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    Summary
    EudraCT Number:2016-003467-19
    Sponsor's Protocol Code Number:CLEE011A2404
    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:2017-01-25
    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 number2016-003467-19
    A.3Full title of the trial
    COMPLEEMENT-1: An open-label, multicenter, Phase IIIb study to assess the safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with hormone receptorpositive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    COMPLEEMENT-1: studio di fase IIIb, multicentrico, in aperto per valutare la sicurezza e l’efficacia di ribociclib (LEE011) in combinazione con letrozolo per il trattamento di uomini e donne in pre/post-menopausa con carcinoma mammario in stadio avanzato positivo per i recettori ormonali, HER2 negativo, non sottoposti a terapia ormonale precedente per la malattia in stadio avanzato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    Studio per valutare la sicurezza e l’efficacia di ribociclib (LEE011) in
    combinazione con letrozolo per il trattamento di uomini e donne in fase di pre/post-menopausa con carcinoma mammario avanzato positivo al recettore ormonale HER2-negativo in una popolazione più ampia
    A.3.2Name or abbreviated title of the trial where available
    COMPLEEMENT-1
    A.4.1Sponsor's protocol code numberCLEE011A2404
    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 SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farma S.p.A.
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityOriggio (VA)
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number00390296541
    B.5.5Fax number003902965066
    B.5.6E-mailinfo.studiclinici@novartis.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 nameribociclib
    D.3.2Product code LEE011
    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 INNRIBOCICLIB
    D.3.9.1CAS number 1374639-75-4
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB180246
    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 Yes
    D.2.1.1.1Trade name letrozole
    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 nameletrozole
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLETROZOLE
    D.3.9.1CAS number 112809-51-5
    D.3.9.4EV Substance CodeSUB08444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 Yes
    D.2.1.1.1Trade name goserelin
    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 nameZoladex
    D.3.4Pharmaceutical form Implant
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPImplantation
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGOSERELIN
    D.3.9.1CAS number 65807-02-5
    D.3.9.3Other descriptive namegoserelin acetate
    D.3.9.4EV Substance CodeSUB07962MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.6
    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
    hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    carcinoma mammario in stadio avanzato positivo per i recettori ormonali, HER2 negativo, non sottoposti a terapia ormonale precedente per la malattia in stadio avanzato
    E.1.1.1Medical condition in easily understood language
    Hormone positive HER2 negative advanced Breast Cancer
    carcinoma mammario in stadio avanzato positivo per i recettori ormonali, HER2 negativo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    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 safety and tolerability of ribociclib with letrozole in men and pre/postmenopausal women with HR+, HER2- aBC who received no prior hormonal therapy for advanced disease
    Valutare la sicurezza e la tollerabilità di ribociclib con letrozolo in uomini e donne in pre/post-menopausa con aBC HR+, HER2-, che non hanno ricevuto alcuna terapia ormonale pregressa per malattia in stadio avanzato
    E.2.2Secondary objectives of the trial
    • To assess the clinical efficacy of ribociclib + letrozole measured by Time-to-Progression (TTP) and tumor response by overall response rate (ORR) and clinical benefit rate (CBR).
    • To evaluate long-term safety of ribociclib + letrozole during Extension Phase
    • To evaluate clinical benefit of ribociclib + letrozole as assessed by investigator during Extension Phase
    Valutare l’efficacia clinica di ribociclib + letrozolo misurata tramite il tempo alla progressione (Time-to-Progression - TTP) e la risposta tumorale tramite il tasso di risposta globale (Overall Response Rate - ORR) e il tasso di beneficio clinico (Clinical Benefit Rate - CBR).

    Valutare l’impatto del trattamento sugli esiti riportati dai pazienti (Patient Reported Outcome - PRO) misurati tramite le variazioni dei punteggi del questionario FACT-B (Functional Assessment of Cancer Therapy – Breast).

    Valutare la sicurezza a lungo termine di ribociclib + letrozolo durante la Fase di Estensione.

    Valutare il beneficio clinico di ribociclib + letrozolo in base alla valutazione dello sperimentatore durante la Fase di Estensione.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient is an adult, male or female ≥ 18 years old at the time of informed consent
    NOTE: Sexually active males should use a condom during intercourse while taking drug and for 21 days after stopping medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
    2. Male or female with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
    3. In the case of women, both pre/perimenopausal and postmenopausal patients are allowed to be included in this study; menopausal status is relevant for the requirement of goserelin to be used concomitantly with ribociclib and letrozole..
    a) Postmenopausal status is defined either by:
    ● Prior bilateral oophorectomy OR
    ● Age ≥ 60 OR
    ● Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range. If patient is taking tamoxifen or toremifene and age < 60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range.
    b) Premenopausal status is defined as either:
    i) Patient had last menstrual period within the last 12 months, OR
    ii) If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, OR
    iii) In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.
    c) Perimenopausal status is defined as neither premenopausal nor postmenopausal
    4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
    5. Patient has HER2-negative breast cancer 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.
    6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
    7. Patient has adequate bone marrow and organ function as defined by ALL of the following laboratory values (as assessed by local laboratory):
    ● Absolute neutrophil count ≥ 1.5 × 109/L
    ● Platelets ≥ 100 × 109/L
    ● Hemoglobin ≥ 9.0 g/dL
    ● Potassium, sodium, calcium corrected for serum albumin and magnesium within normal limits or corrected to within normal limits with supplements before first dose of the study medication
    ● INR ≤ 1.5
    ● Serum creatinine < 1.5 mg/dl or creatinine clearance ≥ 50 mL/min
    ● In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 × ULN. If the patient has liver metastases, ALT and AST should be < 5 × ULN.
    ● Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with well-documented Gilbert’s Syndrome
    8. Patient must have a 12-lead ECG with ALL of the following parameters at screening:
    ● QTcF interval at screening < 450 msec (using Fridericia’s correction)
    ● Resting heart rate ≥ 50 bpm
    9. Patient must be able to swallow ribociclib and letrozole tablets
    10. Patient has signed informed consent obtained before any trial-related activities and according to local guidelines
    11. Patients must be able to communicate with the investigator and comply with the requirements of the study procedures
    E.3 Criteri di inclusione principali(elencare i più importanti):
    1. Pazienti adulti, di sesso maschile o femminile e di età ≥ 18 al momento della firma del consenso informato. Nota: i pazienti di sesso maschile sessualmente attivi devono
    utilizzare il preservativo durante i rapporti sessuali mentre assumono il farmaco in studio e per 21 giorni dopo l’interruzione del trattamento, e non devono concepire un figlio durante questo periodo. Si richiede l’utilizzo del preservativo anche per gli uomini
    sottoposti a vasectomia, al fine di evitare il passaggio del farmaco tramite il liquido seminale.
    2. Uomini o donne con carcinoma mammario in stadio avanzato (in recidiva locoregionale o metastatico) non candidabile alla terapia curativa.
    3. Per le donne, sia le pazienti in pre/perimenopausa e in postmenopausa potranno essere incluse in questo studio; lo stato di menopausa è rilevante per il requisito di utilizzare goserelina in modo concomitante a ribociclib e letrozolo.
    a. La post-menopausa viene definita da uno dei seguenti criteri:
    · Ovariectomia bilaterale precedente
    OPPURE
    · Età > 60 anni
    OPPURE
    Età < 60 anni e amenorrea da > 12 mesi (in assenza di chemioterapia, tamoxifene, toremifene o soppressione ovarica) e livelli di FSH ed estradiolo nel range di post menopausa per il laboratorio locale. Se la paziente assume tamoxifene o toremifene ed ha un’età <60 anni, i livelli di FSH ed estradiolo plasmatico devono essere nel range di
    post-menopausa in base ai range di normalità locali. Nota: per le donne con amenorrea indotta da terapia, sono necessarie diverse misurazioni di FSH e/o estradiolo per assicurare lo stato di menopausa.
    b. Lo stato di pre-menopausa è definito come:
    · La paziente ha avuto l’ultimo ciclo mestruale nei 12 mesi precedenti
    OPPURE
    · Se in terapia con tamoxifene o toremifene negli ultimi 14 giorni, range di pre-menopausa in base ai range di normalità locali
    OPPURE
    · In caso di amenorrea indotta da terapia, i livelli plasmatici di estradiolo e di FSH devono essere nel range di pre-menopausa in base ai range di normalità locali.
    c. Lo stato di perimenopausa è definita come né premenopausa né
    postmenopausa Nota: in tutto il documento, lo stato di perimenopausa e premenopausa saranno raggruppati e indicati come “Pre-menopausa”.
    4. Pazienti con una diagnosi istologica e/o citologica confermata di carcinoma mammario positivo per il recettore dell’estrogeno e/o positivo per il recettore del progesterone, stabilita dal laboratorio locale.
    5. Pazienti con carcinoma mammario HER2 negativo definito dalla negatività del test di ibridizzazione in situ o da uno status IHC di 0, 1+ o 2+. Se IHC fosse 2+ è necessario un test di ibridizzazione in situ negativo (FISH, CISH o SISH) mediante valutazione del
    laboratorio locale.
    6. Eastern Cooperative Oncology Group (ECOG) performance status di ≤ 2.
    7. Pazienti con funzionalità midollare e d’organo adeguata, definita dai seguenti valori di laboratorio (valutazione del laboratorio locale):
    · Conta neutrofilica assoluta ≥ 1.5 x 109/L
    · Piastrine ≥ 100 x 109/L
    · Emoglobina ≥ 9.0 g/dl
    · Potassio, sodio, calcio (corretto per l’albumina sierica), e magnesio entro i limiti della norma o corretti entro i limiti della norma con integratori prima della prima somministrazione di trattamento in studio.
    · INR ≤1.5.
    · Creatinina sierica <1.5 mg/dl o clearance della creatinina ≥50 mL/min.
    · In assenza di metastasi epatiche, le alanino-aminotrasferasi (ALT) e le aspartato aminotrasferasi (AST) devono essere inferiori a 2.5 x ULN. Se il paziente presenta metastasi epatiche i valori di AST e ALT devono essere < 5 x ULN.

    - Bilirubina sierica totale < ULN; o bilirubina totale ≤ 3.0 x ULN con bilirubina diretta entro i limiti della norma in pazienti con sindrome di Gilbert ben documentata.
    8. Pazienti che presentano TUTTI i seguenti parametri all’ECG a 12 derivazioni allo screening:
    · Intervallo QTcF allo screening <450 msec (utilizzando la
    correzione di Fridericia)
    · Frequenza cardiaca a riposo ≥ 50 bpm.
    9. Pazienti in grado di deglutire le compresse di ribociclib e letrozolo.
    10. Pazienti che hanno firmato il modulo di consenso informato prima dell’effettuazione di qualsiasi attività correlata allo studio in base alle linee guida locali.
    11. Pazienti in grado di comunicare con lo Sperimentatore e di aderire ai requisiti delle procedure di studio.
    E.4Principal exclusion criteria
    1. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole
    2. Patient who received any CDK4/6 inhibitor
    3.Patient who received any prior systemic hormonal therapy for advanced breast cancer; no more than one prior regimen of chemotherapy for the treatment of metastatic disease is permitted
    Note:
    ● Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior neo (adjuvant) included letrozole or anastrozole the disease free interval must be greater than 12 months from the completion of treatment until study entry.
    ● Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial are eligible.
    ● Any prior (neo) adjuvant anti-cancer therapy or prior chemotherapy for metastatic disease must be stopped at least 5 half-lives or 7 days, whichever is longer, before study inclusion.
    4. Patient is concurrently using other anti-cancer therapy.
    5. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
    6. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 4.03 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
    7. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to start of treatment, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) and/or from whom ≥ 25% (Ellis R E 1961) of the bone marrow was irradiated.
    8. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
    9. Patient with central nervous system (CNS) metastases unless they meet ALL of the following criteria:
    ● At least 4 weeks from prior therapy for CNS disease completion (including radiation and/or surgery) to starting the study treatment.
    ● Clinically stable CNS lesions at the time of study treatment initiation and not receiving steroids and/or enzyme-inducing anti-epileptic medications for the management of brain metastases for at least 2 weeks.
    10. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
    11. Patient has a known history of HIV infection (testing not mandatory)
    12. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol: (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
    13. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:
    ● History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening
    ● History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    ● Documented cardiomyopathy
    ● Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
    ● Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome,
    ● Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening
    14. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug:
    ● Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
    ● That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
    ● Herbal preparations/medications, dietary supplements
    15. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
    16. Participation in prior investigational study within 30 d prior to enrollment or within 5-half-lives of the investigational product, whichever is longer
    17. Pregnant or nursing (lactating) women
    1. Pazienti con ipersensibilità nota ad uno qualsiasi degli eccipienti di
    ribociclib o letrozolo.
    2. Pazienti sottoposti a precedente terapia con inibitori CDK4/6.
    3. Pazienti precedentemente sottoposti a qualsiasi terapia ormonale sistemica per il carcinoma mammario avanzato; non è consentito più di un precedente regime chemioterapico per il trattamento della malattia metastatica.
    Nota:
    · Sono eleggibili i pazienti che hanno ricevuto terapia (neo) adiuvante per il carcinoma mammario. Se la terapia (neo) adiuvante pregressa comprendeva letrozolo o anastrozolo, l’intervallo libero da malattia deve essere superiore a 12 mesi dal completamento del trattamento fino all’ingresso in studio.
    · Sono eleggibili i pazienti che hanno ricevuto letrozolo o anastrozolo per ≤ 28 giorni per la malattia in stadio avanzato prima dell’inclusione nello studio.
    · Qualsiasi terapia anti-tumorale (neo) adiuvante pregressa o precedente terapia per la malattia metastatica deve essere interrotta almeno 5 emivite o 7 giorni, a seconda di quale periodo sia più lungo, prima dell’ingresso nello studio.
    4. Pazienti in trattamento concomitante con altre terapie anti-tumorali.
    5. Pazienti sottoposti ad intervento chirurgico maggiore nei 14 giorni precedenti l’inizio del trattamento in studio o con effetti collaterali maggiori non ancora risolti.
    6. Pazienti che non sono ancora giunti a risoluzione a Grado ≤1di tutti gli effetti tossici acuti della precedente terapia anti-tumorale in base ai criteri NCI CTCAE versione 4.03 (ad eccezione dell’alopecia o di altre tossicità che non si ritiene costituiscano un rischio di sicurezza per il paziente, a discrezione dello sperimentatore).
    7. Pazienti sottoposti a radioterapia ≤ 4 settimane o a radiazioni a campo limitato a scopo palliativo ≤ 2 settimane prima della randomizzazione, e che non presentano risoluzione a grado 1 o meglio degli effetti collaterali correlati a tale terapia (ad eccezione dell’alopecia) e/o cui è stato irradiato ≥ 25% (Ellis R E 1961) del midollo osseo (fare riferimento all’Appendice 4 del protocollo).
    8. Pazienti con una neoplasia concomitante o una neoplasia entro 3 anni dall’inizio del trattamento in studio, ad eccezione di: carcinoma cutaneo a cellule basali o a cellule squamose adeguatamente trattati, carcinoma cutaneo non melanomatoso o carcinoma della cervice sottoposto a trattamento chirurgico curativo.
    9. Pazienti con metastasi a livello del sistema nervoso centrale (Central Nervous System - CNS) a meno che non soddisfino TUTTI i seguenti criteri:
    · Almeno 4 settimane dal completamento della precedente terapia per la malattia del sistema nervoso centrale (comprese radiazioni e/o intervento chirurgico) all’inizio del trattamento in studio.
    · Lesioni del CNS clinicamente stabili al momento dell’inizio del trattamento e pazienti non in trattamento con steroidi e/o farmaci anti-epilettici induttori enzimatici per la gestione delle metastasi cerebrali per almeno 2 settimane.
    10. Pazienti con funzionalità gastrointestinale deteriorata o patologia gastrointestinale che può alterare in modo significativo l’assorbimento dei farmaci in studio (ad es. malattie ulcerative, nausea non controllata, vomito, diarrea, sindrome da malassorbimento, o resezione dell’intestino tenue).
    11. Pazienti con anamnesi nota di infezione da HIV (test non obbligatorio).
    12. Pazienti affetti da qualsiasi altra condizione medica concomitante severa e/o non controllata che, a giudizio dello sperimentatore, porterebbe a rischi di sicurezza non accettabili, renderebbe controindicata la partecipazione del paziente allo studio clinico o
    comprometterebbe l’aderenza al protocollo (ad es. pancreatite cronica, epatite cronica attiva, infezioni micotiche, batteriche o virali non trattate o non controllate, ecc.).
    E.5 End points
    E.5.1Primary end point(s)
    AEs, Grade 3/4 AEs & SAEs during treatment with ribociclib + letrozole
    Valutazione degli AEs, AEs Grado 3/4 e SAEs nel corso del trattamento con ribociclib + letrozolo
    E.5.1.1Timepoint(s) of evaluation of this end point
    refer to section 10.4. of the protocol
    fare riferimento alla sezione 10.4. del protocollo
    E.5.2Secondary end point(s)
    • Time-to-Progression (TTP) (RECIST 1.1), based on investigators’ assessment
    • Overall response rate (ORR) as defined by RECIST 1.1 for patients with measurable disease
    • Clinical Benefit Rate (CBR) as defined by RECIST 1.1 (including patients with CR, PR, SD, NCRNPD >24 weeks)
    • Patient Reported Outcome (PRO) using FACT-B questionnaire
    • Frequency and severity of AEs & SAEs during Extension Phase
    • Proportion of patients with clinical benefit as assessed by investigator during Extension Phase
    - tempo alla progressione (TTP) definito come il tempo dalla data di inizio del trattamento alla data dell’evento definito come la prima progressione documentata o del decesso dovuto al carcinoma di base (Guida RECIST Novartis v 3.2).
    - ORR calcolato in base alla valutazione degli sperimentatori (secondo i criteri
    RECIST 1.1).
    - CBR calcolato in base alla valutazione degli sperimentatori (secondo i criteri
    RECIST 1.1).
    - esiti riportati dai pazienti (Patient Reported Outcome – PRO) mediante utilizzo di questionario FACT-B
    - frequenza e severità di AEs e SAEs nella fase di estensione
    - beneficio clinico di ribociclib + letrozolo in base alla valutazione dello sperimentatore durante la Fase di Estensione
    E.5.2.1Timepoint(s) of evaluation of this end point
    refer to section 10.5.1 of the protocol
    fare riferimento alla sezione 10.5.1 del protocollo
    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 Yes
    E.6.13.1Other scope of the trial description
    Patient Reported Outcome (PRO)
    Patient Reported Outcome (PRO)
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned95
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA300
    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
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    Colombia
    Costa Rica
    Czech Republic
    Denmark
    Egypt
    Finland
    France
    Greece
    Hong Kong
    Hungary
    India
    Israel
    Italy
    Jordan
    Lebanon
    Malaysia
    Mexico
    Netherlands
    Norway
    Oman
    Panama
    Philippines
    Poland
    Portugal
    Romania
    Russian Federation
    Saudi Arabia
    Singapore
    Slovakia
    Slovenia
    Spain
    Sweden
    Taiwan
    Thailand
    United Arab Emirates
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Planned overall study duration of the Core Phase will be up to 36 months, from FPFV to 18 months counted after LPFV. At the time of Core Phase end (18 months after LPFV), if patients are still deriving benefit and ribociclib is not approved or available and reimbursed, patients may be transitioned to the extension trial period
    La durata complessiva prevista della fase core dello studio sarà fino a 36 mesi, da FPFV a 18 mesi dopo LPFV. Nella fase core (18 mesi dopo LPFV), se i pazienti traggono ancora beneficio e ribociclib non viene approvato o reso disponibile e rimborsato, i pazienti possono essere passati alla fase di estensione
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 1800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1200
    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 state800
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2000
    F.4.2.2In the whole clinical trial 3000
    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)
    At the time of Core Phase end (18 months after LPFV), if patients are still deriving benefit and ribociclib is not approved or available and reimbursed, patients may be transitioned to the extension trial period and continue to receive the drugs until progression, intolerance, death or physician/patient decision, but only safety and clinical
    benefit as assessed by investigator will be collected during the Extension Phase.
    Al momento della fine della fase core (18 mesi dopo LPFV), se i pazienti traggono ancora benefici e ribociclib non è approvato o disponibile e rimborsato, i pazienti possono essere passati alla fese di estensione e continuare a ricevere i farmaci fino a progressione, intolleranza, morte o decisione del medico / paziente, ma nella fase di estensione vengono raccolti solo i dati per la sicurezza e per il beneficio clinico valutato da parte del medico.
    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 Decision2017-04-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-18
    P. End of Trial
    P.End of Trial StatusOngoing
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