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    Summary
    EudraCT Number:2017-004176-62
    Sponsor's Protocol Code Number:CLEE011AIT01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-22
    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 number2017-004176-62
    A.3Full title of the trial
    A phase IIIb, open-label, local, multicenter study of the molecular features of postmenopausal women with hormone receptor-positive (HR+) HER2-negative advanced breast cancer on first-line treatment with ribociclib and letrozole (BioItaLEE)
    Studio locale, multicentrico, di fase IIIb, in aperto sulle caratteristiche molecolari di donne in post-menopausa con carcinoma mammario avanzato positivo per il recettore ormonale (HR+) HER2-negativo, in trattamento di prima linea con ribociclib e letrozolo (BioItaLEE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the molecular features of postmenopausal women with hormone receptor-positive (HR+) HER2 negative advanced breast cancer on first-line treatment with ribociclib and letrozole
    Studio sulle caratteristiche molecolari di donne in post menopausa con carcinoma mammario avanzato positivo per il recettore ormonale (HR+) HER2 negativo, in trattamento di prima linea con ribociclib e letrozolo
    A.3.2Name or abbreviated title of the trial where available
    BioItaLEE
    BioItaLEE
    A.4.1Sponsor's protocol code numberCLEE011AIT01
    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 FARMA S.P.A.
    B.1.3.4CountryItaly
    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 FARMA S.P.A.
    B.4.2CountryItaly
    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
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number0296541
    B.5.5Fax number029659066
    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 Yes
    D.2.1.1.1Trade name Kisqali
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.9.3Other descriptive nameLEE011
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name FEMARA - 30 COMPRESSE 2.5 MG
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    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.3.4Pharmaceutical 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 INNLETROZOLO
    D.3.9.1CAS number 112809-51-5
    D.3.9.2Current sponsor code-
    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
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hormone receptor-positive (HR+) HER2-negative advanced breast cancer
    Carcinoma mammario avanzato positivo per il recettore ormonale (HR+) HER2-negativo
    E.1.1.1Medical condition in easily understood language
    Hormone receptor-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 21.1
    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 identify ctDNA alterations, how they evolve, and evaluate their possible association with clinical outcome.
    Identificare le alterazioni del DNA tumorale circolante (Circulating Tumor DNA - ctDNA), studiare come si evolvono e valutare la loro possibile associazione con l'esito clinico.
    E.2.2Secondary objectives of the trial
    - To identify ctDNA alterations, how they evolve, and evaluate their possible association with clinical outcome.
    - To evaluate serum thymidine kinase 1 activity over time as blood marker of proliferation and its association with clinical outcome.
    - To identify patterns and evolution of ctDNA alterations associated specifically to "long responders" and to patients with early progression (i.e. progressed at first imaging evaluation).
    - To assess mutational and gene-expression aberrations across different patient profiles.
    - To evaluate mutational burden at baseline, its changes over time, and its correlation with outcome.
    - To evaluate correlations between blood and tissue samples.
    - To evaluate tumor microenvironment before and after treatment.
    - To evaluate the safety and tolerability of ribociclib + letrozole in postmenopausal women with HR+, HER2- advanced breast cancer on first-line treatment.
    - To assess the clinical efficacy of ribociclib + letrozole.
    - Valutare l'attività della timidina chinasi 1 sierica nel tempo come marcatore ematico della proliferazione e la sua associazione con l'esito clinico.
    - Identificare i pattern e l'evoluzione delle alterazioni di ctDNA associate in modo specifico ai "responder a lungo termine" e ai pazienti con progressione precoce (ovvero, pazienti che presentano progressione alla prima valutazione di diagnostica per immagini).
    - Valutare le aberrazioni mutazionali e dell'espressione genica in diversi profili di pazienti.
    - Valutare il carico mutazionale al basale, le sue variazioni nel tempo sul ctDNA e la sua correlazione con gli esiti.
    - Valutare le correlazioni tra i tessuti ematici e tissutali.
    - Valutare il microambiente tumorale prima e dopo il trattamento.
    - Valutare la sicurezza e la tollerabilità di ribociclib + letrozolo in donne in post-menopausa con carcinoma mammario avanzato HR+, HER2- in trattamento di prima linea.
    - Valutare l'efficacia clinica di ribociclib + letrozolo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient is a female = 18 years old at the time of informed consent and has signed informed consent before any trial related activities.
    2. Patient has an advanced (locoregionally recurrent not amenable to surgery or metastatic) breast cancer in first-line treatment (treatment naïve for the advanced setting).
    3. Patient is in post-menopause, defined by one of the following:
    - Prior bilateral oophorectomy
    - Age =60
    - 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
    4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogenreceptor
    positive and/or progesterone receptor positive breast cancer by local laboratory.
    5. Patient has an 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 must have either:
    - Measurable disease i.e. at least one target lesion as per RECIST 1.1 criteria
    • OR
    - If no measurable disease is present, then at least one not target lesion as per RECIST 1.1 criteria must be present.
    7. Patient is willing to undergo blood and tumor sample collection for the biological assessments/objectives as scheduled in the protocol.
    Note: patient must have a baseline tumor sample. It is recommended to provide a newly obtained tissue biopsy or an archival tumor tissue derived by a recent biopsy of the locoregionally recurrent or metastatic disease (bone biopsies are acceptable). In cases this is not clinically feasible, the submission of an archival tumor tissue of the primary tumor is acceptable.
    8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status = 2.
    9. Patient has an adequate bone marrow and organ function as defined by ALL 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), magnesium, and phosphorus 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 × Upper Limit of Norma (ULN).
    If the patient has liver metastases, ALT and AST should be < 5 × ULN.
    - Total serum bilirubin < ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin is = 3.0 × ULN or direct bilirubin = 1.5 x ULN.
    10. Patients 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
    11. Patient must be able swallow ribociclib and letrozole capsules/tablets.
    12. Patients must be able to communicate with the investigator and comply with the requirements of the study procedures.
    1. Pazienti donne che hanno firmato il consenso informato prima dell’effettuazione di qualsiasi procedura correlata allo studio.
    2. Pazienti con carcinoma mammario avanzato (con recidiva locoregionale non operabile o metastatico) in trattamento di prima linea (naïve al trattamento per la malattia avanzata).
    3. Pazienti in fase di post-menopausa, definite da uno dei seguenti:
    • Ooforectomia bilaterale pregressa
    • Età = 60 anni
    • Età < 60 anni e amenorrea per 12 mesi o più (in assenza di chemioterapia, tamoxifene, toremifene o soppressione ovarica) e FSH ed estradiolo nel range post-menopausa in base al range di normalità locale
    4. Pazienti con diagnosi confermata istologicamente e/o citologicamente dal laboratorio locale di carcinoma mammario positivo per il recettore degli estrogeni e/o positivo per il recettore del progesterone.
    5. Pazienti con carcinoma mammario HER2- definito come test di ibridizzazione negativo in situ o status IHC di 0, 1+ o 2+. Se l’ICH è 2+, è richiesto un test di ibridizzazione (FISH, CISH o SISH) in situ negativo tramite test di laboratorio locale.
    6. Pazienti devono avere o malattia misurabile, per esempio almeno una lesione target per i criteri RECIST 1.1 o, se è presente malattia non misurabile, almeno una lesione non target in accordo ai criteri RECIST 1.1.
    7. Pazienti disposte a sottoporsi al prelievo di campioni di sangue e di tumore per le valutazioni/obiettivi biologici come pianificato nel protocollo.
    Nota: le pazienti devono avere un campione tumorale al basale. E’ raccomandato fornire una nuova biopsia tissutale o un tessuto d’archivio derivante da una biopsia recente della recidiva locoregionale o della malattia metastatica (biopsie ossee accattate). In caso dove ciò non fosse possibile, è accettabile del tessuto di archivio derivante dal tumore primitivo.
    8. Pazienti con Eastern Cooperative Oncology Group (ECOG) performance status = 2.
    9. Pazienti con adeguata funzionalità del midollo osseo e degli organi come definito da TUTTI i seguenti valori di laboratorio (valutati dal laboratorio locale):
    • Conta assoluta dei neutrofili = 1.5 × 109/L
    • Piastrine = 100 × 109/L
    • Emoglobina = 9.0 g/dL
    • Potassio, sodio, calcio (corretto per albumina sierica), magnesio e fosforo nei limiti di normalità o corretti entro i limiti di normalità con integratori prima della prima somministrazione del trattamento in studio.
    • INR = 1.5
    • Creatinina sierica <1.5 mg/dl o clearance della creatinine > 50 mL/min.
    • In assenza di metastasi epatica, aminotransferasi alanina (ALT) e aspartato aminotransferasi (AST) devono essere inferiori a 2.5 x limite superiore di normalità (Upper Normal Limit – ULN). Se la paziente presenta metastasi epatiche, ALT e AST devono essere < 5 x ULN.
    • Bilirubina sierica totale < ULN ad eccezione di pazienti con sindrome di Gilbert, che possono essere incluse solo se la bilirubina totale è = 3.0 x ULN o la bilirubina diretta è = 1.5 x ULN.
    10. Pazienti con ECG a 12 derivazione con i seguenti parametri allo screening:
    • Intervallo QTcF allo screening < 450 msec (utilizzando la correzione di Fridericia)
    • Frequenza cardiaca a riposo = 50 bpm
    11. Pazienti in grado di deglutire le capsule/compresse di ribociclib e letrozolo.
    12. 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 prior treatment with any CDK4/6 inhibitor.
    3. Patient who received any prior systemic hormonal therapy or chemotherapy for
    advanced breast cancer.
    Note:
    - Patients who received (neo)adjuvant therapy for breast cancer are eligible. If the prior (neo)adjuvant therapy 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.
    4. Patient is currently using other anti-cancer therapy.
    5. Patient has had major surgery within 14 days prior to starting study drug or absence of recovery 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 extended-field radiotherapy = 4 weeks or limited field radiotherapy for palliation = 2 weeks prior to start of treatment, or lack of recovery to grade 1 or better from related side effects of such therapy (except for alopecia or other
    toxicities not considered a safety risk for the patient at investigator’s discretion).
    Patients for whom =25% (Ellis RE 1961) (see Appendix14.2) of the bone marrow has been previously irradiated are also excluded.
    8. Patient has concurrent malignancy or malignancy within 3 years prior to starting study drug, except for adequately treated, basal or squamous cell carcinoma, nonmelanomatous skin cancer or curatively resected cervical cancer.
    9. Patient with central nervous system (CNS) metastases unless ALL the following criteria are met:
    - At least 4 weeks from prior therapy for CNS disease completion (including radiation and/or surgery) to start of the study treatment.
    - Clinically stable CNS lesions at the time of 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 (uncontrolled 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.).
    For further exclusion criteria please refer to the protocol.
    1. Pazienti con ipersensibilità nota ad uno qualsiasi degli eccipienti di ribociclib o letrozolo.
    2. Pazienti che hanno ricevuto un trattamento pregresso con qualsiasi inibitore di CDK4/6.
    3. Pazienti che hanno ricevuto qualsiasi terapia ormonale sistemica o chemioterapia pregressa per carcinoma mammario avanzato.
    Nota:
    • Le pazienti che hanno ricevuto terapia (neo)adiuvante per carcinoma mammario sono eleggibili. Se la pregressa terapia (neo)adiuvante comprendeva letrozolo o anastrozolo, l’intervallo libero da malattia deve essere superiore ai 12 mesi dal completamento del trattamento fino all’ingresso in studio.
    • Le pazienti che hanno ricevuto un trattamento = 28 giorni con letrozolo o anastrozolo per la malattia avanzata prima dell’inclusione nel presente studio sono eleggibili.
    4. Pazienti in trattamento concomitante con altra terapia anti-tumorale.
    5. Pazienti sottoposte a intervento chirurgico maggiore nei 14 giorni precedenti l’inizio del trattamento in studio o assenza di risoluzione di effetti collaterali maggiori.
    6. Pazienti per cui tutti gli effetti tossici acuti della pregressa terapia anti-tumorale non si sono risolti a Grado = 1 secondo i criteri NCI CTCAE versione 4.03 (ad eccezione di alopecia o altre tossicità non considerate un rischio di sicurezza per la paziente a discrezione dello sperimentatore).
    7. Pazienti che hanno ricevuto radioterapia a campo esteso = 4 settimane o radioterapia a campo limitato a scopo palliativo = 2 settimane prima dell’inizio del trattamento, o assenza di risoluzione a Grado 1 o meglio degli effetti collaterali di tale terapia (ad eccezione di alopecia o altre tossicità non considerate un rischio di sicurezza per la paziente a discrezione dello sperimentatore). Sono inoltre escluse le pazienti cui = 25% del midollo osseo è stato precedentemente irradiato.
    8. Pazienti con patologia maligna concomitante o con patologia maligna nei 3 anni precedenti l’inizio del trattamento in studio, ad eccezione di carcinoma cutaneo basocellulare o a cellule squamose, non melanomatoso adeguatamente trattato o carcinoma cervicale resecato a scopo curativo.
    9. Pazienti con metastasi a carico del sistema nervoso centrale (Central Nervous System – CNS) a meno che non siano soddisfatti TUTTI i seguenti criteri:
    • Sono trascorse almeno 4 settimane tra il completamento della terapia pregressa per la malattia del CNS (comprese radiazioni e/o intervento chirurgico) e l’inizio del trattamento in studio.
    • Lesioni del CNS clinicamente stabili al momento dell’inizio del trattamento e paziente non sottoposta a trattamento con steroidi e/o farmaci anti-epilettici induttori enzimatici per la gestione delle metastasi cerebrali da almeno 2 settimane.
    10. Pazienti con deterioramento della funzionalità gastrointestinale o malattia gastrointestinale che potrebbe alterare in modo significativo l’assorbimento dei farmaci in studio (malattie ulcerative non controllate, 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 con qualsiasi altra condizione medica concomitante severa e/o non controllata che, a giudizio dello sperimentatore, potrebbe determinare rischi di sicurezza inaccettabili, costituire una controindicazione per la partecipazione della paziente allo studio clinico o compromettere l’aderenza al protocollo (ad es. pancreatite cronica, epatite cronica attiva, infezioni micotiche, batteriche o virali attive non trattate o non controllate, ecc.).
    Per ulteriori criteri si prega di fare riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    The proportions of patients with ctDNA alterations (i.e. such as but not limited to RB1, ESR1, CCND1, CDKN2A, PIK3CA, TP53 and PTEN) will be provided over time to characterize the biological evolution of the disease in each patient. The association of these alterations with clinical outcomes will be also provided. In particular, the alterations will be analyzed at scheduled sample collections to define potential patterns of response, and at progression of disease to define potential mechanisms of resistance to CDK4/6 inhibitors.
    Saranno fornite le proporzioni di pazienti con alterazioni di ctDNA (quali, a titolo esemplificativo ma non esaustivo, RB1, ESR1, CCND1, CDKN2A, PIK3CA, TP53 and PTEN) nel tempo, per caratterizzare l’evoluzione biologica della malattia in ciascuna paziente. Sarà inoltre fornita l’associazione di tali alterazioni con gli esiti clinici. In particolare, le alterazioni saranno analizzate ai prelievi programmati per definire potenziali pattern di risposta, e alla progressione di malattia per definire potenziali meccanismi di resistenza agli inibitori di CDK4/6.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At scheduled sample collections and at disease progression.
    Ai prelievi programmati e alla progressione della malattia.
    E.5.2Secondary end point(s)
    Descriptive statistics of serum TK1 concentrations will be provided over time (i.e. as both absolute value and change from baseline value). The association of serum TK1 concentrations with clinical outcomes will also be provided.; The proportions of patients with ctDNA alterations (i.e. such as but not limited to RB1, ESR1, CCND1, CDKN2A, PIK3CA, TP53 and PTEN) will be provided over time, according to the scheduled sample collections, in the subsets of long responder patients (i.e Time to Progression > 25 months) and those with early progression (i.e. patients progressed at first imaging evaluation).; Descriptive statistics of tumor mutational burden (TMB), defined as a quantitative measure of the total number of ctDNA mutations per coding area of tumor genome, will be provided over time (i.e. as both absolute value and change from baseline value), according to the scheduled sample collections. The association of TMB values with clinical outcomes will also be provided.; The proportions of patients with mutations as assessed at baseline by means of ctDNA sample and tissue biopsy will be provided and compared between the following patient profiles defined according to disease history (i.e. newly diagnosed vs. recurrent disease).; The proportions of patients with alterations detected at baseline and at disease progression will be compared between the two different procedures of detection (i.e. detection through liquid biopsy vs. tissue biopsy).; Descriptive statistics of tumor microenvironment parameters on tumor biopsy will be provided at baseline and upon disease progression. The association of these tumor micro-environment
    parameters with clinical outcomes will also be provided.; Descriptive statistics of Time-to-Progression (TTP), defined as time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer, will be provided.; Descriptive statistics of Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) as defined by RECIST 1.1 for patients with measurable disease will be also provided.
    Saranno fornite statistiche descrittive delle concentrazioni di TK1 sierica nel tempo (ovvero sia come valore assoluto che come variazione rispetto al basale). Sar¿ inoltre fornita l¿associazione delle concentrazioni di TK1 sierica con gli esiti clinici.; Saranno fornite le proporzioni di pazienti con alterazioni di ctDNA (ovvero, a titolo esemplificativo ma non esaustivo, RB1, ESR1, CCND1, CDKN2A, PIK3CA, TP53 and PTEN) nel tempo, secondo i prelievi pianificati, nel sottogruppo di pazienti rispondenti a lungo termine (Tempo alla Progressione > 25 mesi) e in quelli con progressione precoce (ovvero pazienti con progressione di malattia alla prima valutazione di diagnostica per immagini).; Saranno fornite statistiche descrittive del carico mutazionale del tumore (Tumor Mutational Burden - TMB), definito come una misura quantitativa del numero totale di mutazioni di ctDNA per area di codifica del genoma tumorale, nel tempo (ovvero sia come valore assoluto che come variazione rispetto al basale), in base ai prelievi programmati. Sar¿ inoltre fornita l¿associazione dei valori di TMB con gli esiti clinici.; Le proporzioni di pazienti con mutazioni valutate al basale tramite il campione di ctDNA e la biopsia tissutale saranno fornite e confrontate tra i seguenti profili di pazienti definiti in base alla storia di malattia (ovvero nuova diagnosi vs. malattia ricorrente).; Le proporzioni di pazienti con alterazioni rilevate al basale e alla progressione di malattia saranno confrontate tra due diverse procedure di rilevazione (ovvero rilevazione tramite biopsia liquida vs. biopsia tissutale).; Statistiche descrittive dei parametri del microambiente tumorale alla biopsia tumorale saranno forniti al basale e alla progressione di malattia. Sar¿ inoltre fornita l¿associazione di tali parametri del microambiente tumorale con gli esiti clinici.; Saranno fornite statistiche descrittive del Tempo alla Progressione (Time-to-Progression - TTP), definite come il tempo dalla data di inizio del trattamento alla data dell¿evento definito come la prima progressione documentata o decesso dovuto al carcinoma.; Saranno inoltre fornite le statistiche descrittive di ORR e CBR definiti in base ai criteri RECIST 1.1 per le pazienti con malattia misurabile.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Over time (i.e. as both absolute value and change from baseline value).; At scheduled sample collections.; Over time (i.e. as both absolute value and change from baseline value), according to the scheduled sample collections.; At baseline.; At baseline and at disease progression.; At baseline and upon disease progression.; From date of start of treatment to the date of the first documented progression or death due to underlying cancer, will be provided.; During the study.
    Nel tempo (ovvero sia come valore assoluto che come variazione rispetto al basale).; Ai prelievi programmati.; Nel tempo (ovvero sia come valore assoluto che come variazione rispetto al basale), in base ai prelievi programmati..; Al basale.; Al basale e alla progressione di malattia.; Al basale e alla progressione di malattia.; Dalla data di inizio del trattamento alla data della prima progressione documentata o decesso dovuto al carcinoma.; Nel corso dello studio.
    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 Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 concerned46
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study will be declared after all patients have discontinued all components of the study.
    La fine dello studio verrà dichiarata quando tutte le pazienti avranno discontinuato tutte le componenti dello studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    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: 165
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 135
    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 No
    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 state300
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 300
    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)
    None
    Nessuno
    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 Decision2018-01-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-22
    P. End of Trial
    P.End of Trial StatusOngoing
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