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    Summary
    EudraCT Number:2020-004559-34
    Sponsor's Protocol Code Number:DS8201-A-U306
    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:2021-06-08
    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 number2020-004559-34
    A.3Full title of the trial
    A Phase 3, Multicenter, 2-Arm Randomized, Open-Label Study of Trastuzumab Deruxtecan in Subjects with HER2 Positive Metastatic and/or Unresectable Gastric or Gastro Esophageal Junction (GEJ) Adenocarcinoma Subjects who have Progressed on or After a Trastuzumab-Containing Regimen (DESTINY-Gastric04)
    Studio di fase 3, multicentrico, in aperto, randomizzato a due bracci di trastuzumab deruxtecan in soggetti con adenocarcinoma gastrico o della giunzione gastro-esofagea (GGE) HER2 positivo, metastatico e/o non resecabile che hanno manifestato una progressione durante o dopo un regime contenente trastuzumab (DESTINY-Gastric04)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trastuzumab Deruxtecan for Subjects with HER2-Positive Gastric Cancer or Gastro-Esophageal Junction Adenocarcinoma after Progression on or After a Trastuzumab-Containing Regimen
    Trastuzumab Deruxtecan per soggetti con carcinoma gastrico HER2-positivo o adenocarcinoma della giunzione gastro-esofagea dopo progressione durante o dopo un regime contenente trastuzumab
    A.3.2Name or abbreviated title of the trial where available
    DESTINY-Gastric04
    DESTINY-Gastric04
    A.4.1Sponsor's protocol code numberDS8201-A-U306
    A.5.4Other Identifiers
    Name:IND NumberNumber:136179
    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
    B.5.3.3Post codeNJ 07920
    B.5.3.4CountryUnited States
    B.5.4Telephone number0019089927876
    B.5.5Fax number000000
    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 [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 1826843-81-5
    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 CYRAMZA
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    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 nameRamucirumab
    D.3.2Product code [N/A]
    D.3.4Pharmaceutical form 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 INNRamucirumab
    D.3.9.1CAS number 947687-13-0
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB32795
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 3
    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 Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderEVER Valinject GmbH
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    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 namePaclitaxel
    D.3.2Product code [N/A]
    D.3.4Pharmaceutical form 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 INNPaclitaxel
    D.3.9.1CAS number 33069-62-4
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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 Positive Metastatic and/or Unresectable Gastric or Gastro Esophageal Junction (GEJ)Adenocarcinoma
    Adenocarcinoma della giunzione gastrica o gastro-esofagea (GEJ) metastatico e / o non resecabile HER2 positivo
    E.1.1.1Medical condition in easily understood language
    Metastatic Gastric Adenocarcinoma
    Adenocarcinoma gastrico metastatico
    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 10071114
    E.1.2Term Metastatic gastric adenocarcinoma
    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 compare overall survival (OS) in HER2-positive (defined as IHC 3+ or IHC 2+/ISH+) gastric cancer(GC) and GEJ subjects treated with TDXd vs. Ram + PTX.
    Per confrontare la sopravvivenza globale (OS) nei soggetti con carcinoma gastrico (GC) HER2-positivo (definito come IHC 3+ o IHC 2 + / ISH +) e GEJ trattati con TDXd rispetto a Ram + PTX.
    E.2.2Secondary objectives of the trial
    • To compare PFS in HER2-positive GC and GEJ adenocarcinoma subjects treated with TDXd or Ram + PTX;
    • To evaluate further the clinical efficacy of TDXd and Ram + PTX by objective response rate (ORR based on Investigator assessment;
    • To evaluate further the clinical efficacy of TDXd and Ram + PTX by DoR;
    • To evaluate further the clinical efficacy of TDXd and Ram + PTX by DCR;
    • To evaluate the safety of T-DXd at 6.4 mg/kg dose;
    • To evaluate the Pharmacokinetics (PK) of T-DXd;
    • To evaluate immunogenicity of TDXd
    • Confrontare la PFS in soggetti con adenocarcinoma GC HER2 positivo e GEJ trattati con TDXd o Ram + PTX;
    • Valutare ulteriormente l'efficacia clinica di TDXd e Ram + PTX in base al tasso di risposta obiettiva (ORR basato sulla valutazione dello sperimentatore;
    • Valutare ulteriormente l'efficacia clinica di TDXd e Ram + PTX mediante DoR;
    • Valutare ulteriormente l'efficacia clinica di TDXd e Ram + PTX mediante DCR;
    • Valutare la sicurezza di T-DXd alla dose di 6,4 mg / kg;
    • Valutare la farmacocinetica (PK) di T-DXd;
    • Valutare l'immunogenicità di TDXd
    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 (according to local regulation) and able to provide informed consent for study participation.
    3. Pathologically documented gastric and GEJ adenocarcinoma that has been previously treated in the metastatic setting (unresectable, locally advanced, or metastatic disease).
    4. Progression on or after first-line therapy with a trastuzumab or approved trastuzumab biosimilar-containing regimen.
    Note: Prior adjuvant therapy with a trastuzumab-containing regimen can be counted as a line of therapy if the subject progressed on or within 6 months of completing adjuvant therapy.
    5. Is willing and able to provide an adequate tumor sample for tissue screening to confirm HER2 status by Central Laboratory. See Section 8.1.2.
    6. Centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2 amplification by ISH) as classified by ASCO-CAP on a tumor biopsy obtained after progression on or after a first-line trastuzumab or approved trastuzumab biosimilar-containing regimen.
    7. ECOG PS of 0 or 1 at both Screening and within 3 days prior to randomization.
    8. Adequate laboratory parameters as evidenced by all blood counts (refer protocol for details) within 14 days of randomization.
    9. Has adequate treatment washout period before randomization/enrollment, as described in the protocol.
    10. LVEF =50% within 28 days before randomization per echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
    11. Recovered from the effects of any prior surgery or radiotherapy.
    12. Men and women 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 7 months for female subjects and 4 months for male subjects after the last dose of study drug. Methods considered as highly effective methods of contraception are detailed in Section 10.3.4. For Ram + PTX, sites should follow local label or institutional guidelines.
    13. 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 randomization/enrollment in this study. For Ram + PTX, sites should follow local label or institutional guidelines.
    14. 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. For Ram + PTX, sites should follow local label or institutional guidelines.
    15. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
    1. Firmare e datare lo screening dei tessuti e gli ICF principali, prima dell'inizio di qualsiasi procedura di qualificazione specifica per lo studio.
    2. Adulti (secondo la normativa locale) e in grado di fornire il consenso informato per la partecipazione allo studio.
    3. Adenocarcinoma gastrico e GEJ patologicamente documentato che è stato precedentemente trattato in ambito metastatico (malattia non operabile, localmente avanzata o metastatica).
    4. Progressione durante o dopo la terapia di prima linea con un regime contenente trastuzumab o un regime biosimilare approvato di trastuzumab.
    Nota: una precedente terapia adiuvante con un regime contenente trastuzumab può essere considerata come una linea di terapia se il soggetto è progredito durante o entro 6 mesi dal completamento della terapia adiuvante.
    5. È disposto e in grado di fornire un campione di tumore adeguato per lo screening dei tessuti per confermare lo stato di HER2 da parte del laboratorio centrale. Vedere la sezione 8.1.2.
    6. HER2 positivo confermato a livello centrale (IHC 3+ o IHC 2+ ed evidenza di amplificazione HER2 da ISH) come classificato da ASCO-CAP su una biopsia tumorale ottenuta dopo progressione su o dopo un trastuzumab di prima linea o trastuzumab approvato contenente biosimilare regime.
    7. PS ECOG di 0 o 1 sia allo Screening che entro 3 giorni prima della randomizzazione.
    8. Parametri di laboratorio adeguati come evidenziato da tutti i conteggi ematici (fare riferimento al protocollo per i dettagli) entro 14 giorni dalla randomizzazione.
    9. Ha un adeguato periodo di washout dal trattamento prima della randomizzazione / arruolamento, come descritto nel protocollo.
    10. LVEF = 50% entro 28 giorni prima della randomizzazione per ecocardiogramma (ECHO) o scansione multigata (MUGA).
    11. Recuperato dagli effetti di qualsiasi precedente intervento chirurgico o radioterapia.
    12. Uomini e donne in età fertile / fertile devono accettare di utilizzare una forma di contraccezione altamente efficace o evitare i rapporti durante e al termine dello studio e per almeno 7 mesi per i soggetti di sesso femminile e 4 mesi per i soggetti di sesso maschile dopo l'ultima dose di farmaco in studio. I metodi considerati metodi contraccettivi altamente efficaci sono descritti in dettaglio nella Sezione 10.3.4. Per Ram + PTX, i siti dovrebbero seguire l'etichetta locale o le linee guida istituzionali.
    13. I soggetti di sesso maschile non devono congelare o donare lo sperma a partire dallo Screening e per tutto il periodo di studio e almeno 4 mesi dopo la somministrazione finale del farmaco in studio. La conservazione dello sperma deve essere considerata prima della randomizzazione / arruolamento in questo studio. Per Ram + PTX, i siti dovrebbero seguire l'etichetta locale o le linee guida istituzionali.
    14. I soggetti di sesso femminile non devono donare, o recuperare per uso proprio, ovuli dal momento dello screening e per tutto il periodo di trattamento in studio e per almeno 7 mesi dopo la somministrazione finale del farmaco in studio. Per Ram + PTX, i siti dovrebbero seguire l'etichetta locale o le linee guida istituzionali.
    15. È disposto e in grado di rispettare le visite programmate, il piano di somministrazione del farmaco, i test di laboratorio, altre procedure di studio e le restrizioni dello studio.
    E.4Principal exclusion criteria
    1. Use of anticancer therapy after trastuzumab-containing treatment.
    2. Medical history of myocardial infarction (MI) within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association [NYHA] Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation before enrollment to rule out MI.
    3. Has a QT interval corrected by Fridericia’s formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screening triplicate12-lead electrocardiogram (ECG).
    4. Has a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). Drainage and CART must be at least 2 weeks prior to Screening.
    5. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
    6. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disease (eg, pulmonary emboli within 3 months of the study randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.).
    7. Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented (or a suspicion of) pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the electronic case report form (eCRF) for patients who are included in the study.
    8. Prior pneumonectomy.
    9. Spinal cord compression or clinically active CNS metastases, defined as untreated and symptomatic or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
    a. Subjects with clinically inactive brain metastases may be included in the study.
    b. Subjects with brain metastases who were treated and are no longer symptomatic, and subjects who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy (WBRT) and randomization/study enrollment.
    10. Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated.
    11. History of severe hypersensitivity reactions to either the T-DXd or inactive ingredients in T-DXd.
    12. History of severe hypersensitivity reactions to other monoclonal antibodies or any components used in the ramucirumab drug product preparation.
    13. Known allergy or hypersensitivity to PTX or any components used in the PTX preparation or other contraindication for taxane therapy such as peripheral neuropathy, Grade 2.
    14. Current uncontrolled infection requiring antibiotics, antivirals, or antifungals or an unexplained fever >38.0°C during Screening visits or on the first scheduled day of dosing (at the discretion of the Investigator, subjects with tumor fever may be enrolled), which in the Investigator’s opinion might compromise the subject’s participation in the study or affect the study outcome.
    (Max limit reached - Please refer to the Protocol)
    1. Uso della terapia antitumorale dopo il trattamento contenente trastuzumab.
    2. Storia medica di infarto del miocardio (IM) nei 6 mesi prima della randomizzazione / arruolamento, insufficienza cardiaca congestizia sintomatica (Classe da II a IV della New York Heart Association [NYHA]). I soggetti con livelli di troponina superiori all'ULN allo screening (come definito dal produttore) e senza alcun sintomo correlato a IM dovrebbero sottoporsi a un consulto cardiologico prima dell'arruolamento per escludere IM.
    3. Ha un intervallo QT corretto dal prolungamento della formula di Fridericia (QTcF) a> 470 msec (soggetti di sesso femminile) o> 450 msec (soggetti di sesso maschile) in base alla media dell'elettrocardiogramma a 12 derivazioni (ECG) triplicato di Screening.
    4. Presenta versamento pleurico, ascite o versamento pericardico che richiede drenaggio, shunt peritoneale o terapia di reinfusione di ascite concentrata e priva di cellule (CART). Il drenaggio e il CART devono essere almeno 2 settimane prima dello screening.
    5. Ha una storia di ILD / polmonite (non infettiva) che ha richiesto steroidi, ha una ILD / polmonite in corso, o dove non è possibile escludere una sospetta ILD / polmonite mediante imaging allo Screening.
    6. Malattie polmonari intercorrenti clinicamente significative incluse, ma non limitate a, qualsiasi malattia polmonare sottostante (es. Emboli polmonari entro 3 mesi dalla randomizzazione dello studio, asma grave, BPCO grave, malattia polmonare restrittiva, versamento pleurico, ecc.).
    7. Qualsiasi malattia autoimmune, del tessuto connettivo o infiammatoria (ad es. Artrite reumatoide, sindrome di Sjögren, sarcoidosi, ecc.) In cui vi è un coinvolgimento polmonare documentato (o sospetto di) al momento dello screening. I dettagli completi del disturbo devono essere registrati nel modulo elettronico di segnalazione del caso (eCRF) per i pazienti inclusi nello studio.
    8. Precedente pneumonectomia.
    9. Compressione del midollo spinale o metastasi del SNC clinicamente attive, definite come non trattate e sintomatiche o che richiedono una terapia con corticosteroidi o anticonvulsivanti per controllare i sintomi associati.
    un. Soggetti con metastasi cerebrali clinicamente inattive possono essere inclusi nello studio.
    b. Soggetti con metastasi cerebrali che sono stati trattati e non sono più sintomatici, e soggetti che non necessitano di trattamento con corticosteroidi o anticonvulsivanti possono essere inclusi nello studio se si sono ripresi dall'effetto tossico acuto della radioterapia. Devono essere trascorse un minimo di 2 settimane tra la fine della radioterapia dell'intero cervello (WBRT) e la randomizzazione / l'arruolamento nello studio.
    10. Presenta più tumori primari entro 3 anni, ad eccezione del cancro della pelle non melanomico adeguatamente asportato, della malattia in situ trattata curativamente, altri tumori solidi trattati curativamente.
    11. Storia di gravi reazioni di ipersensibilità al T-DXd o agli ingredienti inattivi in ¿¿T-DXd.
    12. Anamnesi di gravi reazioni di ipersensibilità ad altri anticorpi monoclonali o qualsiasi componente utilizzato nella preparazione del medicinale ramucirumab.
    13. Allergia o ipersensibilità nota al PTX o qualsiasi componente utilizzato nella preparazione del PTX o altre controindicazioni per la terapia con taxani come la neuropatia periferica, Grado 2.
    14. Attuale infezione non controllata che richiede antibiotici, antivirali o antimicotici o una febbre inspiegabile> 38,0 ° C durante le visite di screening o il primo giorno programmato di somministrazione (a discrezione dello sperimentatore, possono essere arruolati soggetti con febbre tumorale), che in l'opinione dello sperimentatore potrebbe compromettere la partecipazione del soggetto allo studio o influenzarne i risultati.
    (LImite max raggiunto - Si prega di fare riferimento al Protocollo)
    E.5 End points
    E.5.1Primary end point(s)
    Overall Survival (OS)
    Sopravvivenza globale (Overall Survival - OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    After at least 237 (70%) OS events are recorded for interim analysis and 339 OS events are recorded for final analysis
    Dopo che sono stati registrati almeno 237 (70%) eventi di OS per l'analisi ad interim e 339 eventi di OS sono stati registrati per l'analisi finale
    E.5.2Secondary end point(s)
    - Progression-Free Survival (PFS)
    - Objective Response Rate (ORR)
    - Duration of Response (DoS)
    - Disease Control Rate (DCR)
    - SAEs, TEAEs and other safety parameters
    - PK profile
    - Immunogenicity (Incidence of ADA and NAb)
    - Sopravvivenza libera da progressione (PFS)
    - Tasso di risposta obiettiva (ORR)
    - Durata della risposta (DoS)
    - Tasso di controllo della malattia (DCR)
    - SAE, TEAE e altri parametri di sicurezza
    - Profilo PK
    - Immunogenicità (incidenza di ADA e NAb)
    E.5.2.1Timepoint(s) of evaluation of this end point
    PFS, ORR: At the time of interim analysis and final analysis;
    DoR, DCR: At the time of primary analysis;
    SAEs, TEAEs and other safety parameters: Continuous monitoring and reported at the time of the primary analysis;
    PK Profile and Immunogenicity: At the time of primary analysis
    PFS, ORR: al momento dell'analisi intermedia e dell'analisi finale;
    DoR, DCR: al momento dell'analisi primaria;
    SAE, TEAE e altri parametri di sicurezza: monitoraggio continuo e segnalati al momento dell'analisi primaria;
    Profilo PK e immunogenicità: al momento dell'analisi primaria
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability, Immunogenicity, Biomarker Analysis, Health economics and outcomes research (HEOR), Quality of Life (QoL), Patient Reported Outcomes (PROs)
    Tollerabilità, immunogenicità, analisi dei biomarcatori, economia sanitaria e ricerca sui risultati (HEOR), qualità della vita (QoL), Risultati segnalati dai pazienti (PRO)
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 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
    Ramucirumab e Paclitaxel
    Ramucirumab and Paclitaxel
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Brazil
    Chile
    China
    Hong Kong
    Israel
    Japan
    Korea, Republic of
    Russian Federation
    Singapore
    Taiwan
    Turkey
    Ukraine
    United States
    Belgium
    France
    Germany
    Hungary
    Ireland
    Italy
    Poland
    Portugal
    Romania
    Spain
    United Kingdom
    Argentina
    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 years3
    E.8.9.1In the Member State concerned months0
    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 months0
    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: 290
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 178
    F.4.2.2In the whole clinical trial 490
    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)
    An alternative study may be available for subjects continuing to derive benefit from treatment with Trastuzumab Deruxtecan.
    Uno studio alternativo può essere disponibile per i soggetti che continuano a trarre beneficio dal trattamento con Trastuzumab Deruxtecan.
    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 Decision2021-06-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-25
    P. End of Trial
    P.End of Trial StatusOngoing
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