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    Summary
    EudraCT Number:2020-003435-13
    Sponsor's Protocol Code Number:MARLENE
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-06-04
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-003435-13
    A.3Full title of the trial
    Metronomic vinorelbin, cyclophosphamide and capecitabine after progression to cyclin-dependent kinase 4/6 inhibitors for hormone receptors positive HER2 negative metastatic breast cancer
    Chemioterapia MetronomicA con vinorelbina, ciclofosfamide e capecitabina dopo pRogressione con inibitori delle chinasi cicLine dipendenti 4/6 per il tumore della mammella in fase metastatica con recettori ormonali positivi HER2 NEgativo (Studio MARLENE).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Metronomic vinorelbin, cyclophosphamide and capecitabine after progression to cyclin-dependent kinase 4/6 inhibitors for hormone receptors positive HER2 negative metastatic breast cancer
    Chemioterapia MetronomicA con vinorelbina, ciclofosfamide e capecitabina dopo pRogressione con inibitori delle chinasi cicLine dipendenti 4/6 per il tumore della mammella in fase metastatica con recettori ormonali positivi HER2 NEgativo (Studio MARLENE).
    A.3.2Name or abbreviated title of the trial where available
    MARLENE
    MARLENE
    A.4.1Sponsor's protocol code numberMARLENE
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFONDAZIONE POLICLINICO UNIV A.GEMELLI IRCCS
    B.5.2Functional name of contact pointDIREZIONE SCIENTIFICA
    B.5.3 Address:
    B.5.3.1Street AddressLARGO A. GEMELLI 8
    B.5.3.2Town/ cityROMA
    B.5.3.3Post code00135
    B.5.3.4CountryItaly
    B.5.4Telephone number0630155701
    B.5.5Fax number0630155701
    B.5.6E-mailDIREZIONE.SCIENTIFICA@POLICLINICOGEMELLI.IT
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVINORELBINA
    D.3.2Product code [VINORELBINA]
    D.3.4Pharmaceutical form Capsule, soft
    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 INNVINORELBINA
    D.3.9.1CAS number 71486-22-1
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCapecitabina
    D.3.2Product code [Capecitabina]
    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 INNCapecitabina
    D.3.9.1CAS number 154361-50-9
    D.3.9.2Current sponsor codeCapecitabina
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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: 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.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCiclofosfamide
    D.3.2Product code [Ciclofosfamide]
    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 INNCiclofosfamide
    D.3.9.1CAS number 50-18-0
    D.3.9.2Current sponsor codeCiclofosfamide
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    HER2 negative hormone receptors positive metastatic breast cancer progressed after CDK 4/6 inhibitors
    Carcinoma della mammella in fase metastatica con recettori ormonali positivi, HER2 negativo in progressione dopo terapia con inibitori delle chinasi cicline dipendenti 4/6
    E.1.1.1Medical condition in easily understood language
    HER2 negative hormone receptors positive metastatic breast cancer progressed after CDK 4/6 inhibitors
    Carcinoma della mammella in fase metastatica con recettori ormonali positivi, HER2 negativo in progressione dopo terapia con inibitori delle chinasi cicline dipendenti 4/6
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10007310
    E.1.2Term Carcinoma breast stage IV
    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 investigate the efficacy of metronomic chemotherapy with vinorelbine, cyclophosphamide and capecitabine in patients with hormone receptors positive HER2 negative metastatic breast cancer progressed after CDK 4/6 inhibitors in terms of time to progression (TTP)
    Studiare l'efficacia della chemioterapia metronomica con vinorelbina, ciclofosfamide e capecitabina in pazienti con carcinoma mammario metastatico HER2 negativo con recettori ormonali positivi progredito dopo terapia con CDK 4/6i in termini di tempo alla progressione (TTP).
    E.2.2Secondary objectives of the trial
    To investigate the efficacy of metronomic chemotherapy with vinorelbine, cyclophosphamide and capecitabine in patients with hormone receptors positive HER2 negative metastatic breast cancer progressed after CDK 4/6 inhibitors in terms of clinical benefit rate (CBR), overall survival (OS).
    To describe the safety and changes of Health-Related Quality of Life (HRQOL) within the study population
    Studiare la sicurezza e l'efficacia della chemioterapia metronomica con vinorelbina, ciclofosfamide e capecitabina in pazienti con carcinoma mammario metastatico HER2 negativo con recettori ormonali positivi progredito dopo terapia con CDK 4/6i in termini di tasso di beneficio clinico (CBR), sopravvivenza globale (OS).
    Descrivere i cambiamenti della qualità della vita correlata alla salute (HRQOL) all'interno della popolazione in studio.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: BIOMARKERS EEXPLORATORY ANALYSIS
    - To investigate whether metronomic chemotherapy with vinorelbine, cyclophosphamide and capecitabine combination reduces Treg and/or MDSC number and/or suppressive potency;
    - To investigate whether metronomic chemotherapy affects vascular endothelial cells at tumour site;
    - To investigate the relationship between the extent of modulation of these immunosuppressive cells and clinical outcome.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: RICERCA DI BIOMARCATORI
    - Studiare se la chemioterapia metronomica con vinorelbina, ciclofosfamide e capecitabina riduce il numero di linfociti T regolatori (Treg) e / o cellulle soppressorie di derivazione mieloide (MDSC) e / o la potenza soppressiva;
    - Indagare se la chemioterapia metronomica con vinorelbina, ciclofosfamide e capecitabina influisce sulle cellule endoteliali vascolari nel sito del tumore;
    - Studiare la relazione tra l'entità della modulazione di queste cellule immunosoppressive e l'esito clinico. Criteri
    E.3Principal inclusion criteria
    - Male or female subjects with any menopausal status age = 18 years and has signed informed consent before any trial related activities are conducted;
    - Subjects with histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of either locally advanced disease not amenable to resection or radiation therapy with curative intent or metastatic disease not amenable to curative therapy;
    - Subjects must have ER-positive and/or PgR-positive, HER2-negative tumor status confirmed per local laboratory testing on their primary tumor or if available on their most recent biopsy from a metastatic lesion (if metastatic disease), or recurrent disease lesion (if locally advanced).
    - Subjects must have one of the following as defined by RECIST v1.1 prior to start study treatment:
    a. Measurable disease as per RECIST 1.1 criteria.
    b. Non measurable (evaluable) bone-only disease.
    - Subjects must be progressed on/after prior CDK4/6 inhibitor combination therapy with either fulvestrant or an AI and it must be the last therapy before the study entry;
    - Subjects must not be candidates to further endocrine therapies or other combinations;
    - Subjects may have previously received at least one and no more than two lines of endocrine therapy for advanced/metastatic breast cancer and meet the following criteria:
    a. Last endocrine therapy to study entry must be given in combination with CDK4/6i;
    b. Progression on or within eight weeks of ending treatment with each prior line of endocrine therapy (single agent or in combination) must be documented;
    c. For subjects who progress during or within 12 months of adjuvant endocrine therapy, this may count as one line of treatment for advanced/metastatic disease;
    d. In the absence of progression, adjuvant therapy does not count as one of the lines of endocrine therapy;
    e. Endocrine therapy must be discontinued prior to study entry, excluding LH-RH analogue;
    - Subjects may have received no more than one line of chemotherapy in the advanced/metastatic setting;
    - Patients may have received any primary and/or adjuvant therapies. For subjects who progress within 12 months of (neo)adjuvant chemotherapy, this will count as one prior line of therapy for advanced/metastatic disease;
    - Patients may have received metronomic capecitabine, methotrexate and cyclophosphamide or standard dose capecitabine in adjuvant setting at least 12 months before study entry;
    - Previous treatment with capecitabine, cyclophosphamide and vinorelbine not in metronomic schedule for advanced disease is allowed, provided that the patient has progressive disease at study entry and the patients should not be defined as “refractory” to treatments (PR o CR o SD > 6 months);
    - Eastern Cooperative Oncology Group (ECOG) performance status = 2;
    - Life expectancy of at least 12 weeks;
    - Able to to swallow the study drug whole as a tablet
    - Patient has adequate bone marrow and organ function;
    - Confirmed negative serum pregnancy test (ß-hCG) within 72 hours before starting study treatment for patients with pre or peri-menopausal status.
    - Soggetti di sesso maschile o femminile con qualsiasi età in stato di menopausa = 18 anni e che abbiano firmato il consenso informato prima che venga condotta qualsiasi attività correlata allo studio;
    - Soggetti con diagnosi istologicamente o citologicamente accertata di adenocarcinoma della mammella con evidenza di malattia localmente avanzata non suscettibile di resezione o radioterapia con intento curativo o malattia metastatica non suscettibile di terapia curativa;
    - I soggetti devono avere uno stato tumorale ER-positivo e / o PgR-positivo, HER2-negativo confermato da test di laboratorio locali sul loro tumore primario o, se disponibile, sulla loro biopsia più recente da una lesione metastatica (se malattia metastatica) o malattia ricorrente lesione (se localmente avanzata).
    - I soggetti devono avere uno dei seguenti, come definito dai criteri RECIST v1.1 prima di iniziare il trattamento in studio:
    a. Malattia misurabile secondo i criteri RECIST 1.1.
    b. Malattia solo ossea non misurabile (valutabile).
    - I soggetti devono essere in progressione durante / dopo una precedente terapia di combinazione con fulvestrant o un AI ed inibitori CDK4/6, che deve essere l'ultima terapia prima dell'ingresso nello studio;
    - I soggetti non devono essere eleggibili per ulteriori terapie endocrine o altre combinazioni;
    - I soggetti possono aver ricevuto in precedenza almeno una e non più di due linee di terapia endocrina per il carcinoma mammario avanzato / metastatico e soddisfare i seguenti criteri:
    a. L'ultima terapia endocrina per l'ingresso nello studio deve essere stata in combinazione con CDK4/6i;
    b. La progressione durante o entro otto settimane dalla fine del trattamento con ogni precedente linea di terapia endocrina (agente singolo o in combinazione) deve essere documentata;
    c. Per i soggetti che progrediscono durante o entro 12 mesi dalla terapia endocrina adiuvante, questa può essere considerata una linea di trattamento per la malattia avanzata / metastatica;
    d. In assenza di progressione, la terapia adiuvante non conta come una delle linee di terapia endocrina;
    e. La terapia endocrina deve essere interrotta prima dell'ingresso nello studio, escluso l'analogo LH-RH;
    - I soggetti possono aver ricevuto non più di una linea di chemioterapia in linea avanzata / metastatica.
    - I pazienti possono aver ricevuto terapie primarie e / o adiuvanti. Per i soggetti che progrediscono entro 12 mesi dalla chemioterapia (neo) adiuvante, questo conterà come una precedente linea di terapia per la malattia avanzata / metastatica;
    - I pazienti possono aver ricevuto capecitabina metronomica, metotrexato e ciclofosfamide o la dose standard di capecitabina in regime adiuvante almeno 12 mesi prima dell'ingresso nello studio;
    - È consentito un precedente trattamento con capecitabina, ciclofosfamide e vinorelbina non in schedula metronomica per la malattia avanzata, a condizione che il paziente abbia una malattia in progressione all'ingresso nello studio e i pazienti non debbano essere definiti "refrattari" ai trattamenti (PR o CR o SD> 6 mesi);
    - Performance status dell'Eastern Cooperative Oncology Group (ECOG) = 2;
    - Aspettativa di vita di almeno 12 settimane;
    - Il paziente abbia un midollo osseo e una funzione d'organo adeguati;
    - Test di gravidanza sierica negativo confermato (ß-hCG) entro 72 ore prima dell'inizio del trattamento in studio per pazienti con stato pre o peri-menopausale.
    E.4Principal exclusion criteria
    1. Previous metronomic chemotherapy for advanced disease with capecitabine, cyclophosphamide and vinorelbine;
    2. Patients defined as “refractory” to capecitabine, cyclophosphamide and vinorelbine (PD o SD < 6 months);
    3. Presence of symptomatic cerebral or leptomeningeal involvement;
    4. Previous or concomitant other malignancy except basal or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix;
    5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements;
    6. Malabsorption syndrome or disease affecting significantly gastrointestinal function or major resection of the stomach or proximal small bowel that could affect absorption of oral vinorelbine;
    7. Patients with known low or absent dihydropyrimidine dehydrogenase (DPD) activity;
    8. History of severe and unexpected reactions to fluoropyrimidine therapy;
    9. Concurrent treatment with any other anti-cancer therapy except LHRH analogue;
    10. Patients with pre-existing motor or sensory peripheral neuropathy grade 2 according to National Cancer Institute criteria;
    11. Major surgery within 28 days before the first dose of study drug;
    12. Radiation therapy within 14 days (28 days for brain lesions per Exclusion Criterion 3) before the first dose of study drug. Note: tumor lesions previously subjected to radiation therapy or other locoregional therapy will be considered measurable only if disease progression after completion of locoregional therapy is clearly documented;
    13. Any concurrent severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with compliance with study procedures or the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study;
    14. Known hypersensitivity reaction to drugs chemically related to capecitabine, cyclophosphamide and vinorelbine or their excipients;
    15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test;
    16. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are willing to use highly effective methods of birth control as determined to be acceptable by the principal investigator and sponsor during the study treatment and through 120 days after the last dose of study drug.
    1. Precedente chemioterapia metronomica per malattia avanzata con capecitabina, ciclofosfamide e vinorelbina;
    2. Pazienti definiti “refrattari” a capecitabina, ciclofosfamide e vinorelbina (PD o SD <6 mesi);
    3. Presenza di coinvolgimento cerebrale o leptomeningeo sintomatico;
    4. Precedente o concomitante altra neoplasia ad eccezione del carcinoma basocellulare o squamocellulare della pelle o carcinoma in situ della cervice adeguatamente trattato;
    5. Malattia intercorrente incontrollata inclusa, ma non limitata a, infezione in corso o attiva, insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, aritmia cardiaca o
    Protocollo Studio clinico MARLENE versione 1.1 del 8 Luglio 2020
    malattie psichiatriche / situazioni sociali che limiterebbero la conformità ai requisiti dello studio;
    6. Sindrome da malassorbimento o malattia che influisce in modo significativo sulla funzione gastrointestinale o resezione maggiore dello stomaco o dell'intestino tenue prossimale che potrebbe influenzare l'assorbimento della vinorelbina orale;
    7. Pazienti con attività di diidropirimidina deidrogenasi (DPD) bassa o assente nota;
    8. Anamnesi di reazioni gravi e inattese alla terapia con fluoropirimidine;
    9. Trattamento concomitante con qualsiasi altra terapia antitumorale eccetto l'analogo dell'LHRH;
    10. Pazienti con neuropatia periferica motoria o sensoriale preesistente di grado 2 secondo i criteri del National Cancer Institute;
    11. Intervento chirurgico maggiore entro 28 giorni prima della prima dose del farmaco in studio;
    12. Radioterapia entro 14 giorni (28 giorni per le lesioni cerebrali secondo il Criterio di Esclusione 3) prima della prima dose del farmaco in studio. Nota: lesioni tumorali precedentemente sottoposte a radioterapia o altra terapia locoregionale saranno considerate misurabili solo se la progressione della malattia dopo il completamento della terapia locoregionale sarà chiaramente documentata;
    13. Qualsiasi condizione medica o psichiatrica grave, acuta o cronica concomitante o anomalia di laboratorio che può aumentare il rischio associato alla partecipazione allo studio o alla somministrazione di prodotti sperimentali o può interferire con la conformità con le procedure dello studio o l'interpretazione dei risultati dello studio e, a giudizio dello sperimentatore, renderebbe il soggetto inappropriato per l'ingresso in questo studio;
    14. Nota reazione di ipersensibilità a farmaci chimicamente correlati a capecitabina, ciclofosfamide e vinorelbina o ai loro eccipienti;
    15. Donne incinte o che allattano, dove la gravidanza è definita come lo stato di una femmina dal concepimento e fino alla fine della gestazione, confermato da un test di laboratorio ß-hCG positivo;
    16. Donne in età fertile, definite come tutte le donne fisiologicamente in grado di rimanere incinte, a meno che non siano disposte a utilizzare metodi di controllo delle nascite altamente efficaci, ritenuti accettabili dallo sperimentatore principale e dallo sponsor durante il trattamento in studio e per 120 giorni dopo l'ultima dose del farmaco in studio.
    E.5 End points
    E.5.1Primary end point(s)
    To assess the Time to Progression of metronomic chemotherapy with vinorelbine, cyclophosphamide and capecitabine in patients with hormone receptors positive HER2 negative metastatic breast cancer progressed after CDK 4/6 inhibitors
    - Valutare il tempo alla progressione (TTP) della chemioterapia metronomica con vinorelbina, ciclofosfamide e capecitabina in pazienti con carcinoma mammario metastatico HER2 negativo con recettori ormonali positivi progredito dopo terapia con CDK 4/6i.
    E.5.1.1Timepoint(s) of evaluation of this end point
    9.5 months first visit last patient
    9.5 mesi dalla prima visita dell'ultimo paziente incluso nello studio
    E.5.2Secondary end point(s)
    • To assess the efficacy of metronomic chemotherapy with vinorelbine, cyclophosphamide and capecitabine for:
    - Clinical benefit rate
    - Overall survival
    • Safety of metronomic chemotherapy after CDK 4/6 inhibitors
    • To assess Health related Quality of Life endpoints using the European Organization for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ-C30) and BR-23.
    - Valutare l'efficacia della chemioterapia metronomica con vinorelbina, ciclofosfamide e capecitabina in termini di:
    o Tasso di beneficio clinico (CBR)
    o Sopravvivenza globale (OS)
    - Valutare la sicurezza della chemioterapia metronomica dopo terapia con CDK 4/6i;
    - Valutare la qualità della vita salute correlata utilizzando due questionari dell'Organizzazione europea per la ricerca e la cura del cancro (EORTC QLQ-C30 e BR-23).
    E.5.2.1Timepoint(s) of evaluation of this end point
    30 months last visit last patient
    30 mesi dall'ultima visita dell'ultimo paziente incluso nello 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 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 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 Yes
    E.8.2.3.1Comparator description
    STUDIO IN SINGOLO BRACCIO
    SINGLE ARM TRIAL
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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
    LVLS
    LVLS
    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: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 25
    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)
    BEST CLINICAL PRACTICE
    MIGLIORE PRATICA CLINICA
    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 Decision2021-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-12-20
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