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    Summary
    EudraCT Number:2017-004456-30
    Sponsor's Protocol Code Number:B9991030
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-11-10
    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 number2017-004456-30
    A.3Full title of the trial
    A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB IN COMBINATION WITH CHEMOTHERAPY FOLLOWED BY MAINTENANCE THERAPY OF AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER
    STUDIO DI FASE 3, RANDOMIZZATO, IN APERTO, MULTICENTRICO PER VALUTARE L’EFFICACIA E LA SICUREZZA DI AVELUMAB IN COMBINAZIONE CON CHEMIOTERAPIA, SEGUITO DA TERAPIA DI MANTENIMENTO CON AVELUMAB IN COMBINAZIONE CON TALAZOPARIB, INIBITORE DELLA POLI-ADENOSINA DIFOSFATO (ADP)-RIBOSIO POLIMERASI (PARP), IN PAZIENTI CON TUMORE DELL’OVAIO AVANZATO PRECEDENTEMENTE NON TRATTATO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB IN COMBINATION WITH CHEMOTHERAPY FOLLOWED BY MAINTENANCE THERAPY OF AVELUMAB IN COMBINATION WITH TALAZOPARIB IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER
    STUDIO PER VALUTARE L’EFFICACIA E LA SICUREZZA DI AVELUMAB IN COMBINAZIONE TALAZOPARIB IN PAZIENTI CON TUMORE DELL’OVAIO AVANZATO PRECEDENTEMENTE NON TRATTATO
    A.3.2Name or abbreviated title of the trial where available
    JAVELIN OVARIAN PARP 100
    JAVELIN OVARIAN PARP 100
    A.4.1Sponsor's protocol code numberB9991030
    A.5.4Other Identifiers
    Name:US INDNumber:IND 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 10
    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 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018007181021
    B.5.5Fax number0013037391119
    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.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Europe Limited
    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 [AVELUMAB]
    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 INNAVELUMAB
    D.3.9.2Current sponsor codeMSB0010718C
    D.3.9.3Other descriptive nameAnti PD-L1
    D.3.9.4EV Substance CodeSUB180078
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameTALAZOPARIB
    D.3.2Product code [TALAZOPARIB]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalazoparib
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.4EV Substance CodeSUB183862
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP 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 AVASTIN - 1 FLACONCINO DA 400 MG DI CONCENTRATO PER SOLUZIONE PER INFUSIONE
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBEVACIZUMAB
    D.3.2Product code [BEVACIZUMAB]
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor code.
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name PACLITAXEL ACCORD HEALTHCARE ITALIA - 6 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO IN VETRO DA 100MG/16.7ML
    D.2.1.1.2Name of the Marketing Authorisation holderACCORD HEALTHCARE ITALIA S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePACLITAXEL
    D.3.2Product code [PACLITAXEL]
    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 codePACLITAXEL
    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.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name CARBOPLATINO AHCL - 10 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO DI VETRO DA 15 ML
    D.2.1.1.2Name of the Marketing Authorisation holderACCORD HEALTHCARE LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCARBOPLATINO
    D.3.2Product code [CARBOPLATINO]
    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 INNCARBOPLATINO
    D.3.9.1CAS number 41575-94-4
    D.3.9.2Current sponsor codeCARBOPLATINO
    D.3.9.4EV Substance CodeSUB06614MIG
    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 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
    PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER
    TUMORE DELL’OVAIO AVANZATO PRECEDENTEMENTE NON TRATTATO
    E.1.1.1Medical condition in easily understood language
    Previously untreated advanced cancer of the ovaries
    TUMORE DELL’OVAIO AVANZATO PRECEDENTEMENTE NON TRATTATO
    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 LLT
    E.1.2Classification code 10033130
    E.1.2Term Ovarian cancer NOS
    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 demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging progression-free survival (PFS) in patients with advanced ovarian cancer with defects in DNA damage repair (DDR+).
    • Dimostrare che avelumab in combinazione con la chemioterapia a base di platino seguito da avelumab più mantenimento con talazoparib sia superiore alla chemioterapia a base di platino più bevacizumab seguiti da mantenimento con bevacizumab nel prolungare la PFS in pazienti affette da carcinoma ovarico avanzato con difetti nella riparazione dei danni al DNA (DDR+).
    E.2.2Secondary objectives of the trial
    - To demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging overall survival (OS) in patients with advanced ovarian cancer with defects in DNA damage repair (DDR+).
    - To demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging PFS in patients with advanced ovarian cancer unselected for DDR status.

    Refer to protocol for the full list of Secondary Objectives.
    • Dimostrare che avelumab in combinazione con la chemioterapia a base di platino seguito da avelumab più mantenimento con talazoparib sia superiore alla chemioterapia a base di platino più bevacizumab seguiti da mantenimento con bevacizumab nel prolungare la sopravvivenza complessiva (OS) in pazienti affette da carcinoma ovarico avanzato con difetti nella riparazione dei danni al DNA (DDR+).
    • Dimostrare che avelumab in combinazione con la chemioterapia a base di platino seguito da avelumab più mantenimento con talazoparib sia superiore alla chemioterapia a base di platino più bevacizumab seguiti da mantenimento con bevacizumab nel prolungare la PFS in pazienti affette da carcinoma ovarico avanzato non selezionate per lo stato di DDR.

    Far riferimento al protocollo per la lista intera degli obiettivi secondari
    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 American Joint Committee on Cancer (AJCC)/UICC TNM and International Federation of Gynecology and Obstetrics (FIGO) Staging System 2014 edition), including carcinosarcoma with high-grade serous component.
    2. Pts must be candidates for bevacizumab in combination with platinum based chemotherapy and previously untreated.
    3. Must have completed a primary surgical debulking procedure, or be candidates for neoadjuvant chemotherapy with planned interval debulking surgery.
    a. Pts who completed primary debulking must have had incompletely resected disease that is macroscopically/grossly visible and at least with lesions >1 mm and be randomized at a maximum of 8 weeks after surgery.
    b. For pts who are candidates for neoadjuvant chemotherapy, the diagnoses must have been confirmed by:
    - Core tissue (not fine-needle aspiration) biopsy is required for diagnosis. The tissue must be consistent with inclusion criteria #1 above.
    - Stage IIIC–IV documented via imaging or surgery (without attempt at cytoreduction).
    - Serum CA-125/CEA ratio >25. If the serum CA-125/CEA ratio is <25, then workup should be negative for the presence of a primary gastrointestinal or
    breast malignancy (<6 weeks before start of neoadjuvant treatment).
    - 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 25 slides, together with an accompanying original Hemotoxylin and Eosin (H&E) slide. 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. Tumor tissue must contain 40% or greater tumor nuclei per central laboratory assessment.
    - Sites may randomize/enroll pts who meet all other eligibility criteria while awaiting central confirmation of tissue acceptance, but must provide
    additional tumor samples in the event that the central lab review shows insufficient sample quality.
    5. Eastern Cooperative Group (ECOG) performance status 0-1.
    6. Age =18 years (or =20 years in Japan).
    7. Adequate bone marrow function including: absolute neutrophil count (ANC) =1,500/mm3 or 1.5 x 109/L; Platelets =100,000/mm3 or =100 x 109/L; hemoglobin =9.0 g/dL (may have been transfused).
    8. Adequate hepatic function defined by a total bilirubin level =1.5 x upper limit of normal range (ULN), an ALT/AST level =2.5 x ULN.
    9. Adequate renal function by estimated creatinine clearance =60 mL/min as calculated using the Cockcroft-Gault method or by 24 hour urine collection for creatinine clearance or according to local institutional standard method.
    10. Adequate blood coagulation parameters: International normalized ratio (INR) =1.5 and aPTT <1.2 times the upper limit of normal.
    11. Ability to swallow study drugs.
    12. Evidence of a personally signed and dated informed consent document indicating that the pt (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
    13. Pts who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.


    Please refers to the Protocol for full list
    1.Carcinoma ovarico epiteliale di stadio III-IV,delle tube di Falloppio o peritoneale primario confermato istologicamente(secondo classificazione di tumore/linfonodi/metastasi [TNM] del Comitato congiunto americano per il tumore (AJCC)/Unione internazionale per il controllo dei tumori [UICC] e il sistema di stadiazione della Federazione internazionale di ginecologia e ostetricia [FIGO], edizione 2014), inclusi i carcinosarcomi con componente sierosa di grado elevato
    2.pz devono essere candidate a bevacizumab con chemioterapia a base di platino e non trattate prima
    3.pz devono aver completato una procedura chirurgica citoriduttiva primaria o essere candidate alla chemioterapia neoadiuvante con chirurgia citoriduttiva di intervallo programmata
    a.pz che hanno completato la citoriduzione primaria con esito la resezione incompleta della malattia che risulta microscopicamente/grossolanamente visibile e con lesioni di almeno >1 mm e devono essere state randomizzate non oltre 8 sett dopo l’intervento chirurgico
    b.Per le pz candidate alla chemioterapia neoadiuvante, le diagnosi devono essere state confermate mediante:
    •un’agobiopsia tissutale(non agoaspirato con ago sottile).Il tessuto deve essere soddisfare il criterio di inclusione n.1 di cui sopra
    •Stadio IIIC-IV documentato mediante tecniche di diagnostica per immagini o intervento chirurgico(senza tentare una citoriduzione)
    •Rapporto CA-125/CEA sierico >25.Se il rapporto CA-125/CEA sierico è <25, il check-up deve essere negativo per la presenza di un tumore maligno mammario o gastrointestinale primario(<6 sett prima dell’inizio del trattamento neoadiuvante)
    •La randomiz. deve avvenire entro 8 sett dalla diagnosi
    4.Disponibilità di un blocchetto di tessuto tumorale di archivio fissato in formalina e incluso in paraffina (FFPE) o almeno 25 vetrini, più un vetrino originale complementare colorato con ematossilina ed eosina (H&E).se non disponibile un tessuto FFPE, deve essere prelevato un campione tumorale de novo (cioè fresco), secondo le pratiche istituzionali locali per le biopsie tumorali.Il tessuto tumorale deve contenere =40% di nuclei tumorali secondo la valutazione del laboratorio centrale
    •I centri possono randomizzare/arruolare pz che soddisfano tutti gli altri criteri di eleggibilità 8in attesa di conferma centrale di accettazione del tessuto, ma dovranno fornire campioni tumorali aggiuntivi qualora dalla revisione eseguita dal lab. centrale emerga una qualità insufficiente del campione
    5.Stato di validità 0-1 secondo il Gruppo cooperativo orientale di oncologia (ECOG) (ved. App2)
    6.Età=18 anni(o=20 anni in Giappone)
    7.Adeguata funzione midollare, comprese: conta neutrofilica assoluta (ANC)=1,500/mm3 o 1,5 x 109/l; piastrine=100.000/mm3 o =100 x 109/l; emoglobina=9,0 g/dl (è consentita la terapia trasfusionale)
    8.Adeguata funzione epatica definita da un livello di bilirubina totale <=1,5 x l’intervallo del limite superiore della norma (ULN) e un livello di alanina/aspartato aminotransferasi (ALT/AST)<=2,5 xULN
    9.Funzione renale adeguata, definita da un valore della clearance della creatinina stimata =60 ml/min calcolata usando il metodo di Cockcroft Gault o mediante raccolta delle urine nelle 24 ore in base al metodo istituzionale standard locale
    10.Adeguati parametri della coagulazione del sangue: rapporto internazionale normalizzato (INR) <=1,5 e tempo di protrombina parziale attivata (aPTT) <1,2 volte il limite superiore della norma.
    11.Capacità di deglutire i farmaci dello studio
    12.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
    13.Pz che accettano e sono in grado di attenersi alle visite programmate, al piano di trattamento, agli esami di laboratorio e alle altre procedure previste dallo studio


    Per la lista completa riferirsi al protocollo di studio
    E.4Principal exclusion criteria
    1. Non-epithelial tumors or ovarian tumors with low malignant potential (ie, borderline tumors) or mucinous tumors.
    2. Patients for whom intraperitoneal cytotoxic chemotherapy is planned.
    3. Prior exposure to immunotherapy with interleukin (IL)-2, interferon alpha (IFN-a), or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, excluding therapeutic anticancer vaccines.
    4. Prior treatment with a PARP inhibitor.
    5. Prior treatment with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab.
    6. Major surgery (other than debulking or exploratory surgery for ovarian cancer) for any reason within 4 weeks prior to randomization and/or incomplete recovery from surgery.
    7. Prior radiotherapy to any portion of the abdominal cavity or pelvis. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease.
    8. Prior targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their ovarian, peritoneal primary or fallopian tube carcinoma.
    9. Prior organ transplantation including allogenic stem cell transplantation.
    10. Diagnosis of Myelodysplastic Syndrome (MDS).
    11. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
    12. Current or anticipated use of a strong P-glycoprotein (Pgp) inhibitor (eg, dronedarone, quinidine, ranolazine, itraconazole, ketoconazole), strong P-gp inducer (eg, rifampin, ritonavir, tipranavir), or strong inhibitor of breast cancer resistance protein (eg, elacridar [GF120918]).
    13. Current use of immunosuppressive medication at the time of randomization, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (eg, intra-articular injection); b. Systemic corticosteroids at physiologic doses =10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
    14. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroidism not requiring immunosuppressive treatment are eligible.
    15. Clinically significant (ie, active) cardiovascular disease: cerebrovascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (greater than New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
    16. Uncontrolled hypertension, defined as systolic >140 mm Hg or diastolic >90 mm Hg documented by 2 blood pressure readings taken at least 1 hour apart. Use of antihypertensive medications to control blood presuure (BP) is allowed.
    17. Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.


    Please refers to the Protocol for full list
    1.Tumori non epiteliali o ovarici con basso potenziale di malignità(cioè tumori borderline) o mucinosi
    2.Pz con chemioterapia citotossica intraperitoneale già programmata
    3.Prec.esposizione all’immunoterapia con i(IL)-2, i(IFN a), o un anticorpo anti PD 1, anti PD L1, anti PD L2, anti CD137 o anti-antigene 4 associato ai linfociti T citotossici (CTLA-4) (incluso ipilimumab) o altro anticorpo o farmaco diretto specificamente contro la co-stimolazione delle cellule T o i pathway dei checkpoint immunitari, esclusi i vaccini terapeutici antitumorali
    4.Prec. trattam. con un inibitore della PARP
    5.Prec. trattam. con ogni farmaco anti-fattore di crescita endoteliale epiteliale(VEGF),compreso bevacizumab
    6.Intervento chirurgico maggiore(diverso da citoriduzione o chirurgia esplorativa per tumore ovarico)per qualunque motivo nelle 4 sett. prima la randomizz. e/o recupero incompleto in seguito a chirurgia
    7.Prec.radioterapia su qualsiasi porzione della cavità addominale o pelvi. In caso di tumore localizzato della mammella, della testa e del collo, o della cute è consentita se completata oltre tre anni prima della registrazione e che la paziente sia rimasta libera da malattia ricorrente o metastatica
    8.Prec terapia mirata (compresi, senza limitazione, vaccini, anticorpi, inibitori tirosin-chinasici) o terapia ormonale per la gestione di carcinoma ovarico, peritoneale primario o delle tube di Falloppio
    9.Precedente trapianto d’organo, incluso trapianto allogenico di cellule staminali.
    10.Diagnosi di sindrome mielodisplastica (SMD)
    11.Metastasi cerebrali sintomatiche accertate richiedenti l’uso di steroidi. Le pz con metastasi cerebrali precedentemente diagnosticate sono idonee se hanno completato il trattam. e se si sono ristabilite dagli effetti acuti della radioterapia o dell’intervento chirurgico prima dell’arruolamento nello studio, se hanno interrotto il trattam. con corticosteroidi per tali metastasi da almeno 4 sett. e se presentano condizioni stabili dal punto di vista neurologico
    12.Uso attuale o previsto di un forte inibitore della glicoproteina P (P-gp) (es. dronedarone, chinidina, ranolazina, itraconazolo, ketoconazolo), forte induttore della P-gp (es. rifampina, ritonavir, tipranavir) o forte inibitore della proteina di resistenza del tumore mammario (es. elacridar [GF120918])
    13.Attuale uso di farmaci immunosoppressivi al momento della randomizzazione ESCLUSI i seguenti: a. steroidi intranasali, inalatori, topici o iniezione locale di steroidi (es. iniezione intra-articolare); b. corticosteroidi sistemici a dosi fisiologiche (=10 mg/die di prednisone o equivalente); c. steroidi come premedicazione per reazioni di ipersensibilità (per es., premedicazione per l’esame TC)
    14.Patologia autoimmune in fase attiva che potrebbe peggiorare in caso di trattam. con agenti immunostimolanti. Le pz con diabete di tipo I, vitiligine, psoriasi, ipo- o ipertiroidismo che non richiedono un trattam. immunosoppressivo sono idonee
    15.Patologia cardiovascolare clinicamente significativa (ovvero, attiva): accidente/ictus cerebrovascolare (<6 mesi prima dell’arruolamento), infarto del miocardio (<6 mesi prima dell’arruolamento), angina instabile, insufficienza cardiaca congestizia (di classe >II secondo la New York Heart Association) o aritmia cardiaca grave con necessità di terapia farmacologica
    16.Ipertensione non controllata, definita come una pressione arteriosa sistolica >140 mmHg o diastolica >90 mmHg documentata da 2 letture della pressione arteriosa acquisite a distanza di almeno 1 ora. È consentito l’uso di farmaci antipertensivi per controllare la pressione arteriosa (P.A.)
    17.Pz con condizioni emorragiche o patologiche attive ad alto rischio di sanguinamento, quali disturbo emorragico noto, coagulopatia o tumore a carico dei vasi maggiori
    18.Infezione attiva che richieda terapia sistemica


    Per la lista completa riferirsi al protocollo di studio
    E.5 End points
    E.5.1Primary end point(s)
    Progression-Free Survival (PFS) as determined based on Blinded Independent Central Review (BICR) assessment per RECIST v1.1 in patients with newly diagnosed advanced ovarian cancer with defects in DNA damage repair (DDR+).
    • PFS determinata in base alla valutazione dalla Revisione centrale indipendente in cieco (BICR) secondo i Criteri di valutazione della risposta nei tumori solidi (RECIST) v1.1 in pazienti affette da carcinoma ovarico avanzato di recedente diagnosi con difetti nella riparazione dei danni al DNA (DDR+).
    E.5.1.1Timepoint(s) of evaluation of this end point
    as per protocol
    come da protocollo
    E.5.2Secondary end point(s)
    OS in patients with tumors that are DDR+ and in patients unselected for DDR status. - PFS based on BICR assessment per RECIST v1.1 in patients unselected for DDR status. - PFS based on investigator assessment per RECIST v1.1 in patients with tumors that are DDR+ and in patients unselected for DDR status. - PFS2 based on investigator assessment in patients with tumors that are DDR+ and in patients unselected for DDR status. - PFS based on investigator assessment per Gynecological Cancer Intergroup (GCIG) criteria in patients with tumors that are DDR+ and in patients unselected for DDR status. - AEs (as graded by NCI CTCAE v4.03); laboratory abnormalities (as graded by NCI CTCAE v4.03); vital signs (blood pressure, pulse rate); electrocardiograms (ECGs). - PK parameters, including Ctrough and Cmax for avelumab and Ctrough for talazoparib. - Anti-drug antibodies (ADA) and neutralizing antibody (NAb) against avelumab. - Disease related symptoms and treatment side effects as measured by the NCCN-FACT FOSI-18 and health-related quality of life (HRQOL) as measured by NCCN-FACT FOSI-18 and the EuroQol Group 5-Dimension 5-Level (EQ-5D-5L). - PD-L1 expression, TMB, genomic scarring and the presence of defects in select genes, considered critical to effective DDR, in baseline tumor tissue. - Assessment of defects in a panel of key oncogenes, including several considered critical to effective DDR and TMB in ctDNA at baseline.
    • OS nelle pazienti con tumori DDR+ e pazienti non selezionate per lo stato di DDR.
    • PFS in base alla valutazione della BICR secondo i criteri RECIST v1.1 in pazienti non selezionate per lo stato di DDR.
    • PFS in base alla valutazione dello sperimentatore secondo i criteri RECIST v1.1 in pazienti con tumori DDR+ e in pazienti non selezionate per lo stato di DDR.
    • PFS dopo la successiva linea di trattamento (PFS2) in base alla valutazione dello sperimentatore in pazienti con tumori DDR+ e in pazienti non selezionate per lo stato di DDR.
    • PFS in base alla valutazione dello sperimentatore secondo i criteri dell’Intergruppo dei tumori ginecologici (GCIG) in pazienti con tumori DDR+ e in pazienti non selezionate per lo stato di DDR.
    • Eventi avversi (EA; definiti in base alla versione 4.03 dei Criteri comuni di terminologia per gli eventi avversi del National Cancer Institute [NCI CTCAE]), valori di laboratorio non normali (definiti in base ai criteri NCI CTCAE v.4.03), segni vitali (pressione arteriosa, frequenza cardiaca), elettrocardiogrammi (ECG).
    • Parametri PK, compresi concentrazione minima (Cmin) e concentrazione massima (Cmax) per avelumab e Cmin per talazoparib.
    • Anticorpi antifarmaco (ADA) e anticorpi neutralizzati (Nab) contro avelumab.
    • Sintomi correlati alla malattia ed effetti collaterali del trattamento misurati mediante la Valutazione funzionale della terapia antitumorale del National Cancer Comprehensive Network (NCCN-FACT)-Indice relativo ai sintomi del carcinoma ovarico (FOSI-18) e qualità della vita correlata alla salute (HRQOL) misurata mediante l’NCCN-FACT FOSI-18 e il Questionario europeo sulla qualità della vita a 5 dimensioni e 5 livelli (EQ-5D-5L).
    • Espressione di PD-L1, TMB, scarring genomico e presenza di difetti in geni selezionati, considerati critici per avere un’efficace DDR, nel tessuto tumorale al basale.
    • Valutazione dei difetti in un pannello di oncogeni chiave, compresi numerosi considerati fondamentali per avere un’efficace DDR, e TMB nel ctDNA al basale.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic 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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the 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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA89
    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
    Canada
    Croatia
    Czechia
    Estonia
    Germany
    Greece
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Poland
    Romania
    Russian Federation
    Singapore
    Slovakia
    Spain
    Taiwan
    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
    last patient last visit
    ultima visita dell'ultimo paziente
    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 months2
    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 months2
    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: 490
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 230
    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 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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 294
    F.4.2.2In the whole clinical trial 720
    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)
    No difference from normal treatment of this condition
    Nessuna differenza dalla terapia standard per questa patologia
    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 Decision2018-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-18
    P. End of Trial
    P.End of Trial StatusCompleted
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