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    Summary
    EudraCT Number:2014-003220-52
    Sponsor's Protocol Code Number:CC-486-BRSTM-001
    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:2016-09-28
    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 number2014-003220-52
    A.3Full title of the trial
    A Phase 2, Randomized, Open-Label, Two-arm Study to Assess the Efficacy
    and Safety of the Epigenetic Modifying Effects of CC-486 (Oral Azacitidine)
    in Combination With Fulvestrant in Postmenopausal Women with ER+,
    HER2- Metastatic Breast Cancer Who Have Progressed on an Aromatase
    Inhibitor
    Studio di Fase 2, randomizzato, in aperto, a due bracci di trattamento per valutare l’efficacia e la sicurezza della terapia modificante epigenetica CC-486 (azacitidina orale) somministrata in combinazione con fulvestrant in donne in stato post-menopausale con tumore della mammella metastatico ER+ e HER2-, in progressione di malattia dopo trattamento con inibitori delle aromatasi
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to see if the combination CC-486 plus fulvestrant is effective
    and safe, compared to fulvestrant alone, in patients with metastatic breast
    cancer that is estrogen receptor-positive and human epidermal growth
    factor receptor 2-negative
    Una sperimentazione clinica per verificare se la combinazione di CC-486 più fulvestrant è efficace e sicura, rispetto a fulvestrant da solo, in pazienti con tumore della mammella metastatico positivo al recettore dell'estrogeno e negativo al recettore 2 del fattore di crescita epidermico umano
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberCC-486-BRSTM-001
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00000000
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    A.5.4Other Identifiers
    Name:NANumber:NA
    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 SponsorCELGENE CORPORATION
    B.1.3.4CountryUnited States
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 888 2601599
    B.5.5Fax number+1 013 2660394
    B.5.6E-mailClinicalTrialDisclosure@celgene.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 nameazacitidina orale
    D.3.2Product code CC-486
    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 INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor codeCC-486
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product 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 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 nameazacitidina orale
    D.3.2Product code CC-486
    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 INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor codeCC-486
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product 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 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 nameazacitidina orale
    D.3.2Product code CC-486
    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 INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor codeCC-486
    D.3.9.4EV Substance CodeSUB05624MIG
    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 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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    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.2.1.1.1Trade name Faslodex 250 mg soluzione iniettabile
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameFulvestrant
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNfulvestrant
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product 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
    Postmenopausal female subjects with estrogen receptor positive (ER+),
    human epidermal growth factor receptor 2 negative (HER2-) metastatic
    breast cancer, who have progressed on an aromatase inhibitor (AI)
    Soggetti di sesso femminile in post-menopausa, con cancro mammario metastatico negativo al recettore 2 del fattore di crescita epidermico umano (HER2), positivo al recettore dell'estrogeno (ER+), che hanno dimostrato progressi con un inibitore dell'aromatasi (IA)
    E.1.1.1Medical condition in easily understood language
    Females who are post-menopause with a breast cancer that has spread
    to other part of the body, and that is estrogen receptor-positive and
    human epidermal growth factor receptor 2-negative
    Soggetti di sesso femminile in postmenopausa,con cancro mammario diffuso in altre parti del corpo positivo al recettore dell'estrogeno e negativo al recettore2del fattore di crescita epidermico umano
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10006187
    E.1.2Term Breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10006204
    E.1.2Term Breast carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10006315
    E.1.2Term Breast tumor malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10006283
    E.1.2Term Breast neoplasm malignant female
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of CC-486 in combination with fulvestrant
    relative to fulvestrant monotherapy, by estimation of the hazard ratio of
    progression free survival (PFS)
    L’obiettivo primario dello studio è valutare l’efficacia di CC-486 in combinazione con fulvestrant rispetto a fulvestrant in monoterapia, in base alla stima del rapporto di rischio (hazard ratio) della sopravvivenza libera da progressione (progression free survival, PFS).
    E.2.2Secondary objectives of the trial
    To estimate response rate (RR), clinical benefit rate (CBR), overall
    survival (OS), and duration of response (DOR) in all treatment arms
    •To evaluate the safety of all treatment arms
    • Stimare il tasso di risposta (response rate, RR), il tasso di beneficio clinico (clinical benefit rate, CBR), la sopravvivenza complessiva (overall survival, OS) e la durata della risposta (duration of response, DOR) in tutti i bracci di trattamento
    • Valutare la sicurezza di tutti i bracci di trattamento

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must satisfy the following criteria to be enrolled in the study:

    1. Subject is female ≥ 18 years of age (at the time of signing the informed consent form) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy.

    2. Subject is considered postmenopausal (ie, if one of the following criteria are met):

    • Prior bilateral oophorectomy

    • Age ≥ 60 years and amenorrhea for 12 or more consecutive months in the absence of chemotherapy, hormonal therapy, or ovarian suppression

    • Age < 60 years old and amenorrhea for 12 or more consecutive months (in the absence of chemotherapy, hormonal therapy, or ovarian suppression) and FSH and estradiol in the postmenopausal range

    Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone
    (LHRH) agonist is not permitted for induction of ovarian suppression in this trial.

    3. Subject has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive breast cancer by local laboratory (based on most recently analyzed biopsy).

    4. Subject has HER2-negative breast cancer (based on most recently analyzed biopsy)
    defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is
    2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.

    5. Subject had disease refractory to an AI defined as either:

    a. recurrence while on adjuvant treatment with an aromatase inhibitor or within 12 months of last treatment administration, or

    b. progression while on an aromatase inhibitor or within one month of last treatment administration.

    Note: The aromatase inhibitor does not have to be the last treatment prior to randomization. Other prior anticancer therapy, eg, tamoxifen, are also allowed. Subjects do not need to meet the definition of “refractory to AI” within any specified time period prior to randomization. Subjects can receive any number of endocrine/hormonal lines of therapy before or after meeting the definition of “refractory to AI”.

    6. Subject has an ECOG performance status of 0-1.




    Confidential and Proprietary 34 CC-486-BRSTM-001 Amendment 1.0 Final: 04 Dec 2014


    7. Subject has radiological documented measurable disease (ie, at least one measureable lesion as per RECIST Version 1.1).

    • If no measurable disease is present, then at least one predominantly lytic bone lesion must be present

    8. Subject has adequate organ functions, evidenced by the following:

    a. AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal range (ULN), or ≤ 5 x
    ULN range if liver metastasis present b. Total bilirubin ≤ 1.5 x ULN
    c. Creatinine ≤ 1.5 x ULN

    d. Potassium within normal range (according to local lab), or correctable with supplements

    9. Subject has adequate bone marrow function, evidenced by the following:
    a. ANC ≥ 1.5 x 109 cells/L
    b. Platelets ≥ 100 x 109 cells/L

    c. Hemoglobin ≥ 9 g/dL

    10. Subject understands and voluntarily signs an informed consent document prior to any study-related assessments/procedures are conducted.

    11. Subject is able to adhere to the study visit schedule and other protocol requirements.
    Per essere arruolati nello studio, i soggetti devono soddisfare i seguenti criteri:
    1. Il soggetto è una donna di età ≥ 18 anni (al momento della firma del modulo di consenso informato) con carcinoma mammario metastatico non curabile con terapia chirurgica o radioterapica.
    2. Il soggetto si può considerare in post-menopausa (ovvero uno dei criteri seguenti è soddisfatto):
    • Precedente ovariectomia bilaterale
    • Età ≥ 60 anni e amenorrea da 12 mesi consecutivi o più in assenza di chemioterapia, terapia ormonale o soppressione dell'attività ovarica
    • Età < 60 anni e amenorrea da 12 mesi consecutivi o più (in assenza di chemioterapia, terapia ormonale o soppressione dell'attività ovarica) e valori di FSH ed estradiolo nella gamma per la post-menopausa
    Nota: In questa sperimentazione non sono ammesse radiazioni alle ovaie o terapia con un agonista dell'ormone di rilascio dell'ormone luteinizzante
    (LHRH) per indurre la soppressione dell'attività ovarica.
    3. Il soggetto presenta una diagnosi di carcinoma mammario positivo per il recettore per gli estrogeni istologicamente e/o citologicamente confermata da un laboratorio locale (sulla base della biopsia analizzata più di recente).
    4. Il soggetto presenta un carcinoma mammario HER2 negativo (sulla base della biopsia analizzata più di recente)
    definito come test di ibridazione in situ negativo o stato IHC pari a 0, 1+ o 2+. Se IHC è
    2+ è necessario un test di ibridazione in situ negativo (FISH, CISH o SISH) eseguito da un laboratorio locale.
    5. Il soggetto presenta una patologia refrattaria a un inibitore dellearomatasi (AI) definita come:
    a. recidiva durante il trattamento in adiuvante con un inibitore delle aromatasi o entro 12 mesi dall'ultima somministrazione del trattamento, oppure
    b. progressione durante il trattamento con un inibitore dellearomatasi o entro un mese dall'ultima somministrazione del trattamento.
    Nota: L'inibitore dellearomatasi non deve necessariamente essere l'ultimo trattamento prima della randomizzazione. Sono ammesse anche altre precedenti terapie antitumorali, ad es. tamoxifene. I soggetti non devono essere necessariamente conformi alla definizione di “refrattario a un inibitore delle aromatasi” entro un determinato lasso di tempo prima della randomizzazione. I soggetti possono ricevere un numero qualsiasi di linee endocrine/ormonali di terapia prima o dopo il raggiungimento della conformità alla definizione “refrattario a un inibitore dellearomatasi”.
    6. Il soggetto presenta uno stato di performance secondo ECOG di 0-1.
    7. Il soggetto presenta una malattia misurabile documentata radiologicamente (cioè almeno una lesione misurabile in base ai RECIST Versione 1.1).
    • Se non si riscontra alcuna malattia misurabile, deve essere presente almeno una lesione ossea di tipo prevalentemente litico.
    8. Il soggetto presenta funzioni degli organi adeguate, dimostrate dai seguenti valori:
    a. AST (SGOT), ALT (SGPT) ≤ 2,5 × limite superiore di normalità (ULN) oppure ≤ 5 x
    ULN in presenza di metastasi epatica b. Bilirubina totale ≤ 1,5 x ULN
    c. Creatinina ≤ 1,5 x ULN
    d. Potassio entro il limite di normalità (secondo il laboratorio locale) oppure correggibile con integratori.
    9. Il soggetto presenta funzioni del midollo osseo adeguate, dimostrate dai seguenti valori:
    a. ANC ≥ 1,5 x 109 cellule/l
    b. Piastrine ≥ 100 x 109 cellule/l
    c. Emoglobina ≥ 9 g/dl
    10. Il soggetto comprende e sottoscrive volontariamente un documento di consenso informato prima che venga effettuata qualsiasi valutazione/procedura legata allo studio.
    11. Il soggetto è in grado di aderire al programma di visite dello studio e ad altri requisiti del protocollo.
    E.4Principal exclusion criteria
    The presence of any of the following will exclude a subject from enrollment:

    1. Subject has received > 1 prior line of chemotherapy in the metastatic setting

    2. Subject has received any chemotherapy within 21 days prior to randomization.

    3. Subject has received prior treatment with fulvestrant.

    4. Subject has been previously treated with azacitidine (any formulation), decitabine, or any other hypomethylating agent.

    5. Subject has symptomatic visceral crisis requiring chemotherapy per investigator judgment.

    6. Subject has received another investigational therapy within 28 days or 5 half lives of randomization, whichever is longer.

    7. Subject has not recovered from the acute toxic effects [Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 1] of prior anticancer therapy, radiation, or major surgery/significant trauma (except alopecia or other toxicities not considered a safety risk for the subject at the investigators discretion).

    8. Subject has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.
    9. Subject has had radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug, and/or from whom ≥ 30% of the bone marrow was irradiated.

    10. Subject has a history of, or current symptomatic brain metastasis.

    a. Patients with asymptomatic brain metastases may participate in this trial. The patient must have completed any prior local treatment for brain metastases ≥ 28 days prior to the start of study treatment (including radiotherapy and/or surgery) and must be receiving no or low stable dose corticosteroids.

    11. Subject has severe renal impairment (creatinine clearance < 30 ml/min).

    12. Subject has any other malignancy within 5 years prior to randomization, with the exception of adequately treated in situ carcinoma of the cervix, uteri, or non- melanomatous skin cancer (all treatment of which should have been completed 6 months prior to enrollment).

    13. Subject has an impaired ability to swallow oral medication.

    14. Subject has a contraindication to receiving IM injections (eg, bleeding disorders, anticoagulant use).

    15. Subject has a known or suspected hypersensitivity or other contraindication to fulvestrant, azacitidine, or any excipients used in the manufacture of fulvestrant and CC-
    486 (Refer to Azacitidine Investigator Brochure).

    16. Subject has a history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.

    17. Subject has persistent diarrhea or malabsorption ≥ NCI CTCAE Grade 2, despite medical management.

    18. Subject has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.

    19. Subject has a known history or current diagnosis of Human Immunodeficiency Virus
    (HIV) infection, regardless of treatment status.

    20. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would, in the investigator’s judgment, contraindicate subject participation in the study (eg, history of thromboembolic event, cardiac dysfunction, chronic pancreatitis, chronic active hepatitis, etc.).

    21. Subject has any condition that confounds the ability to interpret data from the study.

    22. Subject is a female of Childbearing Potential [defined as a sexually mature woman who (1) has not undergone hysterectomy (the surgical removal of the uterus) or bilateral oopherectomy (the surgical removal of both ovaries) or (2) has not been naturally
    postmenopausal for at least 12 consecutive months (ie, has had menses at any time during the preceding 12 consecutive months)].

    23. Subject is lactating or breast feeding




    La presenza di uno qualsiasi dei seguenti criteri escluderà il soggetto dall'arruolamento:
    1.Il soggetto ha ricevuto > 1 linea precedente di chemioterapia in presenza di metastasi
    2. Il soggetto ha ricevuto un qualsiasi trattamento chemioterapico nei 21 giorni precedenti la randomizzazione.
    3.Il soggetto è stato precedentemente sottoposto a trattamento con fulvestrant.
    4.Il soggetto è stato precedentemente trattato con azacitidina (qualsiasi formulazione), decitabina o con qualsiasi altro agente ipometilante.
    5.Il soggetto presenta crisi viscerali sintomatiche che a parere dello sperimentatore richiedono la chemioterapia.
    6.Il soggetto ha ricevuto un'altra terapia sperimentale entro 28 giorni o 5 emivite dalla randomizzazione, a seconda dell'evento che si è protratto più a lungo.
    7.Il soggetto non si è ristabilito dagli effetti tossici acuti [Criteri comuni di terminologia per gli eventi avversi (CTCAE) di grado ≤ 1] di una precedente terapia antitumorale, da precedenti radiazioni o da un precedente intervento chirurgico maggiore/trauma significativo (fatta eccezione per alopecia o altre tossicità che non sono considerate un rischio per la sicurezza del soggetto a discrezione dello sperimentatore)
    8. Il soggetto è stato sottoposto a intervento chirurgico di ampia portata nei 14 giorni precedenti l'inizio del trattamento in studio o non si è ristabilito da effetti collaterali di notevole entità.
    9. Il soggetto è stato sottoposto a radioterapia ≤ 4 settimane o a radioterapia palliativa a campo limitato ≤ 2 settimane prima di iniziare la somministrazione del farmaco in studio e/o dalla quale è stato irradiato ≥ 30% del midollo osseo.
    10. Il soggetto ha presentato o presenta tuttora metastasi cerebrali sintomatiche.
    a. I soggetti con metastasi cerebrali asintomatiche possono prendere parte a questa sperimentazione. Il soggetto deve aver completato qualsiasi precedente trattamento locale per metastasi cerebrali ≥ 28 giorni prima dell'inizio del trattamento sperimentale (compresi radioterapia e/o intervento chirurgico) e ricevere o meno una dose di corticosteroidi bassa e stabile.
    11 Il soggetto presenta una compromissione renale grave (clearance della creatinina < 30 ml/min).
    12 Il soggetto ha manifestato qualsiasi altra neoplasia maligna nei 5 anni precedenti la randomizzazione, ad eccezione di carcinoma in situ adeguatamente trattato di cervice, utero o tumore cutaneo non melanomatoso (in relazione alla quale l'intero trattamento deve essere completato entro i 6 mesi precedenti l'arruolamento).
    13 Il soggetto ha difficoltà nell'ingerire farmaci per via orale.
    14 Il soggetto presenta una controindicazione alle iniezioni intramuscolari (ad es. problemi di sanguinamento, uso di anticoagulanti).
    15. Il soggetto presenta una ipersensibilità nota o sospetta oppure un'altra controindicazione a fulvestrant, azacitidina o a un qualsiasi eccipiente usato nella realizzazione di fulvestrant e CC-486 (fare riferimento all'Investigator Brochure per azacitidina).16. Il soggetto ha un'anamnesi di malattia infiammatoria dell'intestino (ad es. morbo di Crohn, colite ulcerosa), celiachia, precedente gastrectomia o asportazione del tratto intestinale superiore o qualsiasi altra patologia o difetto gastrointestinale in grado di interferire con l'assorbimento, la distribuzione, il metabolismo o l'eliminazione del farmaco sperimentale e/o predisporre il soggetto a un aumentato rischio di tossicità gastrointestinale.
    17. Il soggetto soffre di diarrea cronica o malassorbimento ≥ NCI CTCAE di grado 2, nonostante il trattamento medico.
    18. Il soggetto ha presentato una patologia cardiaca attiva significativa nei 6 mesi precedenti, tra cui angina instabile o angina che ha richiesto intervento chirurgico o medico, aritmia cardiaca significativa o insufficienza cardiaca congestizia di grado 3 o 4 (Classificazione New York Heart Association - NYHA).
    19. Il soggetto ha un'anamnesi nota o una diagnosi corrente di infezione da virus dell'immunodeficienza umana (HIV), a prescindere dallo stato del trattamento.
    20. Il soggetto presenta una qualsiasi condizione medica significativa, anomalia di laboratorio o malattia psichiatrica che a giudizio dello sperimentatore costituirebbe una controindicazione alla partecipazione allo studio (ad es. storia di evento tromboembolico, disfunzione cardiaca, pancreatite cronica, epatite attiva cronica, ecc.).
    21. Il soggetto presenta una condizione che interferisce con la capacità di interpretare i dati dello studio.
    22. Il soggetto è una donna potenzialmente fertile [cioè una donna sessualmente matura che (1) non è stata sottoposta a isterectomia (la rimozione chirurgica dell'utero) o a ooforectomia bilaterale (la rimozione chirurgica di entrambe le ovaie) oppure (2) non si trova in una condizione di post-menopausa naturale da almeno 12 mesi consecutivi (cioè ha avuto le mestruazioni in un momento qualsiasi dei precedenti 12 mesi consecutivi)].
    23. Sogg. sta allattando al seno
    E.5 End points
    E.5.1Primary end point(s)
    Estimation of the hazard ratio of PFS of the combination arm relative to fulvestrant monotherapy arm
    La stima del rapporto di rischio di PFS del braccio combinato relativo a fulvestrant
    E.5.1.1Timepoint(s) of evaluation of this end point
    approximately 28 months after the start of enrollment
    circa 28 mesi dopo l'inizio dell'arruolamento
    E.5.2Secondary end point(s)
    ORR: the combined incidence of CR and PR, based on RECIST Version 1.1 •Clinical benefit rate (CBR) : [Complete response (CR) + PR + SD ( ≥ 24 weeks)] •Overall Survival (OS): time from date of randomization to date of death due to any cause •Duration of response in subjects with objective CR or PR •Safety: incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Grade 3 and higher AEs, AEs of special interest, and laboratory abnormalities and other safety parameters
    Tasso di risposta complessiva (ORR): incidenza combinata di CR e PR, in base a RECIST Versione 1.1 •Tasso di beneficio clinico (CBR) : [Risposta completa (CR)+ risposta parziale (PR) + deviazione standard (SD) (≥ 24 settimane)] •Sopravvivenza globale (OS): il tempo a partire dalla data di randomizzazione fino alla data del decesso per qualsiasi causa. •Durata della risposta in soggetti con CR o PR obiettivo •Sicurezza: incidenza degli eventi avversi emergenti dal trattamento (TEAE), eventi avversi gravi (SAE), AE di grado 3 e superiore, AE di interesse particolare e anomalie degli esami di laboratorio e altri parametri di sicurezza
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR: approximately 28 months after the start of enrollment •CBR: approximately 28 months after the start of enrollment •OS: approximately 28 months after the start of enrollment •Duration of response: approximately 28 months after the start of enrollment •Safety: Continuous starting after signature of informed consent document, until 28 days after treatment discontinuation

    ORR: circa 28 mesi dopo l'inizio dell'arruolamento •CBR: circa 28 mesi dopo l'inizio dell'arruolamento •OS: circa 28 mesi dopo l'inizio dell'arruolamento •Durata della risposta: circa 28 mesi dopo l'inizio dell'arruolamento •Sicurezza: Continua, a partire dalla firma del documento di consenso informato, fino a 28 giorni dopo l'interruzione del trattamento.
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    Italy
    Spain
    United States
    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
    The End of Trial is defined as either the date of the last visit of the last
    subject to complete the study, or the date of receipt of the last data
    point from the last subject that is required for primary, secondary,
    and/or exploratory analysis as pre-specified in the protocol whichever
    is the later date
    La conclusione dello studio clinico è definita come la data dell'ultima visita dell'ultimo soggetto che completa lo studio o la data di ricezione dell'ultimo dato dall'ultimo soggetto necessario per un'analisi primaria, secondaria e/o esplorativa, come preliminarmente specificato nel protocollo, a seconda di quale delle due date sia successiva
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 37
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 No
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 67
    F.4.2.2In the whole clinical trial 92
    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)
    For subjects still receiving benefit from study drug at this time per the investigator's judgment, continued treatment will be provided.
    Ai soggetti che a questo punto, a giudizio dello sperimentatore ricevono ancora benefici dal farmaco in studio, sarà assicurata la prosecuzione del trattamento.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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