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    Summary
    EudraCT Number:2017-002567-17
    Sponsor's Protocol Code Number:8951-CL-0301
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-002567-17
    A.3Full title of the trial
    A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared with Placebo Plus mFOLFOX6 as First-line Treatment of Subjects with Claudin (CLDN)18.2- Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma.
    Studio di Fase 3, Globale, Multicentrico, in Doppio Cieco, Randomizzato Volto a Valutare l’Efficacia di Zolbetuximab (IMAB362) più mFOLFOX6 rispetto a Placebo più mFOLFOX6 come Prima Linea di Trattamento in Soggetti con Adenocarcinoma Gastrico o della Giunzione Gastro-Esofagea (GGE) Metastatico o Localmente Avanzato Non Operabile Positivo per Claudin (CLDN) 18.2 e HER2-negativo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared with Placebo Plus mFOLFOX6 as First-line Treatment of Subjects with Claudin (CLDN)18.2- Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma.
    Studio di Fase 3, Globale, Multicentrico, in Doppio Cieco, Randomizzato Volto a Valutare l’Efficacia di Zolbetuximab (IMAB362) più mFOLFOX6 rispetto a Placebo più mFOLFOX6 come Prima Linea di Trattamento in Soggetti con Adenocarcinoma Gastrico o della Giunzione Gastro-Esofagea (GGE) Metastatico o Localmente Avanzato Non Operabile Positivo per Claudin (CLDN) 18.2 e HER2-negativo.
    A.3.2Name or abbreviated title of the trial where available
    SPOTLIGHT
    SPOTLIGHT
    A.4.1Sponsor's protocol code number8951-CL-0301
    A.5.4Other Identifiers
    Name:INDNumber: 129598
    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 SponsorASTELLAS PHARMA GLOBAL DEVELOPMENT, 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 supportAstellas Pharma Global Development, Inc. (APGD)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointService Desk - Global Clinical Dev.
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031715455878
    B.5.5Fax number0031715455224
    B.5.6E-mailcontacts@nl.astellas.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/803
    D.3 Description of the IMP
    D.3.1Product nameZolbetuximab (IMAB362)
    D.3.2Product code [Zolbetuximab (IMAB362)]
    D.3.4Pharmaceutical form Powder 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 INNZolbetuximab
    D.3.9.1CAS number 1496553-00-4
    D.3.9.2Current sponsor codeIMAB362
    D.3.9.3Other descriptive nameIMAB362
    D.3.9.4EV Substance CodeSUB190351
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
    Adenocarcinoma Gastrico o della Giunzione Gastro-Esofagea (GGE) Metastatico o Localmente Avanzato Non Operabile Positivo per Claudin (CLDN) 18.2 e HER2-negativo
    E.1.1.1Medical condition in easily understood language
    Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
    Adenocarcinoma Gastrico o della Giunzione Gastro-Esofagea (GGE)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10001150
    E.1.2Term Adenocarcinoma gastric
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of zolbetuximab plus mFOLFOX6 compared with placebo plus mFOLFOX6 (as first-line treatment) as measured by Progression Free Survival (PFS) in subjects with Claudin (CLDN)18.2 positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced unresectable or metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma.
    Valutare l’efficacia di zolbetuximab più mFOLFOX6 rispetto a placebo più mFOLFOX6 (come trattamento di prima linea) misurata in base alla sopravvivenza libera da progressione (PFS) in soggetti con adenocarcinoma gastrico o della giunzione gastro-esofagea (GGE) metastatico o localmente avanzato non operabile positivo per claudin (CLDN) 18.2 e negativo per il recettore 2 del fattore di crescita epidermico umano (HER2).
    E.2.2Secondary objectives of the trial
    - To evaluate efficacy as measured by Overall Survival (OS) as a key secondary objective
    - To evaluate efficacy as measured by Objective Response Rate (ORR)
    - To evaluate efficacy as measured by Duration of Response (DOR)
    - To evaluate safety and tolerability of zolbetuximab
    - To evaluate health related quality of life (HRQoL) using the parameters as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OG25, Global Pain (GP) and the EuroQOL Five Dimensions Questionnaire 5L (EQ5D-5L) questionnaires
    - To evaluate the pharmacokinetics of zolbetuximab
    - To evaluate the immunogenicity profile of zolbetuximab
    - To evaluate efficacy as measured by Time to Progression (TTP)
    - To evaluate PFS following subsequent anti-cancer treatment (PFS2)
    - To evaluate Disease Control Rate (DCR)
    - To evaluate potential genomic and/or other biomarkers that may correlate with treatment outcome to zolbetuximab and mFOLFOX6.
    - Valutare efficacia misurata dalla sopravvivenza generale (OS) come principale obiettivo secondario
    - Valutare efficacia misurata in base al tasso di risposta obiettiva (ORR)
    - Valutare efficacia misurata in base alla durata della risposta (DOR)
    - Valutare sicurezza e tollerabilità di zolbetuximab
    - Valutare la qualità della vita correlata alla salute (HRQoL) in base ai parametri dei questionari dell’organizzazione europea per la ricerca e il trattamento del cancro (EORTC) QLQ-C30, QLQ-OG25, dolore globale (GP) e EuroQOL a 5 dimensioni e 5 livelli (EQ5D5L)
    - Valutare la farmacocinetica di zolbetuximab
    - Valutare il profilo di immunogenicità di zolbetuximab
    - Valutare l'efficacia misurata dal tempo alla progressione (TTP)
    - Valutare la PFS dopo il successivo trattamento anti-cancro (PFS2)
    - Valutare il tasso di controllo della malattia (DCR)
    - Valutare i potenziali biomarcatori genomici e/o di altro tipo che possono correlarsi con l'esito del trattamento con zolbetuximab e mFOLFOX6.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] Authorization for US sites) must be obtained from the subject or legally authorized representative (if applicable) prior to any studyrelated procedures.
    2.Subject is considered an adult (e.g., = 18 years of age in the US) according to local regulation at the time of signing the informed consent.
    3.Subject agrees not to participate in another interventional study while on study treatment.
    4.A female subject is eligible to participate if she is not pregnant (negative serum pregnancy test at Screening; female subjects with elevated serum beta human chorionic gonadotropin (ßhCG) and a
    demonstrated non-pregnant status through additional testing are eligible) and at least 1 of the following conditions applies:
    a.Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.3 Contraception Requirements
    OR
    b.WOCBP who agrees to follow the contraceptive guidance as defined in Appendix 12.3 Contraception Requirements throughout the treatment period and for at least 6 months after the final study drug
    administration.
    5.Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study treatment administration.
    6.Female subject must not donate ova starting at Screening and throughout the study period, and for 6 months after the final study drug administration.
    7.A sexually active male subject with female partner(s) who are of childbearing potential must agree to use contraception as detailed in Appendix 12.3 Contraception Requirements during the treatment period
    and for at least 6 months after the final study drug administration.
    8.Male subject must not donate sperm starting at Screening and throughout the study period and for 6 months after the final study drug administration.
    9.Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or for the time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
    Disease Specific Criteria:
    10.Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.
    11.Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to randomization.
    12.Subject has radiologically evaluable disease (measurable and/or nonmeasurable disease according to RECIST 1.1), per local assessment, = 28 days prior to randomization. For subjects with only 1 evaluable lesion and prior radiotherapy =3 months before randomization, the lesion must either be outside the field of prior radiotherapy or have documented progression following radiation therapy.
    13.Subject's tumor expresses CLDN18.2 in = 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.
    14.Subject has a HER2-Negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen.
    Physical or Laboratory Findings
    15.Subject has ECOG performance status 0 to 1.
    16.Subject has predicted life expectancy ~12 weeks in the opinion of the investigator.
    17.Subject must meet all of the following criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to randomization. In case of multiple central laboratory data within this period, the most recent data should be used to determine eligibility.
    a.Hemoglobin (Hgb) = 9 g/dL. Subjects requiring transfusions are eligible if they have a post-transfusion Hgb = 9 g/dL.
    b.Absolute neutrophil count = 1.5 x 109/L
    c.Platelets = 100 x 109/L
    d.Albumin = 2.5 g/dL
    e.Total bilirubin = 1.5 x upper limit of normal (ULN) without liver metastases (or < 3.0 x ULN if liver metastases are present)
    .... (see the protocol)
    1. Il soggetto o il rappresentante legalmente autorizzato deve fornire il modulo di consenso informato scritto e l’informativa sulla privacy (se applicabile), approvati dal comitato istituzionale di revisione (IRB)/comitato etico indipendente (CEI) secondo le normative nazionali (per es., l’autorizzazione ai sensi della legge sulla portabilità e responsabilità dell’assicurazione sanitaria Health Insurance Portability and
    Accountability Act [HIPAA] per i centri negli Stati Uniti), prima di qualsiasi procedura correlata allo studio.
    2. Il soggetto è considerato adulto (per es. età =18 anni negli Stati Uniti) secondo le normative locali al momento della firma del modulo di consenso informato.
    3. Il soggetto si impegna a non partecipare a un altro studio interventistico durante il trattamento dello studio.
    4. Una donna può partecipare se non è incinta (test di gravidanza sierica negativo allo Screening, soggetti femminili con elevata gonadotropina corionica beta sierica (ßhCG) e uno stato di non gravidanza dimostrato attraverso test aggiuntivi sono ammissibili) e almeno 1 delle seguenti condizioni si applica:
    a.Non una donna in età fertile (WOCBP) come definito nell'appendice 12.3 Requisiti di contraccezione O
    b.WOCBP che accetta di seguire la guida ai contraccettivi come definita nell'appendice 12.3 Requisiti di contraccezione per tutto il periodo di trattamento e per almeno 6 mesi dopo il farmaco di studio finale
    amministrazione.
    5. Il soggetto femminile deve accettare di non allattare al seno a partire dallo Screening e per tutto il periodo di studio e per 6 mesi dopo la somministrazione del trattamento finale dello studio.
    6. Le donne non devono donare ovuli a partire da Screening e per tutto il periodo di studio, e per 6 mesi dopo la somministrazione del farmaco in studio finale.
    7. Un soggetto maschile sessualmente attivo con partner(s) femminile(i) che sono potenzialmente fertili deve accettare di usare la contraccezione come specificato nell'appendice 12.3 Requisiti contraccettivi durante il periodo di trattamento e per almeno 6 mesi dopo la somministrazione del farmaco finale dello studio.
    8. Il soggetto di sesso maschile non deve donare sperma a partire dallo Screening e per tutto il periodo di studio e per 6 mesi dopo la somministrazione del farmaco finale dello studio.
    9. Il soggetto maschile con un/i partner(s) in stato di gravidanza o allattamento deve accettare di rimanere astinente o usare il preservativo per la durata della gravidanza o per il periodo in cui il partner allatta al seno durante il periodo di studio e per 6 mesi dopo la somministrazione del farmaco finale dello studio.
    Criteri specifici per la malattia:
    10. Il soggetto ha una diagnosi istologicamente confermata di adenocarcinoma gastrico o GEJ.
    11. Il soggetto ha una malattia localmente avanzata non resecabile o metastatica confermata radiologicamente entro 28 giorni prima della randomizzazione.
    12. Il soggetto presenta una malattia radiologicamente valutabile (malattia misurabile e/o non misurabile secondo RECIST 1.1), secondo la valutazione locale, = 28 giorni prima della randomizzazione. Per i soggetti con una sola lesione valutabile e una precedente radioterapia = 3 mesi prima della randomizzazione, la lesione deve essere o al di fuori del campo della radioterapia precedente o avere una progressione documentata dopo la radioterapia.
    13. Il tumore del soggetto esprime CLDN18,2 in = 75% delle cellule tumorali che dimostrano una colorazione membranosa da moderata a forte come determinato dal test IHC centrale.
    14. Il soggetto ha un tumore HER2-negativo come determinato da test locali o centrali su un campione di tumore gastrico o GEJ.
    Risultati fisici o di laboratorio
    15. Il soggetto ha lo stato delle prestazioni ECOG da 0 a 1.
    16. Il soggetto ha previsto un'aspettativa di vita di 12 settimane secondo il parere dello sperimentatore.
    ... (si veda il protocollo)
    E.4Principal exclusion criteria
    Prohibited Treatment or Therapies
    1.Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-adjuvant or adjuvant
    chemotherapy as long as it was completed at least 6 months prior to randomization. Subject may have received treatment with herbal medications that have known antitumor activity > 28 days prior
    randomization.
    2.Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma = 14 days prior to randomization and recovered from any related toxicity.
    3.Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids, or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
    4.Subject has received other investigational agents or devices within 28 days prior to randomization.
    Medical History or Concurrent Disease
    5.Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies.
    6.Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
    7. Subject has prior severe allergic reaction or intolerance to any component of mFOLFOX6.
    8.Subject has known dihydropyrimidine dehydrogenase deficiency (DPD). (NOTE: Screening for DPD deficiency should be conducted per local requirements.)
    9.Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.
    10.Per investigator judgment, subject has significant gastric bleeding and/or untreated gastric ulcers that exclude the subject from participation.
    11.Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive HBs Ag) or C infection. NOTE: Screening for these infections
    should be conducted per local requirements.
    a.For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test will be performed and if positive, the subject will be excluded.
    b.Subjects with positive hepatitis C (HCV) serology, but negative HCV RNA test are eligible.
    c.Subjects treated with HCV with undetectable viral load results are eligible.
    12.Subject has an active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization.
    13.Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.
    14.Subject has significant cardiovascular disease, including any of the following:
    a.Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident or
    hypertensive crisis within 6 months prior to randomization.
    b.History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointesc. QTc interval > 450 msec for male subjects: QTc interval > 470 msec for female subjects
    d.History or family history of congenital long QT syndrome
    e.Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible).
    15.Subject has a history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer.
    16.Subject has known peripheral sensory neuropathy > grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality.
    ...(see the protocol)
    Trattamento o terapie vietate
    1. Il soggetto ha ricevuto una precedente chemioterapia sistemica per adenocarcinoma gastrico o GEJ localmente avanzato non resecabile o metastatico. Tuttavia, il soggetto può aver ricevuto chemioterapia neo-adiuvante o adiuvante purché completata almeno 6 mesi prima della randomizzazione. Il soggetto può essere stato trattato con farmaci erboristici che presentano attività antitumorale nota > 28 giorni prima della randomizzazione.
    2. Il soggetto ha ricevuto radioterapia per adenocarcinoma gastrico o GEJ localmente avanzato non resecabile o metastatico =14 giorni prima della randomizzazione e ha recuperato da ogni relativa tossicità.
    3. Il soggetto ha ricevuto una terapia immunosoppressiva sistemica, inclusi corticosteroidi sistemici entro 14 giorni prima della randomizzazione. Sono ammessi soggetti che usano una dose sostitutiva fisiologica di idrocortisone o il suo equivalente (definito fino a 30 mg al giorno di idrocortisone o fino a 10 mg al giorno di prednisone), ricevendo una dose singola di corticosteroidi sistemici, o ricevendo corticosteoridi sistemici come premedicazione per l’uso della radiologia per immagini a constrasto.
    4. Il soggetto ha ricevuto altri agenti o dispositivi investigativi nei 28 giorni precedenti la randomizzazione.
    Storia medica o malattia concomitante
    5. Il soggetto presenta una precedente reazione allergica grave o intolleranza agli ingredienti noti di zolbetuximab o altri anticorpi monoclonali, compresi gli anticorpi umanizzati o chimerici.
    6. Il soggetto ha bota ipersensibilità, intolleranza o controindicazione immediata o tardiva a qualsiasi componente del trattamento in studio.
    7. Il soggetto ha una precedente reazione allergica grave o intolleranza a qualsiasi componente di mFOLFOX6.
    8. Il soggetto presenta carenza di diidropirimidina deidrogenasi (DPD) nota (NOTA: lo screening per la carenza di DPD deve essere effettuato in base ai requisiti locali).
    9. Il soggetto ha una sindrome gastrica completa o una parziale sindrome gastrica con vomito persistente / ricorrente.
    10. A giudizio dello sperimentatore, il soggetto ha un significativo sanguinamento gastrico e/o ulcere gastriche non trattate che escludono il soggetto dalla partecipazione.
    11. Il soggetto ha una storia nota di test positivo per l'infezione da virus dell'immunodeficienza umana (HIV) o infezione da epatite B (HB positiva positiva) o C nota. NOTA: lo screening per queste infezioni dovrebbe essere condotto in accordo ai requisiti locali.
    a.Per i soggetti che sono negativi per HBs Ag, ma HBc Ab positivo, verrà eseguito un test del DNA HB e, se positivo, il soggetto verrà escluso.
    b.Sono ammessi i soggetti con sierologia positiva da epatite C (HCV), ma i risultati negativi del test HCV RNA.
    c.Sono ammessi i soggetti trattati con HCV con risultati di carico virale non individuabile.
    12. Il soggetto ha una malattia autoimmune attiva che ha richiesto un trattamento sistemico negli ultimi 3 mesi prima della randomizzazione.
    13. Il soggetto presenta un'infezione attiva che richiede una terapia sistemica non completamente risolta entro 7 giorni prima della randomizzazione.
    14. Il soggetto presenta una significativa malattia cardiovascolare, inclusa una delle seguenti:
    a. Insufficienza cardiaca congestizia (definita come New York Heart Association di classe III o IV), infarto miocardico, angina instabile, angioplastica coronarica, stenting, innesto di bypass dell'arteria coronaria, incidente cerebrovascolare o crisi ipertensiva entro 6 mesi prima della randomizzazione.
    b. Storia di aritmie ventricolari clinicamente significative (cioè tachicardia ventricolare sostenuta, fibrillazione ventricolare o torsione di punta
    c. Intervallo QTc> 450 msec per soggetti di sesso maschile: intervallo QTc >470 msec per i soggetti di sesso femminile
    d. Anamnesi familiare di sindrome congenita da QT lungo
    e. Aritmie cardiache che richiedono farmaci antiaritmici (soggetto con fibrillazione atriale... (si veda il protocollo)
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS, which is defined as the time from the date of randomization until the date of radiological PD (per Response evaluation Criteria In Solid Tumors [RECIST] 1.1 by independent review committee [IRC]) or death from any cause, whichever is earliest.
    PFS, definita come l’intervallo di tempo dalla data della randomizzazione alla data di PD radiologica (secondo i criteri RECIST 1.1 dell’IRC) o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis will be performed when the protocol-defined number of PFS events have been observed.
    L'analisi primaria sarà effettuata quando verrà raggiunto il numero di eventi PFS definiti dal protocollo.
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    -OS, defined as the time from the date of randomization until the date of death from any cause
    -ORR, defined as the proportion of subjects who have a best overall response (BOR) of CR or PR as assessed by IRC per RECIST 1.1
    -DOR, defined as the time from the date of the first response (CR/PR) until the date of PD as as-sessed by IRC per RECIST 1.1 or date of death from any cause, whichever is earliest
    -Safety and tolerability, as measured by AEs, laboratory test results, vital signs, electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) performance status
    -HRQoL, as collected via EORTC QLQ-C30, QLQ-OG25, GP and EQ5D-5L questionnaires
    -Pharmacokinetics of zolbetuximab Ctrough
    -Immunogenicity of zolbetuximab as measured by the frequency of antidrug antibody (ADA) posi-tive subjects.
    Gli endpoint secondari sono:
    - OS, definita come l’intervallo di tempo dalla data della randomizzazione alla data del decesso per qualsiasi causa
    - ORR, definita come la percentuale di soggetti che raggiunge la migliore risposta complessiva (BOR) di CR o PR in base alla valutazione dell’IRC secondo i criteri RECIST 1.1
    - DOR, definita come l’intervallo di tempo dalla data della prima risposta (CR/PR) fino alla data di PD valutata dall’IRC secondo i criteri RECIST 1.1 o alla data del decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo
    - Sicurezza e tollerabilità, misurate in termini di AE, risultati dei test di laboratorio, segni vitali, ECG e stato di validità ECOG
    - HRQoL, secondo i questionari EORTC QLQ-C30, QLQ-OG25, GP e EQ5D-5L
    - Farmacocinetica di zolbetuximab Ctrough
    - Immunogenicità di zolbetuximab misurata dalla frequenza dei soggetti positivi agli anticorpi anti-farmaco (ADA).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoint analysis will be performed at the protocol defined primary PFS analysis and at the final OS analysis after 100% of the planned death events have been observed.
    L'analisi dell'endpoint secondario sarà effettuata all'analisi primaria della PFS definita nel protocollo e all'analisi dell'OS finale dopo che verrà raggiunto il 100% dei decessi pianificati.
    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 No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Immunogenicità
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned19
    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
    Australia
    Belgium
    Brazil
    Canada
    Chile
    China
    Colombia
    Costa Rica
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Peru
    Poland
    Spain
    Taiwan
    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
    The end of study in all participating countries is defined as the last subject's last visit, or last contact.
    La conclusione della sperimentazione in tutte le nazioni partecipanti è definita come l'ultima visita dell'ultimo soggetto, o l'ultimo contatto.
    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 months5
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days14
    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: 385
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 165
    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 state27
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 156
    F.4.2.2In the whole clinical trial 550
    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)
    After the end of participation in the trial, patients will receive treatment according to current local medical practice.
    Al termine della partecipazione alla sperimentazione, i pazienti riceveranno il trattamento dovuto in accordo alla pratica medica locale corrente.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-27
    P. End of Trial
    P.End of Trial StatusOngoing
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