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    Summary
    EudraCT Number:2015-001633-24
    Sponsor's Protocol Code Number:D419BC00001
    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:2020-09-21
    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 number2015-001633-24
    A.3Full title of the trial
    A Phase III, Randomized, Open-label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 Monotherapy and MEDI4736 in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Unresectable Stage IV Urothelial Cancer
    Studio internazionale multicentrico controllato randomizzato di fase III, in aperto, sul trattamento di prima linea con MEDI4736 in monoterapia e MEDI4736 in combinazione con Tremelimumab verso la chemioterapia standard a base di platino nel trattamento di prima linea in pazienti affetti da tumore uroteliale di stadio IV non operabile
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of First Line MEDI4736 with or without Tremelimumab versus Standard of Care Chemotherapy in Advanced Unresectable Urothelial Cancer
    Studio di Prima Linea MEDI4736 con o senza Tremelimumab verso la chemioterapia standard nel tumore uroteliale avanzato non resecabile
    A.3.2Name or abbreviated title of the trial where available
    DANUBE
    DANUBE
    A.4.1Sponsor's protocol code numberD419BC00001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02516241
    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 SponsorASTRAZENECA AB
    B.1.3.4CountrySweden
    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 supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact pointClinical Trial Transparency
    B.5.3 Address:
    B.5.3.1Street AddressKarlebyhus, Astraall¿n
    B.5.3.2Town/ cityS¿dert¿lje
    B.5.3.3Post code151 85
    B.5.3.4CountrySweden
    B.5.4Telephone number00000000
    B.5.5Fax number000000000
    B.5.6E-mailClinicalTrialTransparency@astrazeneca.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 nameMEDI4736
    D.3.2Product code MEDI4736
    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 INNDurvalumab
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.9.3Other descriptive name
    D.3.9.4EV Substance Code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 nameTremelimumab
    D.3.2Product code MEDI1123
    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 INNTremelimumab
    D.3.9.1CAS number 745013-19-6
    D.3.9.2Current sponsor codeMEDI1123
    D.3.9.3Other descriptive nameMEDI1123
    D.3.9.4EV Substance Code-
    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: 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.2.5The 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 nameGemcitabina
    D.3.2Product code [na]
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGEMCITABINA
    D.3.9.1CAS number 95058-81-4
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive name-
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0 to 2
    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: 4
    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.2.5The 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 nameCisplatino
    D.3.2Product code [na]
    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 INNCISPLATINO
    D.3.9.1CAS number 15663-27-1
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameCisplatin
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 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 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 nameCarboplatino
    D.3.2Product code [L01XA02]
    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 code-
    D.3.9.3Other descriptive nameCarboplatin
    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
    Adult patients (age > = 18 years) with histologically or cytologically documented transitional cell carcinoma (transitional cell and mixed transitional/non transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra), unresectable Stage IV (ie, > = T4bN0M0 for bladder), and who are chemotherapy-naive.
    Pazienti adulti (età > = 18) con carcinoma a cellule transizionali (con istologia a cellule transizionali e mista di cellule
    transizionali/non transizionali) dell’urotelio (inclusi la pelvi renale, gli ureteri, la vescica urinaria e l’uretra), documentato
    istologicamente o citologicamente, non resecabile, allo stadio IV (ad esempio, > = T4bN0M0 per la vescica), che non siano stati
    trattati precedentemente con chemioterapia di prima linea.
    E.1.1.1Medical condition in easily understood language
    Urothelial Cancer
    Tumore uroteliale
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10022880
    E.1.2Term Invasive bladder cancer stage IV
    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
    1. To assess the efficacy of MEDI4736 + tremelimumab combination
    therapy versus SoC in terms of OS in patients with unresectable Stage IV
    UC;
    2. To assess the efficacy of MEDI4736 monotherapy versus SoC in terms
    of OS in patients with unresectable Stage IV PD L1 High UC
    1. Valutare l’efficacia della terapia combinata MEDI4736 + tremelimumab rispetto al trattamento SoC in termini di OS, in pazienti con tumore uroteliale non operabile allo stadio IV.
    2. Valutare l'efficacia di MEDI4736 in monoterapia rispetto al trattamento SoC in termini di OS in pazienti con tumore uroteliale non operabile allo stadio IV ed elevati livelli di espressione di PD L1.
    E.2.2Secondary objectives of the trial
    1. To assess the efficacy of MEDI4736 +tremelimumab combination
    therapy versus SoC in terms of PFS in patients with UC.
    2. To assess the efficacy of MEDI4736 monotherapy compared to SoC in
    terms of PFS in patients with PD-L1-High UC
    3. To further assess the efficacy of MEDI4736 + tremelimumab
    combination therapy compared to SoC in terms of ORR.
    4. To further assess the efficacy of MEDI4736 monotherapy compared to
    SoC in terms of ORR
    5. To assess disease-related symptoms and HRQoL in UC patients treated
    with MEDI4736 monotherapy and MEDI4736 + tremelimumab
    combination therapy compared with SoC and each other using the FACTBL
    questionnaire.
    6. To assess the PK of MEDI4736 monotherapy and MEDI4736 +
    tremelimumab combination therapy.
    7. To investigate the immunogenicity of MEDI4736 monotherapy and
    MEDI4736 + tremelimumab combination therapy
    8. To assess the efficacy profile of MEDI4736 monotherapy in patients
    who are not cisplatin-eligible
    Valutare l'efficacia di MEDI4736 in monoterapia rispetto al trattamento SoC in termini di PFS in pazienti con UC
    Valutare l'efficacia della monoterapia con MEDI4736 rispetto alla terapia con SoC in termini di PFS nei pazienti con UC ed elevati livelli di espressione di PD L1
    Valutare i sintomi correlati alla malattia e l’Health Related Quality of Life HRQoL nei pazienti affetti da UC trattati con MEDI4736 in monoterapia e MEDI4736 + tremelimumab in terapia combinata rispetto a terapia con SoC e l’una rispetto all’altra utilizzando il questionario FACTBL
    Valutare la PK della terapia combinata con MEDI4736+tremelimumab e di MEDI4736 in monoterapia
    Valutare l'immunogenicità della terapia combinata con MEDI4736 + tremelimumab e di MEDI4736 in monoterapia
    Valutare l'efficacia della terapia combinata con MEDI4736 + tremelimumab rispetto al trattamento SoC in termini di Objective Response Rate ORR
    Valutare l'efficacia di MEDI4736 in monoterapia rispetto al trattamento SoC in termini di ORR
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma of the urothelium who have not been previously treated with first-line chemotherapy.
    2) Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria:
    • Creatinine clearance <60 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or by measured 24-hour urine collection • Common Terminology Criteria for Adverse Events (CTCAE) Grade > =2 audiometric hearing loss
    • CTCAE Grade 2 peripheral neuropathy
    • New York Heart Association Class III heart failure.
    3) Tumor PD-L1 status, with IHC assay confirmed by a reference laboratory, must be known prior to randomization.
    1) Pazienti affetti da carcinoma a cellule transizionali dell’urotelio, documentato istologicamente o citologicamente, non
    operabile, allo stadio IV, che non siano stati trattati precedentemente con chemioterapia di prima linea.
    2) Pazienti eleggibili o non eleggibili per la chemioterapia a base di cisplatino. La non eleggibilità al trattamento con cisplatino
    viene determinata quando è soddisfatto uno dei seguenti criteri: • Clearance della creatinina (CrCl) < 60 mL/min calcolata
    utilizzando l’equazione di Cockcroft-Gault (utilizzando il peso corporeo effettivo; si veda Appendix A) o misurandola dall’urina
    raccolta nelle 24 ore • Perdita dell’udito di grado > = 2 sulla base del Common Terminology Criteria for Adverse Events (CTCAE);
    • Neuropatia periferica di grado 2 secondo CTCAE;
    • Arresto cardiaco di classe III secondo la New York Heart Association
    3) Prima della randomizzazione deve essere noto lo status di PD-L1 nel tumore, che deve essere confermato da un laboratorio di
    riferimento mediante il test IHC.
    E.4Principal exclusion criteria
    1, Prior exposure to immune-mediated therapy, including but not limited
    to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies,
    including therapeutic anticancer vaccines. Prior local intervesical
    chemotherapy or immunotherapy is allowed if completed at least 28
    days prior to the initiation of study treatment. 2, History of allogenic
    organ transplantation that requires use of immunosuppressive agents. 3,
    Active or prior documented autoimmune or inflammatory disorders. The
    following are exceptions to this criterion: • Patients with vitiligo or
    alopecia • Patients with hypothyroidism (eg, following Hashimoto
    syndrome) stable on hormone replacement • Any chronic skin condition
    that does not require systemic therapy • Patients without active disease
    in the last 3 years may be included but only after consultation with
    AstraZeneca • Patients with celiac disease controlled by diet alone may
    be included but only after consultation with AstraZeneca. 4, Brain
    metastases or spinal cord compression unless the patient's condition is
    stable and off steroids for at least 14 days prior to the start of study
    treatment. Patients with suspected or known brain metastases at
    screening should have an MRI (preferred)/CT, preferably with IV
    contrast to access baseline disease status. 5, Active infection including
    tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus
    (HIV). 6, Current or prior use of immunosuppressive medication within
    14 days before the first dose of investigational product (IP). The
    following are exceptions to this criterion: • Intranasal, inhaled, topical
    steroids, or local steroid injections (eg, intra articular injection) •
    Systemic corticosteroids at physiologic doses not to exceed 10 mg/day
    of prednisone or its equivalent • Steroids as premedication for
    hypersensitivity reactions (eg, CT scan premedication). 7, Receipt of live
    attenuated vaccine within 30 days prior to the first dose of IP. Note:
    Patients, if enrolled, should not receive live vaccine during the study and
    up to 30 days after the last dose of IP.
    1) Precedente esposizione a terapia immuno-mediata, che include ma non è limitata ad anticorpi anti-CTLA-4, anti-PD-1, anti-PDL1,
    o anti-PD-L2, inclusi vaccini terapeutici anticancro. La precedente chemioterapia endovescicale locale o immunoterapia sono
    consentite, se vengono completate almeno 28 giorni prima dell'inizio del trattamento di studio.
    2) Precedente storia di trapianto d’organo allogenico che comporta l’utilizzo di agenti immunosoppressivi.
    3) Precedente storia documentata, o attiva presenza di disturbi autoimmuni o infiammatori. Di seguito le eccezioni a questo
    criterio: •Pazienti con vitiligine e alopecia •Pazienti con ipotiroidismo (es. Sindrome di Hashimoto) stabile con terapia ormonale
    •Qualsiasi condizione cronica della pelle che non necessita di terapia sistemica.•Possono essere inclusi i pazienti che negli ultimi 3
    anni non hanno avuto malattia attiva, ma solo dopo la consultazione con AstraZeneca •Possono essere inclusi i pazienti affetti da
    celiachia, controllata solo con la dieta, ma solo dopo la consultazione con AstraZeneca
    4) Metastasi cerebrali o compressione della corda midollare, salvo condizioni stabili del paziente (asintomatico senza evidenza di
    nuove o emergenti metastasi cerebrali) e non deve aver assunto steroidi per almeno 14 giorni prima dell'inizio del trattamento in
    studio. I pazienti con sospette o conosciute metastasi cerebrali allo screening dovrebbero sottoporsi a RMN (preferita)/TAC,
    preferibilmente utilizzando un contrasto IV per valutare lo stato della malattia al baseline al cervello prima di entrare nello studio
    5) Infezioni attive inclusa l’epatite B, epatite C, o virus dell’immunodeficienza umana (HIV)
    6) Trattamento concomitante o antecedente con immunosoppressori nei 14 giorni precedenti alla prima dose di MEDI4736 o
    tremelimumab. Di seguito sono elencate le eccezioni al presente criterio:
    • Steroidi topici, intranasali, inalatori o iniezione locale di steroidi (es.: iniezione intra-articolare)
    • Corticosteroidi sistemici alla dose fisiologica non superiore a 10 mg/die di prednisone o equivalente
    • Steroidi come pretrattamento per le reazioni di ipersensibilità (es.: premedicazione per la TC)
    7) Ricezione di vaccini vivi attenuati entro i 30 giorni precedenti alla prima dose del farmaco in studio. Nota: I pazienti, se arruolati,
    non devono ricevere vaccini vivi attenuati durante lo studio e dopo i 30 giorni successivi all’ultima dose di farmaco di studio
    assunta.
    E.5 End points
    E.5.1Primary end point(s)
    overall survival (OS).
    Sopravvivenza Globale (OS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 4 years
    Fino a 4 anni
    E.5.2Secondary end point(s)
    OS24; Objective response rate; Duration of response; Disease control rate; Best objective response; Proportion of patients alive and progression-free at 12 months.; PROGRESSION FREE SURVIVAL (PFS); Proportion of patients alive and progression-free at 24 months.; PROGRESSION FREE SURVIVAL (PFS); Proportion of patients alive and progression-free at 24 months.
    Proporzione di pazienti vivi a 24 mesi dalla randomizzazione (OS24); Tasso di risposta obiettiva ; Durata della risposta; Tasso di controllo della patologia ; Miglior risposta obiettiva; Proporzione di pazienti vivi e liberi da progressione di malattia a 12 mesi dalla randomizzazione ; Sopravvivenza libera da progressione di malattia (PFS); Proporzione di pazienti vivi a 24 mesi dalla randomizzazione (OS24); Sopravvivenza libera da progressione di malattia (PFS); Proporzione di pazienti vivi a 24 mesi dalla randomizzazione (OS24)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 4 years; Up yo 4 years; Up to 4 years; Up yo 4 years; Up to 4 years; Up to 4 years; up to 4 years; up to 4 years; up to 4 years; up to 4 years
    Fino a 4 anni; Fino a 4 anni; Fino a 4 anni; Fino a 4 anni; Fino a 4 anni; Fino a 4 anni; Fino a 4 anni; Fino a 4 anni; Fino a 4 anni; Fino a 4 anni
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 EEA93
    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
    Austria
    Belgium
    Brazil
    Canada
    China
    Denmark
    France
    Germany
    Greece
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Poland
    Portugal
    Russian Federation
    Spain
    Taiwan
    Turkey
    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 months0
    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 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: 820
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 365
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state93
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 442
    F.4.2.2In the whole clinical trial 1185
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After end of treatment with study drug, patients should be managed according to local standard of care.
    Al termine del trattamento con i farmaci sperimentali, i pazienti saranno trattati con chemioterapia standard secondo pratica clinica.
    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 Decision2015-11-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-26
    P. End of Trial
    P.End of Trial StatusOngoing
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