune disease.
    • Systemic cancer chemotherapy within 2 weeks prior to study.
    • Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation.
    • Active malignancy other than ALL with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix.
    • Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator.
    • Nursing women or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter.
    •Storia di o attuale patologia rilevante del SNC (epilessia di grado =2, crisi epilettiche, paresi, afasia, apoplessia clinicamente rilevante, lesioni cerebrali gravi, demenza, morbo di Parkinson, sindrome cerebrale organica, psicosi).
    •Funzionalità cardiaca alterata, inclusi uno dei seguenti:
    - LVEF <45% come determinato dalla scansione MUGA o dall'ecocardiogramma.
    - Blocco di branca sinistra completo.
    - Uso di un pacemaker cardiaco.
    - Depressione ST di >1mm in 2 o più leads e/o inversione dell’onda T in 2 o più leads contigui.
    - Sindrome congenita del QT lungo.
    - Storia di o presenza di significativa aritmia ventricolare o atriale.
    - Bradicardia a riposo clinicamente significativa (<50 battiti al minuto).
    - QTc >450 msec nel tracciato dell’ECG (utilizzando la formula QTcF).
    - Blocco di branca destra più emiblocco anteriore sinistro, blocco bifascicolare.
    - Infarto del miocardio entro 3 mesi prima dell’inizio del ponatinib.
    - Angina pectoris.
    •Altre malattie vascolari e cardiache clinicamente significative (ad esempio, insufficienza cardiaca congestiva, ipertensione incontrollata, storia di ipertensione labile o storia di scarsa conformità con un regime antipertensivo).
    •Alterazione della funzionalità gastrointestinale o malattia gastrointestinale che può alterare significativamente l’assorbimento del ponatinib (ad esempio, malattie ulcerative, nausea incontrollata, vomito, diarrea, sindrome da malassorbimento o piccola resezione intestinale).
    •Ipertrigliceridemia non controllata (trigliceridi >450 mg/dL).
    •Assunzione di farmaci noti per essere associate a Torsades de Pointes e di farmaci o integratori a base di erbe noti per essere potenti inibitori del CYP3A4 entro almeno 14 giorni prima della prima dose di ponatinib.
    •Storia di o attuale malattia autoimmune.
    •Chemioterapia sistemica entro 2 settimane prima dello studio.
    •Ipersensibilità conosciuta alle immunoglobuline o a qualsiasi altro componente della formulazione del farmaco in studio.
    •Altra neoplasia attiva oltre la LAL ad eccezione del carcinoma della pelle basocellulare o a cellule squamose o del carcinoma "in situ" della cervice.
    •Infezione attiva, qualsiasi altra malattia o condizione medica che possa interferire con lo svolgimento dello studio a giudizio dello sperimentatore.
    •Donne che allattano o donne potenzialmente fertili che non sono disposte ad utilizzare una forma efficace di contraccezione durante la partecipazione allo studio e per almeno 3 mesi dal termine, oppure pazienti maschi non disposti a garantire una contraccezione efficace durante la partecipazione allo studio e per almeno i 3 mesi successivi.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is to evaluate the efficacy of a sequential approach based on the administration of Ponatinib plus and Blinatumomab vs chemotherapy combined with Imatinib, in terms of (EFS), a composite endpoint, with events defined as: non achievement of MRD negativity (CMR or PNQ), deaths for any reason, toxicity and resistance (due or not to an ABL1 mutation development) in adult Ph+ ALL (=18 years, no upper age limit).
    L'endpoint primario di questo studio è valutare l'efficacia di un approccio sequenziale basato sulla somministrazione di Ponatinib plus e Blinatumomab vs chemioterapia combinata con Imatinib, in termini di (EFS), un endpoint composito, con eventi definiti come: mancato raggiungimento della negatività MRD (CMR o PNQ), decessi per qualsiasi motivo, tossicità e resistenza (dovute o meno allo sviluppo di una mutazione ABL1) nella LLA Ph + adulta (=18 anni, nessun limite superiore di età).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the beginning and at the end of the study
    All'inizio e alla fine dello studio.
    E.5.2Secondary end point(s)
    • The feasibility of patients’ stratification to allo-SCT allocation on the basis of a refined MRD evaluation and on the presence/absence of IKZF1-plus).
    • Capability of Blinatumomab to further reduce the MRD levels after Ponatinib induction.
    • CMR or PNQ duration.
    • DFS at 1 and 3 years.
    • OS at 1 and 3 years.
    • CIR.
    • Safety profile. Safety profile in terms of incidence of grade =3 CTC-NCI side effects and toxicities.
    • Comparison of patients’ quality of life (QoL) profiles over time by randomization arms.
    • La fattibilità della stratificazione dei pazienti per l'allocazione allo-SCT sulla base di una raffinata valutazione MRD e sulla presenza / assenza di IKZF1-plus.
    • Capacità di Blinatumomab di ridurre ulteriormente i livelli di MRD dopo l'induzione di Ponatinib.
    • Durata CMR o PNQ.
    • DFS a 1 e 3 anni.
    • OS a 1 e 3 anni.
    • CIR.
    • Profilo di sicurezza. Profilo di sicurezza in termini di incidenza di effetti collaterali e tossicità CTC-NCI di grado =3.
    • Confronto dei profili della qualità di vita (QoL) dei pazienti nel tempo per bracci di randomizzazione.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 1and 3 years.
    Ad 1 e a 3 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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    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 Yes
    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 trial3
    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 concerned66
    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 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
    Last Visit Last Subject
    Ultima visita dell'ultimo paziente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months3
    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: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 106
    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 state236
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 236
    F.4.2.2In the whole clinical trial 236
    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 activity 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
    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 Decision2021-05-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-07
    P. End of Trial
    P.End of Trial StatusOngoing
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