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    Summary
    EudraCT Number:2018-001072-37
    Sponsor's Protocol Code Number:IRFMN-EN-7556
    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:2021-01-05
    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 number2018-001072-37
    A.3Full title of the trial
    AtTEnd: Atezolizumab Trial in Endometrial cancer - Phase III double-blind randomized placebo controlled trial of atezolizumab in combination with paclitaxel and carboplatin in women with advanced/recurrent endometrial cancer.
    Studio AtTEnd (Atezolizumab nel carcinoma dell’endometrio) - Studio clinico randomizzato controllato in doppio cieco di fase III che confronta l’aggiunta di ateolizumab a paclitaxel e carboplatino verso placebo in donne con carcinoma dell’endometrio in fase avanzata o recidivante.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    International study that compares a chemotherapy regimen with atezolizumab, paclitaxel and carboplatin versus a regimen with placebo, paclitaxel and carboplatin in patients affected by advanced or recurrent endometrial cancer
    Studio internazionale che compara un regime di chemioterapia contenente atezolizumab con paclitaxel e carboplatino con un regime contenente placebo con paclitaxel e carboplatino nelle pazienti affette da carcinoma dell’endometrio in fase avanzata o recidivante.
    A.3.2Name or abbreviated title of the trial where available
    AtTEnd
    AtTEnd
    A.4.1Sponsor's protocol code numberIRFMN-EN-7556
    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 SponsorIRCCS- ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS Istituto di Ricerche Farmacologiche Mario Negri
    B.5.2Functional name of contact pointLaboratorio Metodologia per la rice
    B.5.3 Address:
    B.5.3.1Street AddressVia G. La Masa
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20156
    B.5.3.4CountryItaly
    B.5.4Telephone number0239014648
    B.5.5Fax number0233200231
    B.5.6E-mailattend@marionegri.it
    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 Yes
    D.2.1.1.1Trade name Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationSwitzerland
    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 nameAtezolizumab
    D.3.2Product code [RO5541267]
    D.3.4Pharmaceutical form 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 INNAtezolizumab
    D.3.9.1CAS number 1380723-44-3
    D.3.9.2Current sponsor codeRO5541267-F03-01
    D.3.9.3Other descriptive nameTecentriq
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Yes
    D.2.1.1.1Trade name PACLITAXEL MYLAN GENERICS - 6 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO DI VETRO DA 16.7 ML
    D.2.1.1.2Name of the Marketing Authorisation holderMYLAN S.P.A.
    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 [NA]
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.2Current sponsor codena
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    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 SANDOZ GMBH - 10MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO IN VETRO DA 45ML
    D.2.1.1.2Name of the Marketing Authorisation holderSANDOZ GMBH
    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 [na]
    D.3.4Pharmaceutical form 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 codena
    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 number9
    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
    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
    Newly diagnosed, histologically-confirmed stage III-IV endometrial carcinoma/carcinosarcoma with residual disease after surgery, either measurable or evaluable, and naïve to first line systemic anti-cancer treatment. Recurrent endometrial cancer patients if not yet treated for recurrent disease
    Soggetti con nuova diagnosi, con conferma istologica di carcinoma dell'endometrio/carcinosarcoma di stadio III-IV con malattia residua dopo la chirurgia, misurabile o valutabile, e naive al trattamento antitumorale di prima linea. Pazienti con carcinoma endometriale in recidiva se non ancora trattati per la recidiva
    E.1.1.1Medical condition in easily understood language
    Advanced or recurrent endometrial cancer
    Carcinoma dell'endometrio in fase avanzata o recidivante
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10014772
    E.1.2Term Endometrioid adenocarcinoma recurrent
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10014776
    E.1.2Term Endometrioid adenocarcinoma stage III
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10014777
    E.1.2Term Endometrioid adenocarcinoma stage IV
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10014770
    E.1.2Term Endometrioid adenocarcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy in terms of PFS and OS of first-line atezolizumab versus placebo in combination with carboplatin and paclitaxel in patients with advanced stage III/IV or recurrent endometrial cancer.
    Confrontare nelle pazienti con carcinoma endometriale in stadio III / IV o ricorrente l'efficacia in prima linea di “atezolizumab+carboplatino+paclitaxel” verso “placebo+carboplatino+paclitaxel” in termini di PFS e sopravvivenza globale (OS).
    E.2.2Secondary objectives of the trial
    1. To determine the efficacy of atezolizumab as measured by:
    • Objective response rate (ORR) as assessed per RECIST v1.1 and median response duration
    • Time from randomization to second progression

    2. To assess the safety and tolerability of the addition of atezolizumab.
    3. To evaluate the effects of the addition of atezolizumab to carbo-taxol chemotherapy on Health-related Quality of Life (HRQoL) and patient function (physical, role).
    4. To evaluate any treatment burden patients may experience in association with atezolizumab versus placebo.
    5. To evaluate and compare between treatment arms patients' health status as measured by the EQ-5D-5L (including EQ VAS) to generate utility score.
    1. Determinare l'efficacia di atezolizumab misurando:
    • L’ ORR valutato secondo RECIST v1.1 e la durata della risposta mediana
    • Il tempo dalla randomizzazione alla seconda progressione
    2. Valutare la sicurezza e la tollerabilità dell'aggiunta di atezolizumab.
    3. Valutare gli effetti dell'aggiunta di atezolizumab alla chemioterapia con carbo-taxolo sulla “Health-related Quality of life” e sulla condizione del paziente.
    4. Valutare il deterioramento che il paziente può subire con l'aggiunta di atezolizumab a paclitaxel + carboplatino rispetto al placebo + paclitaxel + carboplatino
    5. Valutare e confrontare la salute delle pazienti tra i bracci di trattamento attraverso l’utilizzo del questionario EQ-5D-5L che permette di generare “utility scores”.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    I-1. Newly diagnosed, histologically-confirmed stage III-IV endometrial carcinoma/carcinosarcoma with residual disease after surgery, either measurable or evaluable, and naïve to first line systemic anti-cancer treatment. Recurrent endometrial cancer patients if not yet treated for recurrent disease.
    I-2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
    I-3. Age = 18 years
    I-4. In recurrent patients, only one prior line of systemic platinum-based regimen is permitted if the platinum-free interval = 6 months. Such prior line is the up-front/adjuvant treatment which can be concurrent chemoradiation or concurrent chemoradiation followed by chemotherapy or only chemotherapy.
    I-5. Patients with history of primary breast cancer may be eligible provided they completed their definitive anticancer treatment more than 3 years ago and they remain breast cancer disease free prior to start of study treatment.
    I-6. Previous pelvic and outside pelvis radiation is allowed, except for whole abdominal radiotherapy, if completed more than 6 weeks ago.
    I-7. Signed informed consent and ability to comply with treatment and follow-up.
    I-8. Representative FFPE tumor sample or, only if unfeasible, at least 20 unstained slides from initial surgery or from diagnostic biopsy, in case surgery was not performed, available and sent to central laboratory for Micro Satellite (MS) determination prior to randomization.
    I-9. Patients must have normal organ and bone marrow function :
    a. Haemoglobin = 10.0 g/dL.
    b. Absolute neutrophil count (ANC) = 1.5 x 109/L.
    c. Platelet count = 100 x 109/L.
    d. Total bilirubin = 1.5 x institutional upper limit of normal (ULN).
    e. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) = 2.5 x ULN, unless liver metastases are present in which case they must be = 5 x ULN.
    f. Serum creatinine = 1.5 x institutional ULN
    I-1. Soggetti con nuova diagnosi, con conferma istologica di carcinoma dell'endometrio/carcinosarcoma di stadio III-IV dopo la chirurgia, con malattia residua misurabile o valutabile o se inoperabile dopo una biopsia diagnostica, e naive al trattamento antitumorale di prima linea. Pazienti con carcinoma endometriale in recidiva se non ancora trattati per la recidiva.
    I-2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
    I-3. Età = 18 anni
    I-4. Una linea precedente di chemioterapia a base di platino è consentita se unica e terminata da più di (Platinum Free Interval, PFI= 6 mesi) 6 mesi. Tale linea sarebbe un trattamento up-front/adiuvante che potrebbe essere costituito da sola chemioterapia, oppure chemioradioterapia oppure chemioradioterapia seguita da chemioterapia.
    I-5. Le pazienti con storia di carcinoma mammario primario possono essere eleggibili a condizione che abbiano completato il trattamento antitumorale da più di 3 anni e non abbiano avuto una recidiva del cancro al seno prima dell'inizio del trattamento instudio.
    I-6.Una radioterapia precedente, pelvica e extra-pelvicae pelviesterne è consentita, se completata da più di 6 settimane prima. Una precedente radioterapia dell’intero addome, invece, non è consentita
    I-7. Consenso informato scritto e capacità di seguire il trattamento e il follow-up.
    I-8. Campione tumorale paraffinato rappresentativo o, solo se non disponibile, almeno 20 vetrini non colorati, ottenuti durante la chirurgia iniziale o, in caso in cui la chirurgia non sia stata effettuata, da una biopsia diagnostica devono essere inviati al laboratorio centrale per la determinazione dello stato del Micro Satellite (MS) prima della randomizzazione.
    I-9. Le pazienti devono avere una normale funzionalità degli organi e del midollo osseo:
    a. Emoglobina = 10,0 g / dl.
    b. Conta assoluta dei neutrofili (ANC) = 1,5 x 109 / L.
    c. Conta piastrinica = 100 x 109 / L.
    d. Bilirubina totale = 1,5 x limite superiore normale (ULN).
    e. Aspartato aminotransferasi / Siero transaminasi glutammico-ossalacetico (ASAT / SGOT) e alanina aminotransferasi / siero glutammico piruvato transaminasi (ALAT / SGPT) = 2,5 x ULN, a meno che non siano presenti metastasi epatiche, nel qual caso devono essere = 5 x ULN.
    f. Creatinina sierica = 1,5 x ULN
    E.4Principal exclusion criteria
    E-1. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast. Patients with a history of localized malignancy diagnosed over 5 years ago may be eligible provided they completed their adjuvant systemic therapy prior to randomization and that the patient remains free of recurrent or metastatic disease
    E-2. Patients with uterine leiomyosarcoma.
    E-3. Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered from the effects of any major surgery
    E-4. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
    E-5. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted).
    E-6. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA4 .
    E-7. Treatment with systemic immunostimulatory agents.
    E-8. Treatment with systemic corticosteroids or other systemic immunosuppressive medications.
    E-9. History of autoimmune disease
    E-10. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
    E-11. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C .
    E-12. Active tuberculosis (all patients will have tuberculin [PPD] skin test or Interferon-Gamma Releasing Assay [IGRA] done locally prior to inclusion to study)
    E-13. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
    E-14. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only (example approximately October to March in the Northern Hemisphere). Patients must not receive live, attenuated influenza vaccine.
    E-15. Clinically significant (e.g. active) cardiovascular disease, including:
    a. Myocardial infarction or unstable angina within = 6 months of randomization,
    b. New York Heart Association (NYHA) = grade 2 congestive heart failure (CHF),
    c. Poorly controlled cardiac arrhythmia despite medication (patients with rate controlled atrial fibrillation are eligible),
    d. Peripheral vascular disease grade = 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision)
    E-16. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
    E-17. History or clinical suspicion of brain metastases or spinal cord compression.
    E-18. History or evidence upon neurological examination of central nervous system (CNS) disease, unless asymptomatic and adequately treated with standard medical therapy
    E-19. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications
    E-20. Women of childbearing potential not willing to use highly-effective means of contraception
    E-21. Pregnant or lactating women
    E-22. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
    E-23. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation
    E-24. Known hypersensitivity reaction or allergy to drugs chemically related to carboplatin, paclitaxel, or their excipients
    E-1. Presenza di altre neoplasie negli ultimi 5 anni ad eccezione di: tumori cutanei (non melanoma) adeguatamente trattati, cancro della cervice trattato con successo, carcinoma duttale in situ (DCIS) del seno. Le pazienti con una storia di neoplasia localizzata diagnosticata da oltre 5 anni sono eleggibili a condizione che abbiano completato la loro terapia adiuvante prima della randomizzazione e che la paziente non abbia avuto una recidiva della malattia o delle metastasi
    E-2. Pazienti con leiomiosarcoma uterino
    E-3. Pazienti sottoposte a chirurgia maggiore meno di 4 settimane dall'inizio del trattamento in studio o pazienti che non si sono completamente riprese dai maggiori effetti dell’intervento chirurgico.
    E-4. Precedente trapianto di midollo osseo allogenico o precedente trapianto di organi solidi.
    E-5. Somministrazione di altri farmaci chemioterapici concomitanti, qualsiasi altra terapia antitumorale o terapia ormonale anti-neoplastica o radioterapia concomitante durante il periodo di trattamento (è consentito l’uso della terapia ormonale sostitutiva).
    E-6. Trattamento precedente con agonisti CD137 o terapie con blocco del sistema immunitario, o anticorpi terapeutici anti-PD1, anti-PDL1 o anti-CTLA4
    E-7. Trattamento con agenti immunostimolatori sistemici, inclusi ma non limitati all’interferone-alfa (IFN-a) e interleuchina-2 (IL-2) entro 4 settimane o cinque emivite del farmaco (a seconda di quale sia più breve) prima del ciclo 1, giorno 1
    E-8. Trattamento con corticosteroidi sistemici o altri farmaci immunosoppressivi sistemici
    E-9. Storia di malattia autoimmune
    E-10. Pazienti immunocompromesse
    E-11. Pazienti con epatite B attiva o epatite C
    E-12. Tubercolosi attiva (tutte le pazienti dovranno presentare un test cutaneo alla tubercolina [PPD] o Interferon-Gamma Releasing Assay [IGRA] eseguiti localmente prima dell'inclusione nello studio)
    E-13. Segni o sintomi di infezione entro 2 settimane prima del ciclo 1, giorno 1
    E-14. Somministrazione di un vaccino vivo attenuato entro 4 settimane prima del ciclo 1, giorno 1 o previsione che un tale vaccino vivo attenuato sarà richiesto durante il periodo di svolgimento dello studio
    E-15. Malattia cardiovascolare clinicamente significativa (es. attiva), tra cui:
    a. Infarto miocardico o angina instabile entro 6 mesi dalla random
    b. Insufficienza cardiaca congestizia (CHF) di grado = 2 definita dal New York Heart Association (NYHA)
    c. Aritmia cardiaca scarsamente controllata nonostante i farmaci (pazienti con fibrillazione atriale ma frequenza ventricolare controllata sono eleggibili)
    d. Patologia vascolare periferica di grado = 3
    E-16. ECG a riposo con QTc> 470 msec o una storia familiare di sindrome del QT lungo
    E-17. Storia o sospetto clinico della presenza di metastasi cerebrali o della compressione del midollo spinale
    E-18. Storia o segni neurologici di malattia del SNC, a meno che non sia asintomatica e adeguatamente trattata con terapia medica standard
    E-19. Indizi di qualsiasi altra malattia, disfunzione metabolica, referti di esami fisici o di laboratorio che forniscano il ragionevole sospetto di una malattia o di una condizione che controindica l'uso di un farmaco sperimentale o che pone la paziente ad alto rischio di complicanze correlate al trattamento
    E-20. Le donne in età fertile che non sono disposte a utilizzare mezzi contraccettivi altamente efficaci
    E-21. Donne in gravidanza o in allattamento
    E-22. Storia di gravi reazioni allergiche, anafilattiche o di altre reazioni di ipersensibilità agli anticorpi chimerici o umanizzati o alle proteine di fusione
    E-23. Ipersensibilità nota o allergia ai prodotti biofarmaceutici prodotti nelle cellule dell'ovaio di criceto cinese o a qualsiasi componente di atezolizumab
    E-24. Reazione di ipersensibilità nota o allergia ai farmaci chimicamente correlati al carboplatino, al paclitaxel o ai loro eccipienti
    E.5 End points
    E.5.1Primary end point(s)
    The study has two coprimary endpoints: OS and PFS.
    PFS is defined as the time from randomization to the date of first progression or death from any cause, whichever comes first.
    Progression will be established as the radiological disease progression according to RECIST 1.1 or death from any cause, whichever occurs first.
    OS is defined as the time from randomization until the date of death from any cause.
    Lo studio ha un endpoint composito: - OS è definito come il tempo dalla randomizzazione fino alla data della morte per qualsiasi causa. - PFS è definito come il tempo dalla randomizzazione alla prima data in cui si verifica una progressione secondo i criteri RECIST v 1.1 o alla morte per qualsiasi causa, a seconda di quale si verifica prima.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumor assessments should be performed every 9 weeks during the chemotherapy treatment then every 12 weeks during the maintenance treatment (atezolizumab or placebo) for the first year from randomization. After the first year the assessment during the maintenance phase should be performed every 6 months until progression. Survival data will be collected up to the time of the final analysis.
    La valutazione sarà effettuata ogni 9 settimane per i primi 6-8 cicli di trattamento e successivamente ogni 12 settimane fino al peggioramento della malattia o fino alla conclusione dell’intera terapia prevista dal protocollo. Dopo l’interruzione del trattamento, la valutazione proseguirà ogni 12 settimane fino a 1 anno e successivamente ogni 6 mesi per altri 2 anni. I dati di sopravvivenza saranno raccolti fino alla data di analisi finale dello studio.
    E.5.2Secondary end point(s)
    Objective Response Rate (ORR), defined as the percentage of patients with an objective response as determined by RECIST 1.1; Duration of response, defined as the time from the date of first documentation of response (complete response (CR) or partial response (PR), whichever occurs first) to the date of documented PD or death; - Second Progression Free Survival (PFS2), defined as the time from randomization to the earliest of the progression event subsequent to that used for the primary variable PFS, or date of death. ; Change from baseline in quality of life
    scores evaluated on subscales and total scores using the EORTC QLQ C30 and QLQ-EN24; Proportion of patients reporting each response option at each assessment timepoint by treatment arm for item GP5 from the FACT-G instrument; Health utility scores of the EuroQoL 5
    Dimension, 5 Level Questionnaire (EQ-5D-5L). European Quality of Life Visual Analogue Scale (EQ VAS); Safety and tolerability will be assessed in
    terms of AEs, deaths, laboratory data, vital signs and ECG. AE will be described according to MedDRA terms (version 20.0) and graded according to CTCAE version 4.03.; The endpoints for compliance are:
    number of administered cycles; reasons for discontinuation and treatment modification; dose intensity.
    La risposta obiettiva è definita come risposta completa (CR) o PR determinata dallo sperimentatore con l'uso di RECIST v1.1.; La durata della risposta è definita come il tempo dalla data della prima risposta documentata (CR o PR, a seconda di quale si verifica prima) alla data della PD documentata o della morte.; PFS2 è definito come il tempo dalla randomizzazione al primo evento di progressione successivo a quello utilizzato per la variabile primaria PFS o la data di morte.; Sarà valutata la media dello score ottenuto dai questionari EORTC QLQ-C30 e QLQ-EN24che i
    pazienti compileranno all’ingresso e durante il trattamento in studio; Proporzione di ognuna delle cinque possibili opzioni di risposta all'item GP5 del questionario FACTG; I dati economici sanitari, valutati con il questionario EQ-5D-5L,; La sicurezza e la tollerabilità saranno valutate in termini di eventi avversi, morti, dati di laboratorio, segni vitali e ECG.; La compliace sarà misurata come numero di cicli somministrati, ragioni per interruzione e
    modifiche di trattamento, dose del trattamento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor assessments should be performed every 9 weeks during the chemotherapy treatment then every 12 weeks during the maintenance treatment (atezolizumab or placebo) for the first year from randomization. After the first year the assessment during the maintenance phase should be performed every 6 months until progression. ; Tumor assessments should be performed every 9 weeks during the chemotherapy treatment then every 12 weeks during the maintenance treatment (atezolizumab or placebo) for the first year from randomization. After the first year the assessment during the maintenance phase should be performed every 6 months until progression.; As per clinical practice; The endpoints will be evaluated at baseline, at cycle 3, 6 during chemotherapy and after the end of chemotherapy at cycle 4 a
    La valutazione sarà effettuata ogni 9 settimane per i primi 6-8 cicli di trattamento e successivamente ogni 12 settimane fino al peggioramento della malattia o fino alla conclusione dell’intera terapia prevista dal protocollo. Dopo l’interruzione del trattamento, la valutazione proseguirà ogni 12 settimane fino a 1 anno e successivamente ogni 6 mesi per altri 2 anni. ; La valutazione sarà effettuata ogni 9 settimane per i primi 6-8 cicli di trattamento e successivamente ogni 12 settimane fino al peggioramento della malattia o fino alla conclusione dell’intera terapia prevista dal protocollo. Dopo l’interruzione del trattamento, la valutazione proseguirà ogni 12 settimane fino a 1 anno e successivamente ogni 6 mesi per altri 2 anni. ; Le valutazioni saranno effettuate secondo pratica clinic
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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 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 concerned21
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA62
    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
    Japan
    New Zealand
    Austria
    Germany
    Italy
    Spain
    Switzerland
    United Kingdom
    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 years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 330
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 220
    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 state170
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 430
    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)
    NA
    NA
    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 Decision2018-07-10
    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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