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    Summary
    EudraCT Number:2015-003239-36
    Sponsor's Protocol Code Number:B9991010
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-06-18
    Trial results View 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 number2015-003239-36
    A.3Full title of the trial
    A Randomized, Open-Label, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Avelumab (MSB0010718C) in Combination with and/or Following Chemotherapy in Patients with previously Untreated Epithelial Ovarian Cancer
    Studio randomizzato, in aperto, multicentrico, di fase 3 per valutare l’efficacia e la sicurezza di Avelumab (MSB0010718C) in associazione a e/o successivamente a chemioterapia in pazienti affetti da tumore ovarico epiteliale non precedentemente trattato.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Determine the Effect and Safety of Avelumab When Combined with Chemotherapy or Following Chemotherapy in Patients who have Previously Untreated Epithelial Ovarian Cancer.
    Studio per determinare l'effetto e la sicurezza di Avelumab quando combinato con chemioterapia o in seguito a chemioterapia in pazienti che non sono state precedentemente trattate per tumore ovarico epiteliale.
    A.3.2Name or abbreviated title of the trial where available
    Javelin Ovarian 100
    Javelin Ovarian 100
    A.4.1Sponsor's protocol code numberB9991010
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02718417
    A.5.4Other Identifiers
    Name:US INDNumber:126,174
    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 SponsorPFIZER 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 supportPfizer Inc, 235 East 42nd Street New York NY
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10071
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.5Fax number+13037391119
    B.5.6E-mailclinicaltrials.govcallcenter@pfizer.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 nameAvelumab
    D.3.2Product code MSB0010718C
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAvelumab
    D.3.9.2Current sponsor codeMSB0010718C
    D.3.9.4EV Substance CodeSUB176547
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Epithelial ovarian cancer (EOC)
    Tumore Ovarico Epiteliale
    E.1.1.1Medical condition in easily understood language
    Cancer of the ovaries
    Cancro alle ovaie
    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 10033128
    E.1.2Term Ovarian 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
    1. To demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab maintenance (Arm C) is superior to platinum-based chemotherapy alone followed by observation (Arm A) in prolonging progression free survival (PFS) in patients with previously untreated epithelial ovarian cancer (EOC).
    2. To demonstrate that platinum-based chemotherapy alone followed by avelumab maintenance (Arm B) is superior to platinum-based
    chemotherapy alone followed by observation (Arm A) in prolonging PFS in patients with previously untreated EOC.
    1. Dimostrare la superiorità di avelumab in associazione a chemioterapia a base di platino seguita da mantenimento con avelumab (Braccio C) rispetto a chemioterapia basata su platino da sola seguita da osservazione (Braccio A) nel prolungamento della sopravvivenza libera da progressione (PFS) nelle pazienti con carcinoma ovarico precedentemente non trattato.

    2.Dimostrare la superiorità della chemioterapia basata su platino da sola seguita da mantenimento con avelumab (Braccio B) rispetto a chemioterapia basata su platino da sola seguita da osservazione (Braccio A) nel prolungare la PFS nelle pazienti con carcinoma ovarico precedentemente non trattato.
    E.2.2Secondary objectives of the trial
    To compare Arm C and Arm B to Arm A in patients with untreated EOC, with respect to overall survival.
    • To evaluate the anti-tumor activity in each arm.
    • To evaluate the overall safety profile in each arm.
    • To evaluate the pharmacokinetics of paclitaxel and carboplatin alone
    and in combination with avelumab.
    • To evaluate the PK of avelumab alone and in combination with carboplatin-paclitaxel (Arms B and C).
    • To evaluate the immunogenicity of avelumab alone and in combination with carboplatinpaclitaxel (Arms B and C).
    • To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab in combination with and/or following carboplatin-paclitaxel in pre-treatment tumor tissue, that may aid in the
    identification of patient subpopulations most likely to benefit from
    treatment.
    • To evaluate patient reported outcome in each treatment arm in
    patients with previously untreated EOC including the assessment of
    treatment side effects and diseaserelated symptoms.
    Confrontare il Braccio C e il Braccio B con il Braccio A nelle pazienti con carcinoma ovarico precedentemente non trattato, relativamente alla sopravvivenza complessiva.
    • Valutare l’attività antitumorale in ciascun braccio. • • Valutare il profilo di sicurezza complessiva in ciascun braccio.
    • Valutare la farmacocinetica (PK) di paclitaxel e carboplatino da soli e in associazione ad avelumab. • Valutare la PK di avelumab da solo e in associazione a carboplatino‑paclitaxel (Braccio B e C).
    • Valutare l’immunogenicità di avelumab da solo e in associazione a carboplatino‑paclitaxel.
    • Valutare i biomarcatori predittivi candidati della sensibilità o resistenza ad avelumab in associazione a e/o dopo carboplatino‑paclitaxel nel tessuto tumorale precedente al trattamento che possano aiutare a identificare le sotto-popolazioni di pazienti che più probabilmente beneficerebbero del trattamento.
    • Valutare gli esiti riferiti dal paziente.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed Stage III-IV epithelial ovarian, fallopian tube,
    or primary peritoneal cancer (according to AJCC/
    UICC TNM and International Federation of Gynecology and Obstetrics (FIGO) Staging System 2014 edition), including malignant mixed Müllerian tumors with high grade serous component.
    2. Patients must be candidates for platinum-based chemotherapy and
    previously untreated.
    3. Patients must have completed a surgical debulking procedure, or be
    candidates for neoadjuvant chemotherapy.
    a. For patients enrolling after debulking surgery, the following conditions
    must be met:
    • The minimum surgery required is an abdominal surgery with an
    attempt at cytoreduction providing tissue for histologic evaluation and
    establishing and documenting the primary site and stage.
    • Patient must be randomized at a maximum of 8 weeks after surgery.
    b. For patients who are candidates for neoadjuvant chemotherapy, the
    following conditions must be met:
    • A core tissue (not fine needle aspiration) biopsy is required. The tissue
    must be consistent with a tumor of Müllerian origin.
    • Stage IIIC–IV documented via imaging or surgery (without attempt at
    cytoreduction).
    • Serum CA125/ CEA ratio > 25. If the serum CA125/CEA ratio is < 25,
    workup should be negative for the presence of a primary gastrointestinal
    or breast malignancy (< 6 weeks before randomization).
    • Plan to receive carboplatin-paclitaxel neoadjuvant chemotherapy.
    • Randomization must occur within 8 weeks after diagnosis.
    4. Availability of an archival formalin-fixed, paraffin-embedded (FFPE)
    tumor tissue block or a minimum of 15 slides. If archived FFPE tissue is
    not available, a
    de novo (ie, fresh) tumor sample must be obtained in accordance with
    local institutional practice for tumor biopsies.
    5. Eastern Cooperative Group (ECOG) performance status 0-1
    6. Age ≥18 years (or ≥20 years in Japan).
    7. Adequate hematological function (ANC ≥1.5 x 10 to the power 9/L,
    Hgb ≥9.0 g/dL, and platelet count ≥100 x 10 to the power 9/L).
    8. Adequate liver function tests (ALT/AST ≤2.5 x ULN, total serum
    bilirubin level ≤1.5 x ULN).
    9. Adequate renal function by estimated creatinine clearance ≥50
    mL/min as calculated using the Cockcroft-Gault method.
    10. Estimated life expectancy of at least 12 weeks.
    11. Evidence of a personally signed and dated informed consent
    document indicating that the patient (or a legally acceptable
    representative) has been informed of all pertinent aspects of the study.
    12. Patients who are willing and able to comply with scheduled visits,
    treatment plan, laboratory tests, and other study procedures.
    13. Patients of childbearing potential and at risk for pregnancy must
    agree to use 2 highly effective methods of contraception throughout the
    study and for at least 60 days after the last dose of assigned treatment.
    Patients of non-childbearing potential must meet at least one of the
    following criteria:
    • Have undergone a documented hysterectomy and/or bilateral ophorectomy;
    • Have medically confirmed ovarian failure; or
    • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative
    pathological or physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state.
    All other patients (including patients with tubal ligations) will be considered to be of childbearing potential.
    1. Tumore ovarico epiteliale di stadio III-IV, delle tube di Falloppio o peritoneale primario confermato istologicamente (secondo il sistema di stadiazione edizione 2014 di AJCC/UICC TNM e della International Federation of Gynecology and Obstetrics [FIGO]), inclusi i tumori mulleriani misti maligni con componente sierosa di grado elevato.
    2. Le pazienti devono essere candidate alla chemioterapia a base di platino e non trattate in precedenza.
    3. Le pazienti devono aver completato una procedura di rimozione chirurgica della massa, o essere candidate a chemioterapia neoadiuvante.
    a. Per le pazienti in arruolamento dopo la rimozione chirurgica della massa, devono essere soddisfatte le seguenti condizioni:
    • L'intervento chirurgico minimo richiesto è un intervento addominale per tentare una citoriduzione che fornisca tessuto per la valutazione istologica e la determinazione e la documentazione del sito primario e dello stadio.
    • Le pazienti devono essere randomizzate al massimo 8 settimane dopo l'intervento chirurgico.
    b. Per le pazienti candidate alla chemioterapia neoadiuvante, devono essere soddisfatte le seguenti condizioni:
    • È necessaria un'agobiopsia tissutale (non agoaspirato con ago sottile). Il tessuto deve corrispondere a un tumore di origine mulleriana.
    • Lo stadio IIIC-IV deve essere documentato mediante tecniche di diagnostica per immagini o intervento chirurgico (senza tentare una citoriduzione).
    • Rapporto CA125/ CEA sierico > 25. Se il rapporto CA125/CEA sierico è < 25, il check-up deve essere negativo per la presenza di un tumore maligno mammario o gastrointestinale primario (< 6 settimane prima della randomizzazione).
    • È stato programmato il trattamento con la chemioterapia neoadiuvante con carboplatino‑paclitaxel.
    • La randomizzazione deve avvenire entro 8 settimane dalla diagnosi.
    4. Disponibilità di un blocchetto di tessuto tumorale di archivio fissato in formalina e incluso in paraffina (formalin‑fixed, paraffin‑embedded, FFPE) o di un minimo di 15 vetrini.
    Qualora non sia disponibile un tessuto FFPE, deve essere prelevato un campione tumorale de novo (cioè fresco), secondo le pratiche locali dell'istituto per le biopsie tumorali.
    5. Stato di validità secondo il Gruppo cooperativo orientale (Eastern Cooperative Group, ECOG) da 0 a 1 (consultare l'Appendice 2).
    6. Età ≥18 anni (o ≥ 20 anni in Giappone).
    7. Adeguata funzionalità ematologica (ANC ≥1.5 x 10 alla potenza 9/l, Hgb ≥9.0 g/d, e conta piastrinica ≥100 x 10 to the power 9/L).
    8. Adeguati test di funzionalità epatica (ALT/AST ≤2.5 x ULN, livello di bilirubina sierica totale ≤1.5 x ULN).
    9. Adeguata funzionalità renale secondo la clearance della creatinina stimata ≥50 ml/min calcolata utilizzando il metodo di Cockcroft‑Gault.
    10. Aspettativa di vita stimata di almeno 12 settimane.
    11. Dimostrazione di un documento di consenso informato personalmente firmato e datato, indicante che la paziente (o un rappresentante legalmente accettabile) è stata informata su tutti gli aspetti pertinenti allo studio.
    12. Pazienti che accettano e sono in grado di attenersi alle visite programmate, ai piani di trattamento, ai test di laboratorio e alle altre procedure previste dallo studio.
    13. Le pazienti potenzialmente fertili e a rischio di gravidanza devono accettare di utilizzare 2 metodi contraccettivi altamente efficaci per tutta la durata dello studio e per almeno 60 giorni dopo l'ultima dose del trattamento assegnato.
    Le pazienti non potenzialmente fertili devono soddisfare almeno uno dei seguenti criteri:
    • Soggetti che hanno subito un'isterectomia e/o un'ovariectomia bilaterale documentate;
    • che presentano insufficienza ovarica clinicamente confermata o
    • sono in fase postmenopausale, definita come segue: cessazione del normale ciclo mestruale da almeno 12 mesi consecutivi in assenza di altra causa patologica o fisiologica; lo stato può essere confermato dalla presenza di un livello sierico di ormone follicolo-stimolante (follicle-stimulating hormone, FSH) che conferma lo stato di post-menopausa.
    Tutte le altre pazienti (incluse quelle con legatura delle tube) verranno considerate potenzialmente fertili.
    E.4Principal exclusion criteria
    1. Non-epithelial tumors, or ovarian tumors with low malignant potential
    (ie, borderline tumors).
    2. Mucinous tumors.
    3. Patients for whom, in the opinion of the Investigator, there is clinical benefit to administer bevacizumab as a first-line treatment and for whom bevacizumab is approved and available in this setting.
    4. Cancer for which intraperitoneal cytotoxic chemotherapy is planned.
    5. Prior systemic anti-cancer treatment for EOC, FTC, or PPC.
    6. Prior immunotherapy with IL-2, IFN-α, or anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte associated antigen 4
    (anti-CTLA-4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
    7. Major surgery (other than debulking surgery) for any reason within 4 weeks prior to randomization and/or incomplete recovery from surgery.
    8. Known brain, leptomeningeal, or spinal cord metastases.
    9. Current or prior use of immunosuppressive medication within 7 days prior to randomization, except the following: intranasal, inhaled, topical
    steroids, or local steroid injections (eg, intra-articular injection); systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent; steroids as premedication for hypersensitivity reactions [eg, computed tomography (CT) scan premedication].
    10. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents except patients with diabetes type I, vitiligo,
    psoriasis, hypo- or hyperthyroidism not requiring immunosuppressive treatment.
    11. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, oronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident,
    transient ischemic attack, deep vein thrombosis or symptomatic pulmonary embolism.
    12. Active and clinically significant bacterial, fungal or viral infection, any positive tests for hepatitis B (HBV), hepatitis C (HCV) indicating acute or chronic infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive), known history of a positive test for human ommunodeficiency virus (HIV), or acquired
    immunodeficiency syndrome (AIDS) related illness.
    13. Administration of a live vaccine within 30 days prior to study entry.
    14. Known severe hypersensitivity reactions to monoclonal antibodies, carboplatin, paclitaxel, or other platinum-containing compounds (NCICTCAE v4.03 Grade ≥3).
    15. Persisting NCI CTCAE v4.03 Grade >1 toxicity related to prior therapy.
    16. Previous malignant disease other than the target malignancy to be investigated in this trial within the last 5 years with the exception of adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS).
    17. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members
    otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of the study.
    18. Participation in other clinical studies involving investigational drug(s) within 4 weeks prior to study randomization and/or during study participation.19. Other severe/severe acute or chronic medical, including colitis, inflammatory bowel disease, and pneumonitis, or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior) or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    20. Pregnant patients or breastfeeding patients.
    21. Patients with bleeding tumors.
    1. Tumori non epiteliali o tumori ovarici con basso potenziale di malignità (cioè tumori borderline).
    2. Tumori mucinosi.
    3. Pazienti per le quali, vista l'opinione dello Sperimentatore c'è un beneficio clinico con la somministrazione di bevacizumab e per le quali il bevacizumab come prima linea di trattamento è stata approvata e disponibile.
    4. Tumore per il quale è stata programmata chemioterapia citotossica intraperitoneale.
    5. Precedente trattamento antitumorale sistemico per EOC, FTC o PPC.
    6. Precedente immunoterapia con IL-2, IFN‑α, o anti‑PD‑1, anti‑PD‑L1, anti‑PD‑L2, anti‑CD137 o anticorpo contro antigene 4 associato ai linfociti T citotossici (anti-CTLA-4) (incluso ipilimumab) o qualunque altro anticorpo o farmaco diretti specificamente contro la co-stimolazione delle cellule T o i pathway immunitari checkpoint.
    7. Intervento chirurgico maggiore (diverso dalla rimozione chirurgica della massa) per qualunque motivo nelle 4 settimane precedenti la randomizzazione e/o recupero incompleto in seguito a intervento chirurgico.
    8. Metastasi note al cervello, al midollo spinale o leptomeningee.
    9. Uso attuale o precedente di farmaci immunosoppressori nei 7 giorni precedenti la randomizzazione, a accezione dei seguenti: steroidi per via intranasale, per inalazione o topici, o iniezioni locali di steroidi (ad es. iniezione intra-articolare); corticosteroidi per via sistemica a dosi fisiologiche {ut}10 mg/die di prednisone o equivalente; steroidi come premedicazione per reazioni di ipersensibilità [per es. premedicazione per tomografia computerizzata (TC)].
    10. Patologia autoimmune in fase attiva che potrebbe peggiorare in caso di trattamento con agenti immunostimolanti a eccezione delle pazienti affette da diabete di tipo I, vitiligine, psoriasi, ipo- o ipertiroidismo che non richiedano trattamento immunosoppressivo.
    11. Uno qualsiasi dei seguenti nei 6 mesi precedenti: infarto miocardico, angina grave/instabile, chirurgia di bypass aortocoronarico o arteria periferica, insufficienza cardiaca congestizia sintomatica, accidente cerebrovascolare, attacco ischemico transitorio, trombosi venosa profonda o embolia polmonare sintomatica.
    12. Infezioni batteriche, micotiche o virali attive e clinicamente significative, qualunque test positivo per epatite B (HBV), epatite C (HCV) indicante infezione acuta o cronica, immunodeficienza virale da HIV o patologie connesse alla sindrome da immunodeficienza acquisita (AIDS) note.
    13. Somministrazione di un vaccino vivo nei 30 giorni precedenti l'ingresso nello studio.
    14. Reazioni note di grave ipersensibilità ad anticorpi monoclonali, carboplatino o paclitaxel (di grado >3 .secondo i criteri NCI-CTCAE v 4.03), qualsiasi anamnesi di anafilassi o asma non controllata (ovvero, 3 o più caratteristiche di asma parzialmente controllata).
    15. Tossicità persistente di grado >1 secondo i criteri NCI-CTCAE v 4.03 correlata a terapia
    precedente.
    16. Precedente malignità diversa dalla malignità bersaglio oggetto di studio in questa sperimentazione negli ultimi 5 anni a eccezione del carcinoma cutaneo baso cellulare o squamo cellulare adeguatamente trattato, del carcinoma cervicale in situ, del carcinoma lobulare in situ (lobular carcinoma in situ, LCIS) o del carcinoma duttale in situ (ductal carcinoma in situ, DCIS).
    17. Pazienti che siano membri del personale del centro sperimentale direttamente coinvolti nella conduzione dello studio e loro familiari, membri del personale del centro altrimenti sotto la supervisione dello sperimentatore o dipendenti di Pfizer direttamente coinvolti nella conduzione dello studio.
    18. Partecipazione ad altri studi clinici con uno o più farmaci sperimentali nelle 4 settimane precedenti la randomizzazione nello studio e/o durante la partecipazione allo studio.
    19.Altre patologie mediche gravi, acute o croniche, tra cui colite, malattia infiammatoria intestinale e polmonite, o patologia psichiatrica, inclusi comportamento o ideazione suicidaria in corso o recente (entro l'ultimo anno), o valori anomali di laboratorio che possano aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco sperimentale, o che possano interferire con l'interpretazione dei risultati dello studio e che, a giudizio dello sperimentatore, renderebbero il paziente inadatto all'ammissione allo stesso.
    20. Pazienti in gravidanza o in allattamento.
    21. Pazienti con tumori sanguinanti.
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS) as determined by the blinded indipendent central review (BICR) by RECIST v1.1.
    Progressione libera da sopravvivenza, determinata dal revisore centrale indipendente in cieco, RECIST versione 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    as per protocol
    come da protocollo
    E.5.2Secondary end point(s)
    • Efficacy: Overall survival (OS), PFS by Investigator assessment as well as Objective response (OR), Duration of response (DR), Maintenance PFS by BICR assessments and Investigator assessment, pathological Complete Response (pCR), PFS2, and PFS by Gynecological Cancer Intergroup (GCIG) criteria
    • Safety: AEs (as graded by NCI CTCAE v.4.03); laboratory abnormalities (as graded by NCI CTCAE v.4.03); vital signs (blood pressure, pulse rate); electrocardiograms (ECGs)
    • Patient-Reported Outcomes: FOSI-18 and EuroQoL5 Dimension (EQ- 5D-5L)
    • Pharmacokinetics: PK parameters, including Ctrough, Cmax, volume of distribution (Vd), clearance (CL), area under the concentration time curve (AUC) for avelumab, paclitaxel, and carboplatin, as data permit
    • Immunogenicity: anti-drug antibodies (ADA) and neutralizing antibodies (Nab) against avelumab
    • Candidate predictive biomarkers in tumor tissue including, but not limited to, PD-L1 expression and tumor infiltrating CD8+ T lymphocytes as assessed by immunohistochemistry (IHC)
    Efficacia: sopravivvenza globale (OS), PFS di valutazione dello sperimentatore, come inoltre la risposta obiettiva (OR), durata della risposta (DR), Manutenzione PFS, valutazioni BICR e valutazione dello sperimentatore, Risposta completa patologica (PCR), PFS2, e PFS valutata secondo i criteri della Gynecologic Cancer Intergroup (GCIG).
    • Sicurezza: eventi avversi (come classificato da NCI CTCAE v.4.03); anomalie di laboratorio (Come classificato dal NCI CTCAE v.4.03); segni vitali (pressione arteriosa, polso rate); elettrocardiogrammi (ECG)
    • riferito dal paziente Risultati: FOSI-18 e EuroQoL5 Dimension (EQ- 5D-5L)
    • Farmacocinetica: parametri farmacocinetici, tra cui Ctrough, Cmax, il volume di distribuzione (Vd), la clearance (CL), area sotto il tempo di concentrazione curva (AUC) per avelumab, paclitaxel e carboplatino, come permesso dai dati
    • immunogenicità: anticorpi anti-droga (ADA) e neutralizzante anticorpi (Nab) contro avelumab
    • candidati biomarcatori predittivi del tessuto tumorale tra cui, ma non limitato a, espressione PD-L1 e tumore infiltrante linfociti T CD8 + valutata mediante immunoistochimica (IHC)

    E.5.2.1Timepoint(s) of evaluation of this end point
    as per protocol
    come da protocollo
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic 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 No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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
    Chemioterapia
    Chemotherapy
    E.8.2.4Number of treatment arms in the trial3
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA84
    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
    Bulgaria
    Canada
    Croatia
    Estonia
    Germany
    Hong Kong
    Hungary
    Ireland
    Italy
    Japan
    Korea, Democratic People's Republic of
    Latvia
    Mexico
    Netherlands
    Poland
    Romania
    Russian Federation
    Singapore
    Slovakia
    Spain
    Switzerland
    Taiwan
    Turkey
    Ukraine
    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 years5
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months11
    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.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 476
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 475
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 554
    F.4.2.2In the whole clinical trial 951
    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)
    For patients who remain on treatment with avelumab at the end of study, another source of access to avelumab will be proposed.
    Per i pazienti che rimangono in trattamento con avelumab alla fine dello studio , sarà proposta un'altra fonte di accesso alle avelumab.
    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 Decision2016-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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