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    Summary
    EudraCT Number:2013-003893-29
    Sponsor's Protocol Code Number:BAY80-6946/17067
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-06-17
    Trial results View 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 number2013-003893-29
    A.3Full title of the trial
    A Phase III, randomized, double-blind, placebo-controlled study evaluatingthe efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin's lymphoma (iNHL) - CHRONOS-3
    Studio di Fase III, randomizzato, in doppio cieco, controllato con placebo, per valutare l¿efficacia e la sicurezza di copanlisib in associazione con rituximab in pazienti affetti da linfoma non-Hodgkin indolente a cellule B recidivato (iNHL)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin's lymphoma.
    Copanlisib e rituximab nel iNHL recidivato
    A.3.2Name or abbreviated title of the trial where available
    CHRONOS 3
    CHRONOS 3
    A.4.1Sponsor's protocol code numberBAY80-6946/17067
    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 SponsorBAYER AG
    B.1.3.4CountryGermany
    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 supportBayer HealthCare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clin. Trials Contact CTP Team
    B.5.3 Address:
    B.5.3.1Street Addressna
    B.5.3.2Town/ cityBerlino
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayer.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 nameCOPANLISIB
    D.3.2Product code BAY84-1236
    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 INNCOPANLISIB
    D.3.9.2Current sponsor codeBAY 84-1236
    D.3.9.4EV Substance CodeSUB 32033
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 RoleComparator
    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 MABTHERA - 2 FIALE 100 MG 10 ML
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION LIMITED
    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 nameRITUXIMAB
    D.3.2Product code [na]
    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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed indolent B-cell non-Hodgkin's lymphoma
    linfoma non-Hodgkin indolente a cellule B recidivato (iNHL)
    E.1.1.1Medical condition in easily understood language
    Relapsed indolent B-cell non-Hodgkin's lymphoma
    linfoma non-Hodgkin indolente a cellule B recidivato
    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 23.0
    E.1.2Level PT
    E.1.2Classification code 10029600
    E.1.2Term Non-Hodgkin's lymphoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is: - To evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging
    progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab, and who either had a treatment-free interval of =12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.
    L'obiettivo primario di questo studio è quello di valutare se copanlisib in associazione con rituxlmab sia superiore al placebo in associazione con rituximab nel prolungare la sopravvivenza libera da progressione (PFS) in pazienti affetti da iNHL recidivato, che abbiano ricevuto una o più linee di
    trattamento, incluso rituximab, e che hanno un intervallo libero da trattamento superiore o uguale a 12 mesi dopo il completamento di un trattamento con rituximab, o i quali rifiutano il trattamento chemioterapico /per i quali è controindicata la chemioterapia per motivi di età, comorbidità, e/o tossicità residua.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate:¿ The following characteristics of disease-related symptoms: "time to deterioration" and "time to improvement" ¿ Other radiological and clinical indicators of treatment efficacy¿ Safety and tolerability of copanlisibThe other objectives of this study are to evaluate:- Pharmacokinetics- Biomarkers- Quality of life
    Gli obiettivi secondari di questo studio sono valutare:
    ¿ ¿ il tempo al miglioramento e al peggioramento dei sintomi correlati alla malattia
    ¿ Altri indicatore clinici o radiologici dell¿efficacia del trattamento
    ¿ la sicurezza e tollerabilit¿ di copanlisib
    Gli altri obiettivi di questo studio sono valutare:
    ¿ La farmacocinetica
    ¿ I biomarcatori
    ¿ La qualit¿ di vita
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Ability to understand and willingness to sign written ICF. Signed ICF
    must be obtained before any study specific procedure.
    2. Histologically confirmed diagnosis of iNHL in CD20 positive patients,
    with histological subtype limited to: -Follicular lymphoma (FL) grade 1-
    2-3a, -Small lymphocytic lymphoma (SLL) with absolute monoclonal
    XML File Identifier: /KmHxAMofFIzISiHnmvUdPQkY/4=
    Page 15/35
    lymphocyte count <5x109/L at study entry, -Lymphoplasmacytoid
    lymphoma/Waldenström macroglobulinemia (LPL/WM), -Marginal zone
    lymphoma (MZL) (splenic, nodal, or extra-nodal)
    3. Patients must have relapsed (recurrence after complete response or
    presented progression after partial response) after the last rituximab,
    rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g.
    obinutuzumab) containing therapy (other previous treatment lines after
    rituximab are allowed). A previous regimen is defined as one of
    following: at least 2 mths of single-agent therapy (less than 2 mths of
    therapy is allowed for patients who responded to single-agent rituximab,
    rituximab biosimilars, or anti-CD20 monoclonal antibody); at least 2
    consecutive cycles of polychemotherapy; acceptable provided there is no
    resistance. Patients with prior intolerance to PI3K inhibitors other than
    copanlisib are eligible.
    4. Non-WM patients must have at least one bi-dimensionally measurable
    lesion (not been previously irradiated) according to Lugano
    Classification. For patients with splenic MZL this requirement may be
    restricted to splenomegaly alone since that is usually the only
    manifestation of measurable disease.
    5. Patients affected by WM who do not have at least one bidimensionally
    measurable lesion in baseline radiologic assessment must
    have measurable disease, defined as presence of IgM paraprotein with a
    minimum IgM level =2 x upper limit of normal and positive
    immunofixation test
    6. Male/female patients =18 yrs of age
    7. ECOG performance status =2
    8. Life expectancy at least 3 mths
    9. Availability of fresh tissue and/or archival tumor tissue for central
    pathology (obtained within 5 yrs of the consent date) at Screening
    10. Women of childbearing potential (WOCBP) and men must agree to
    use effective contraception when sexually active. This applies for time
    period between signing of ICF and 12 mths (for WOCBP) and 5 mths (for
    men) after last administration of study treatment. A high FSH level in
    postmenopausal range may be used to confirm a post-menopausal state
    in women not using hormonal contraception or hormonal replacement
    therapy. The investigator/a designated associate is requested to advise
    the patient how to achieve highly effective birth control (failure rate of
    less than 1%), e.g. IUD, IUS, bilateral tubal occlusion, vasectomized
    partner and sexual abstinence. Use of condoms by male patients
    required unless female partner permanently sterile
    11. Adequate baseline laboratory values collected no more than 7 days
    before starting study treatment: -Total bilirubin =1.5 x ULN (<3 x ULN
    for patients with Gilbert-Meulengracht syndrome or for patients with
    cholestasis due to compressive adenopathies of the hepatic hilum), -ALT
    and AST =2.5 x ULN (=umm5 x ULN for patients with liver involvement
    by lymphoma), -Lipase =1.5 x ULN, -GFR =30 mL/min/1.73m2 according
    to the Modification of Diet in Renal Disease (MDRD) abbreviated formula,
    -International normalized ratio (INR) =1.5 and partial thromboplastin
    time (PTT) =1.5 x ULN. PT can be used instead of INR if =1.5 x ULN, -
    Platelet count =75,000/mm3. For patients with confirmed
    lymphomatous bone marrow infiltration, platelet count =50,000/mm3.
    Platelet transfusion should not be given less than 7 days before exam
    collection, -Hb =8g/dL, Packed red blood cell transfusion or
    erythropoietin should not be given less than 7 days before exam
    collection, -ANC =1,000/mm3, For patients with confirmed
    lymphomatous bone marrow infiltration, ...
    TEXT EXCEEDS THE LIMITS (FOR THE COMPLETE LIST SEE MAIN PROTOCOL)
    Diagnosi istologicamente confermata di iNHL in pazientiCD20-positivo con sottotipo istologico limitato a:
    • Linfoma follicolare (FL) G1-2-3a
    • Linfoma linfocitico (SLL) con conta linfocitaria monoclonale assoluta <5x109/L all’ingresso nello studio
    • Linfoma linfoplasmocitoide / macroglobulinemia di Waldenström (LPL/WM)
    • Linfoma marginale (MZL) (splenico, nodale od extra-nodale)
    I pazienti devono essere recidivati (ricaduti dopo risposta completa o in progressione dopo risposta parziale) dopo l’ultima terapia contenente rituximab, farmaci biosimilari di rituximab o anticorpi monoclonali anti-CD20 (ad esempio obinutuzumab) (sono permesse ulteriori precedenti linee terapeutiche dopo rituximab). Una precedente linea terapeutica è definita come uno dei seguenti regimi: almeno 2 mesi consecutivi di monoterapia (sono permessi meno di 2 mesi di terapia per quei pazienti che hanno risposto alla monoterapia con rituximab, farmaci biosimilari di rituximab o anticorpi monoclonali anti-CD20); almeno 2 cicli consecutivi di polichemioterapia; trapianto autologo; radioimmunoterapia.

    Una precedente esposizione ad altri inibitori della PI3K è accettabile (eccetto
    copanlisib), se c'è evidenza che non sia stata sviluppata resistenza. I pazienti con
    pregressa intolleranza ad altri inibitori della PI3K diversi da copanlisib sono
    eleggibili.
    I pazienti non affetti da WM devono avere almeno una lesione misurabile bi-dimensionalmente (che non sia stata precedentemente irradiata) secondo le raccomandazioni del "Revised Recommendations for lnitial Evaluation, Staging, and Response Criteria for Malignant Assessment of Hodgkin and Non-Hodgkln Lymphoma: The Lugano Classification. Per i pazienti con MZL splenico questo requisito può essere limitato alla sola splenomegalia dal momento che solitamente questa è l’unica manifestazione della malattia misurabile.
    I pazienti affetti da WM, che non presentano almeno una lesione misurabile bidimenslonalmente alla valutazione basale, devono avere una malattia misurabile definita come la presenza di una componente monoclonale M (lgM) con un livello minimo di lgM =2 volte oltre il limite superiore della norma (ULN) e con risultato positivo al test dell'immunofissazione.
    Pazienti di sesso maschile o femminile =18 anni d' età
    Performance Status secondo l' Eastern Cooperative Oncology Group (ECOG) = 2
    Aspettativa di vita di almeno 3 mesi
    Disponibilità di tessuto tumorale fresco e/o di tessuto tumorale archiviato allo screening da inviare al laboratorio centrale di patologia, (ottenuto entro 5 anni dalla data di firma del consenso informato)
    Parametri di laboratorio al basale adeguati valutati entro 7 giorni prima di iniziare il trattamento dello studio […]
    Frazione di elezione ventricolare =45%
    Pazienti devono:
    •avere un Intervallo libero da progressione di malattia e da trattamento superiore o uguale a 12 mesi dopo il completamento di un trattamento con rituximab
    OPPURE
    • presentare una controindicazione per la chemioterapia per motivi di età, comorbidità e/o tossicità residua di trattamenti precedenti, o rifiutare il trattamento chemioterapico. Questi pazienti devono anche aver avuto un intervallo libero da progressione di malattia e da trattamento = a 6 mesi dopo il completamento di un trattamento con rituximab. I pazienti per i quali la chemioterapia è controindicata sono definiti dalle seguenti caratteristiche:
    - Età =80 anni
    - Età <80 anni e almeno una delle seguenti caratteristiche: almeno 3 commorbidità di grado 3 CIRS·G oppure almeno 1 commorbidità di grado 4 CIRS·G (se compatibile con la partecipazione allo studio)
    E.4Principal exclusion criteria
    1. Previous assignment to treatment during this study
    2. Close affiliation with site
    3. FL grade 3b or transformed disease, or CLL
    4. Progression free interval or treatment free interval of less than 12
    mths since the last rituximab, rituximab biosimilars-, or anti-CD20
    monoclonal antibody (e.g. obinutuzumab) containing treatment
    (including maintenance with these drugs). For patients considered
    unwilling/unfit to receive chemotherapy: progression free interval or
    treatment free interval of less than 6 mths since the last rituximab,
    rituximab biosimilars-, or anti-CD20 monoclonal antibody containing
    treatment (including maintenance with these drugs), as assessed by the
    investigator
    5. Previous/concurrent cancer that is distinct in primary site or histology
    from indolent B-cell NHL (as described in Inc. criteria 2)within 5 yrs
    prior to treatm start except for curatively treated cervical carcinoma in
    situ, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis &
    T1), and asymptomatic prostate cancer without known metastatic
    disease and with no requirement for therapy or requiring only hormonal
    therapy and with normal prostate-specific antigen for =1 yr prior to
    randomization
    6. Known lymphomatous involvement of central nervous system
    7. Congestive heart failure > NYHA class 2
    8. Unstable angina, new-onset angina. Myocardial infarction less than 6
    mths before start of test drug
    9. Uncontrolled arterial Hypertension despite optimal medical
    management
    10. Patients with HbA1c >8.5% at Screening
    11. Arterial or venous thrombotic or embolic events such as
    cerebrovascular accident, DVT or pulmonary embolism within 3 mths
    before start of study treatment
    12. Non-healing wound, ulcer, or bone fracture
    13. Active, clinically serious infections >CTCAE Grade 2
    14. Known history of HIV infection
    15. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened
    for HBV and HCV up to 28 days prior to study drug start. Patients
    positive for HBsAg or HBcAb will be eligible if negative for HBV-DNA,
    these patients should receive prophylactic antiviral therapy; patients
    positive for anti-HCV antibody will be eligible if negative for HCV-RNA
    16. seizure disorder requiring medication
    17. evidence or history of bleeding diathesis. Any hemorrhage or
    bleeding event =CTCAE Grade 3 within 4 wks prior to start of study
    treatm
    19. Proteinuria of CTCAE Grade 3
    20. History/concurrent condition of interstitial lung disease of any
    severity and/or severely impaired lung function
    21. Concurrent diagnosis of pheochromocytoma
    22. Pregnant or breast-feeding patients. Women of childbearing
    potential must have a serum pregnancy test performed a max of 7 days
    before start of treatm and negative result must be documented before
    start of treatm
    23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any
    prior therapy/procedure, excluding alopecia, peripheral neuropathy, and
    bone marrow parameters
    24. Known hypersensitivity to any of test drugs, test drug classes, or
    excipients in formulation
    25. Substance abuse, medical, psychological or social conditions that
    may interfere with the patient's participation in the study or evaluation
    of study results
    26. Any illness or medical conditions that are unstable or could
    jeopardize safety of patients and compliance in study
    28. Treatment with investigational drugs other than PI3K inhibitors less
    than 28 days before start of treatment, unless evidence of progression
    since last treatm.
    29. Ongoing immunosuppressive therapy
    30. Radiotherapy or immuno-/chemotherapy less than 4 wks before
    start of treatment, unless evidence of progression since last treatm.
    31. Radioimmunotherapy or autologous transplant less than 3 mths
    before start of treatm, unless evidence of progression since last treatm
    32. Myeloid growth factors less than 7 days before start of treatm ...

    TEXT EXCEEDS THE LIMITS (FOR THE COMPLETE LIST SEE MAIN PROTOCOL)
    E.5.1 End point primario (ripetere se necessario): Sopravvivenza libera da progressione di malattia (PFS)
    E.5.1.1 Tempo/i di rilevazione di questo end point: La variabile di efficacia primaria è la PFS, valutata mediante revisione centralizzata. I pazienti vivi senza progressione di malattia documentata al momento dell'analisi verranno censiti alla data della loro ultima rivalutazione del tumore
    E.5.2 End point secondario (ripetere se necessario): - Objective tumor response rate (ORR) - Duratlon of response (DOR) - Complete response rate (CRR) - Time to progression (TIP) - Overall survival (OS) - Time lo deterioration In DRS-P - Time to improvement in DRS.P
    E.5.2.1 Tempo/i di rilevazione di questo end point: L'OS, il TTP, il DOR ed il tempo al peggioramento e di miglioramento di DRSP di almeno = 3 punti verranno analizzati utilizzando un test di rango logaritmico stratificato simile a quello dell'end point primario, la PFS. L'ORR ed il CRR verranno analizzati mediante il test di Cochran-Mantel-Haenszel. I test verranno aggiustali per gli stessi fattori di stratificazione impiegali per la PFS.
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS)
    Sopravvivenza liera da progressione di malattia (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time (in days) from randomization to PD or death from any cause (if no progression is documented). The actual date of tumor assessments will be used for this calculation. PFS for patients without PD or death at the time of analysis will be censored at the date of their last tumor evaluation. PFS for patients who have neither tumor assessments nor death after baseline will be censored at Day 1.
    La variabile di efficacia primaria è la PFS, valutata mediante revisione centralizzata. I pazienti vivi senza progressione di malattia documentata al momento dell’analisi verranno censorizzati alla data della loro ultima rivalutazione del tumore.
    E.5.2Secondary end point(s)
    - Objective tumor response rate (ORR) - Duration of response (DOR)- Complete response rate (CRR)- Time to progression (TTP)- Overall survival (OS)- Time to deterioration in DRS-P - Time to improvement in DRS-P
    - Objective tumor response rate (ORR)
    - Duration of response (DOR)
    - Complete response rate (CRR)
    - Time to progression (TTP)
    - Overall survival (OS)
    - Time to deterioration in DRS-P - Time to improvement in DRS-P
    E.5.2.1Timepoint(s) of evaluation of this end point
    - ORR - assessed in all patients up to the time of analysis of PFS. - DOR: time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until PD or death from any cause, whichever is earlier- CRR: assessed in all patients up to the time of analysis of PFS.- TTP: time from randomization to PD or death related to PD, whichever is earlier- OS: time (in days) from randomization until death from any cause. - Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire. - Time to improvement in DRS-P of at least 3 points, as measured by theFLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less.
    L¿OS, il TTP, il DOR ed il tempo al peggioramento e di miglioramento di DRS-P di almeno = 3 punti verranno analizzati utilizzando un test di rango logaritmico stratificato simile a quello dell¿end point primario, la PFS.
    L¿ORR ed il CRR verranno analizzati mediante il test d¿ Cochran-Mantel-Haenszel. I test verranno aggiustati per gli stessi fattori di stratificazione impiegati per la PFS.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers and Quality of Life
    Biomarcatori e Quality of Life
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Chile
    China
    Colombia
    Hong Kong
    Korea, Republic of
    Mexico
    Philippines
    Russian Federation
    Singapore
    South Africa
    Taiwan
    Thailand
    Turkey
    Ukraine
    United States
    Vietnam
    Austria
    Belgium
    Bulgaria
    Denmark
    France
    Germany
    Hungary
    Ireland
    Italy
    Lithuania
    Poland
    Portugal
    Spain
    Sweden
    Czechia
    Argentina
    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
    LVLS
    LVLS
    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: 227
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 340
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 450
    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)
    After the end of this study, further therapy is at the discretion of the investigator.
    Dopo la fine dello studio la terapia sar¿ definita a discrezione dello Sperimentatore
    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 Decision2015-05-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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