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    Summary
    EudraCT Number:2020-003982-20
    Sponsor's Protocol Code Number:DS8201-A-U305
    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:2021-05-24
    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 number2020-003982-20
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (TDM1) in Subjects with High-Risk HER2-Positive Primary Breast Cancer Who Have Residual Invasive Disease in Breast or Axillary Lymph Nodes Following Neoadjuvant Therapy
    Studio di fase 3, multicentrico, randomizzato, in aperto, con controllo attivo, condotto su trastuzumab deruxtecan (T-DXd) rispetto a trastuzumab emtansine (T-DM1), in soggetti con carcinoma mammario primario HER2-positivo ad alto rischio che presentano malattia invasiva residua nella mammella o linfonodi ascellari in seguito a terapia neoadiuvante
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial comparing Trastuzumab Deruxtecan with Trastuzumab Emtansine in high-risk HER2-positive patients with residual breast cancer following neoadjuvant therapy
    Sperimentazione clinica per confrontare Trastuzumab Deruxtecan con Trastuzumab Emtansinein pazienti con HER2-positivo ad alto rischio e carcinoma mammario invasivo residuo dopo terapia neoadiuvante
    A.3.2Name or abbreviated title of the trial where available
    DESTINY-Breast05
    DESTINY-Breast05
    A.4.1Sponsor's protocol code numberDS8201-A-U305
    A.5.4Other Identifiers
    Name:INDNumber:127553
    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 SponsorDAIICHI SANKYO INC.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDaiichi Sankyo Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDaiichi Sankyo Inc.
    B.5.2Functional name of contact pointDavid Rusnak
    B.5.3 Address:
    B.5.3.1Street Address211 Mount Airy Road
    B.5.3.2Town/ cityBasking Ridge NJ
    B.5.3.3Post code07920
    B.5.3.4CountryUnited States
    B.5.4Telephone number0019089927876
    B.5.6E-maildrusnak@dsi.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 nameTrastuzumab deruxtecan
    D.3.2Product code [T-DXd, DS-8201a]
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTrastuzumab deruxtecan
    D.3.9.1CAS number 1599440-13-7
    D.3.9.2Current sponsor codeDS-8201a
    D.3.9.4EV Substance CodeSUB188357
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name KADCYLA
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 nameKADCYLA
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTRASTUZUMAB EMTANSINE
    D.3.9.1CAS number 1018448-65-1
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB35467
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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
    High-Risk HER2-Positive Breast Cancer
    Carcinoma mammario HER2-positivo ad alto rischio
    E.1.1.1Medical condition in easily understood language
    HER2 positive breast cancer
    Carcinoma mammario HER2-positivo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER2 positive breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate IDFS with T-DXd treatment as compared to T-DM1
    Valutare l’IDFS con il trattamento con T-DXd rispetto a T-DM1
    E.2.2Secondary objectives of the trial
    - To evaluate DFS with T-DXd treatment as compared to T-DM1
    - To evaluate OS with T-DXd treatment as compared to T-DM1
    - To evaluate DRFI with T-DXd treatment as compared to T-DM1
    - To evaluate BMFI with T-DXd treatment as compared to T-DM1
    - To evaluate safety of T-DXd
    - To evaluate pharmacokinetics (PK) of T-DXd
    - To evaluate immunogenicity of T-DXd
    -Valutare la DFS con il trattamento con T-DXd rispetto a T-DM1
    -Valutare l’OS con il trattamento con T-DXd rispetto a T-DM1
    -Valutare il DRFI con il trattamento con T-DXd rispetto a T-DM1
    -Valutare il BMFI con il trattamento con T-DXd rispetto a T-DM1
    -Valutare la sicurezza di T-DXd
    -Valutare la farmacocinetica (PK) di T-DXd
    -Valutare l’immunogenicità di T-DXd
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Sign and date the tissue screening and main ICFs, prior to the start of any study-specific qualification procedures.
    2. Adults =18 years old
    3. HER2-positive breast cancer, meeting all of the criteria listed in the protocol
    4. Histologically confirmed invasive breast carcinoma at time of disease presentation. Subjects with inflammatory breast cancer are allowed providing all eligibility criteria are met.
    5. Clinical stage at disease presentation of T1-4, N0-3, M0 prior to neoadjuvant therapy (Note: Patients presenting with T1N0 tumors will not be eligible).
    6. Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes following completion of neoadjuvant therapy meeting one of the high risk criteria described in detail in the protocol.
    7. Completion of neoadjuvant systemic chemotherapy and HER2-directed treatment.
    8. Adequate excision as confirmed per medical records: surgical removal of all clinically evident disease in the breast and lymph nodes.
    9. An interval of no more than 12 weeks between the date of last surgery and the date of randomization.
    10. Known hormone receptor (HR) status, per local laboratory assessment, as defined by ASCO-CAP guidelines (=1%): HR-positive status defined by either positive estrogen receptor (ER) or positive progesterone receptor (PR) status. HR-negative status defined by both known negative ER and known negative PR.
    11. Left ventricular ejection fraction (LVEF) = 50% within 28 days prior to randomization.
    12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
    13. Has adequate organ function within 14 days before randomization as defined in the protocol.
    14. Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 4 months for males and 7 months for females after the last dose of study drug.
    15. Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrolment in this study.
    16. Female subjects must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
    1. Firma e data del modulo di consenso informato per lo screening del tessuto e per lo studio principale, prima di iniziare qualsiasi procedura dello studio
    2. Adulti di età =18 anni
    3. Carcinoma mammario HER2-positivo che soddisfi tutti i i criteri elencati nel protocollo
    4. Carcinoma mammario invasivo confermato istologicamente. Soggetti con carcinoma mammario infiammatorio possono essere inclusi se soddisfano tutti i criteri di eleggibilità
    5. Stadio clinico al manifestarsi della malattia: T1-4, N0-3, M0 (nota: i pazienti che presentano tumori T1N0 non saranno considerati idonei).
    6. Evidenza patologica di carcinoma invasivo residuo nella mammella e/o linfonodi ascellari, dopo il completamento della terapia neoadiuvante, che soddisfa uno dei seguenti criteri ad alto rischio.
    7. Completamento della chemioterapia sistemica neoadiuvante, compreso il mirato contro l’HER2.
    8. Escissione adeguata come confermata dalle cartelle cliniche: rimozione chirurgica di tutta la malattia clinicamente evidente nella mammella e nei linfonodi.
    9. Un intervallo non superiore a 12 settimane tra la data dell’ultimo intervento chirurgico e la data di randomizzazione.
    10. Stato noto di HR, secondo la valutazione del laboratorio locale, come definito dalle linee guida ASCO-CAP (=1%): Stato di positività di HR definito dallo stato di positività al recettore degli estrogeni (ER) e/o dalla positività al recettore del progesterone (PR). Stato di negatività di HR definito dallo stato di negatività noto sia per l’ER che per il PR.
    11. Frazione di eiezione ventricolare sinistra (LVEF) =50% nei 28 giorni prima della randomizzazione.
    12. Stato di validità secondo il Gruppo cooperativo orientale di oncologia (ECOG) di 0 o 1 allo screening.
    13. Adeguata funzionalità degli organi nei 14 giorni precedenti la randomizzazione.
    14. Soggetti maschili e femminili in grado di procreare devono accettare di utilizzare un metodo di contraccezione altamente efficace o evitare rapporti sessuali durante e fino al completamento dello studio e per almeno 4 mesi per i maschi e 7 mesi per le femmine dopo l'ultima dose del farmaco in studio.
    15. Soggetti di sesso maschile non devono congelare o donare lo sperma a partire dallo screening e per tutta la durata dello studio e per almeno 4 mesi dopo l'ultima somministrazione del farmaco in studio. La conservazione dello sperma dovrebbe essere considerata prima dell'arruolamento nello studio.
    16. Soggetti di sesso femminile non devono donare o conservare per uso proprio ovuli dallo screening e per tutta la durata dello studio e per almeno 7 mesi dopo l'ultima somministrazione del farmaco in studio.
    E.4Principal exclusion criteria
    1. Stage IV (metastatic) breast cancer.
    2. History of any prior (ipsi- or contralateral) breast cancer except lobular carcinoma in situ (LCIS).
    3. Evidence of clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery.
    4. An overall response of progressive disease according to the investigator at the conclusion of preoperative systemic therapy
    5. Prior treatment with T-DXd, T-DM1 or other anti-HER2 ADC.
    6. History of exposure to the following cumulative doses of anthracyclines.
    7. History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ (CIS) of the cervix, nonmelanoma skin carcinoma, Stage I melanoma skin carcinoma, Stage I uterine cancer, or other appropriately treated non-breast malignancies.
    8. History of (noninfectious) ILD/pneumonitis that required steroids or has ILD/pneumonitis noted on computed tomography (CT) scan of the chest at Screening (asymptomatic interstitial changes confined to recent radiation therapy fields are not excluded).
    9. Known pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within three months prior to randomization, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, etc.).
    10. Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior lobectomy or pneumonectomy.
    11. Uncontrolled or significant cardiovascular disease, including: Medical history of myocardial infarction within 6 months before randomization, symptomatic congestive heart failure (CHF) (New York Heart Association
    Class II to IV), troponin levels consistent with myocardial infarction as defined according to the manufacturer 28 days prior to randomization.
    12. Has a corrected QT interval per Fridericia's formula (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on screening 12-lead electrocardiogram (ECG).
    13. History of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
    14. History of severe hypersensitivity reactions to other monoclonal antibodies (MAb).
    15. Inadequate washout period before Randomization/Cycle 1 Day 1, as defined in the protocol.
    16. Substance abuse or medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
    17. Social, familial, or geographical factors that would interfere with study participation or follow-up.
    18. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
    19. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C infection.
    20. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade = 1 or baseline.
    21. Is pregnant or breastfeeding or planning to become pregnant.
    1. Carcinoma mammario allo stadio IV (metastatico)
    2. Anamnesi di qualsiasi carcinoma mammario precedente (ipsi- o controlaterale), eccetto il carcinoma lobulare in situ (CLIS).
    3. Evidenza di malattia macroscopica clinicamente evidente, ricorrente o residua, dopo la terapia neoadiuvante e l’intervento chirurgico.
    4. Risposta di progressione di malattia secondo lo sperimentatore alla fine della terapia sistemica preoperativa
    5. Precedente trattamento con T-DXd, T-DM1 o altro coniugato anticorpo-farmaco (ADC) anti-HER2
    6. Anamnesi di esposizione alle seguenti dosi cumulative di antracicline:
    7. Anamnesi di altre malignità negli ultimi 5 anni, ad eccezione di CIS della cervice adeguatamente trattato, tumore della pelle non melanoma, tumore della pelle melanoma allo stadio I, tumore uterino allo stadio I o altre malignità non mammarie adeguatamente trattate.
    8. Anamnesi di malattia polmonare interstiziale (ILD) (non infettiva)/infiammazione polmonare che ha richiesto l’uso di steroidi e/o è stata annotata nella tomografia computerizzata (TC) del torace allo screening (non sono esclusi i cambiamenti interstiziali asintomatici limitati agli ambiti della recente radioterapia).
    9. Compromissione polmonare nota risultante da malattie polmonari intercorrenti tra cui, a titolo esemplificativo e non esaustivo, qualsiasi disturbo polmonare sottostante (ad es. embolia polmonare nei tre mesi precedenti la randomizzazione, asma grave, malattia polmonare ostruttiva cronica [COPD] grave, malattia polmonare restrittiva).
    10. Qualsiasi patologia autoimmune, del tessuto connettivale o infiammatoria con coinvolgimento polmonare (ad es. artrite reumatoide, sindrome di Sjögren, sarcoidosi, ecc.) o precedente lobectomia o pneumonectomia.
    11. Malattia cardiovascolare non controllata o significativa che comprende: anamnesi medica di infarto del miocardio nei 6 mesi precedenti la randomizzazione, insufficienza cardiaca congestizia (CHF) sintomatica (classe da II a IV secondo la New York Heart Association [Associazione dei cardiologi di New York]), livelli di troponina coerenti con una diagnosi di infarto del miocardio secondo la definizione del produttore 28 giorni prima della randomizzazione.
    12. Intervallo QT corretto secondo la formula Fridericia (QTcF) prolungata a > 470 msec (femmine) o > 450 msec (maschi) sulla base dell'ECG a 12-derivazioni allo screening.
    13. Anamnesi di reazioni gravi di ipersensibilità sia alla sostanza farmaceutica che agli ingredienti inattivi del prodotto farmaceutico.
    14. Anamnesi di reazioni gravi di ipersensibilità ad altri anticorpi monoclonali (MAb).
    15. Inadeguato periodo di washout period prima della Randomizzazione/Ciclo 1 Giorno 1, come definito nel protocollo.
    16. Abuso di sostanze o condizioni mediche clinicamente significative come cardiache o psicologiche che potrebbero, secondo lo sperimentatore, interferire con la partecipazione del soggetto allo studio clinico o con la valutazione dei risultati dello stesso.
    17. Fattori sociali, familiari o geografici che potrebbero inferferire con la partecipazione allo studio o il follow-up.
    18. Infezione non controllata che richieda antibiotici IV, antivirali o antifungini.
    19. Infezione nota di HIV o epatite B o C attiva.
    20. Tossicità non risolte dalla precedente terapia anticancro, definite come tossicità (oltre all'alopecia) non ancora risolte al Grado = 1 o al basale.
    21. In stato di gravidanza o allattamento o in procinto di iniziare una gravidanza.
    E.5 End points
    E.5.1Primary end point(s)
    - IDFS is defined as the time from randomization to invasive local, axillary or distant recurrence, invasive contralateral breast cancer, or death from any cause.
    - IDFS will be determined based on disease recurrence per Investigator assessment based on all available clinical assessments.
    - L’IDFS è definita come l’intervallo di tempo dalla randomizzazione alla recidiva locale invasiva, ascellare o distante, al carcinoma mammario invasivo controlaterale o al decesso per qualsiasi causa.
    - L’IDFS verrà determinata in base alla recidiva della malattia, che sarà valutata dallo Sperimentatore sulla base di tutte le valutazioni cliniche disponibili.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After at least 145 IDFS events are recorded for interim analysis and 207 IDFS events are recorded for final analysis
    Dopo che almeno 145 eventi IDFS siano stati registrati per l'analisi ad-interim e 207 eventi IDFS siano stati registrati per l'analisi finale
    E.5.2Secondary end point(s)
    - DFS is defined as the time between randomization and the date of the first occurrence of an IDFS event including second primary non-breast cancer event or contralateral or ipsilateral DCIS. DFS will be determined based on disease recurrence per Investigator assessment.
    - OS is defined as the time from randomization to death due to any cause.
    - DRFI is defined as the time between randomization and the date of distant breast cancer recurrence. DRFI will be determined based on disease recurrence per Investigator assessment.
    - BMFI is defined as time from randomization to documentation of involvement of the CNS by metastatic cancer including parenchymal brain and spinal cord metastases as well as leptomeningeal carcinomatosis. BMFI will be determined based on disease recurrence per Investigator assessment.
    - AEs including SAEs, TEAEs, and AESIs Physical examination findings, ECOG PS, vital sign measurements, standard clinical laboratory parameters, ECG parameters, ECHO/MUGA findings, and CT scans
    - Serum concentrations of T-DXd, total anti HER2 antibody, and MAAA 1181a in the PK sampling cohort
    - Percentage of subjects who are positive for ADAs at baseline, and postbaseline and treatment-emergent ADA positive. Titer and NAb will be determined for positive ADA samples.
    - La DFS è definita come l’intervallo di tempo tra la randomizzazione e la data della prima occorrenza di un evento di IDFS, inclusi eventi di carcinomi non mammari primari secondari o DCIS controlaterali o ipsilaterali. La DFS sarà determinata in base alla recidiva della malattia secondo la valutazione dello Sperimentatore.
    - L’OS è definita come l’intervallo di tempo dalla randomizzazione al decesso per qualsiasi causa.
    - Il DRFI è definito come l’intervallo di tempo trascorso tra la randomizzazione e la data della recidiva distante del carcinoma mammario. Il DRFI sarà determinato in base alla recidiva della malattia secondo la valutazione dello Sperimentatore.
    - Il BMFI è definito come l’intervallo temporale dalla randomizzazione alla documentazione di tumore metastatico a carico del SNC, comprese metastasi nel parenchima cerebrale e nel midollo spinale, nonché carcinomatosi leptomeningea. Il BMFI sarà determinato in base alla recidiva della malattia secondo la valutazione dello Sperimentatore.
    - EA, compresi TEAE, AESI e SAE
    Risultati degli esami obiettivi, PS secondo i criteri di valutazione dell’ECOG, misurazioni dei segni vitali, parametri clinici di laboratorio standard, parametri ECG, risultati delle ECO e delle MUGA; TAC
    - Concentrazioni sieriche di T-DXd, totale di anticorpi anti HER2 e MAAA 1181a nella coorte per il prelievo di campioni per la PK
    - Percentuale di soggetti che sono positivi agli ADA al basale e al post-basale, e positivi agli ADA emergenti dal trattamento. Titolo e NAb saranno determinati per i campioni positivi agli ADA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Continuous monitoring and reported at the time of the final analysis.; Continuo monitoraggio e rapporto al tempo dell'analisi finale
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity, QOL
    Immunogenicità, Qualità della Vita
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned18
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA220
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    China
    Czechia
    Denmark
    France
    Germany
    Greece
    Hong Kong
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Peru
    Poland
    Portugal
    Romania
    Russian Federation
    Singapore
    Spain
    Taiwan
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial 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: 1464
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 136
    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 state158
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 620
    F.4.2.2In the whole clinical trial 1600
    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)
    The study treatment period of 14 cycles (~42 weeks) combined with the prior neoadjuvant therapy with trastuzumab comprises approx. 1 year of HER2-targeted treatment, which is standard approach for this patient population and matches the paradigm for KATHERINE study with T-DM1. Note that if subjects do have disease recurrence they would move into the long-term follow-up phase of our study and they could receive other anti-cancer therapy per investigator discretion/SOC.
    Il periodo di trattamento dello studio di 14 cicli (~42 settimane) combinato con la precedente terapia neoadiuvante con trastuzumab copre circa 1 anno di trattamento mirato ad HER2, che è l'approccio standard per questa popolazione di pazienti e coincide con il paradigma per lo studio KATHERINE con T-DM1. Se i soggetti hanno recidiva di malattia saranno spostati nella fase di follow-up a lungo termine dello studio e potranno ricevere terapia anti-cancro a discrezione dello sperimentatore/SOC.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation National Surgical Adjuvant Breast and Bowel Project (NSABP)
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation GBG Forschungs GmbH
    G.4.3.4Network Country Germany
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation SOLTI
    G.4.3.4Network Country Spain
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-16
    P. End of Trial
    P.End of Trial StatusOngoing
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