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    Summary
    EudraCT Number:2011-005194-23
    Sponsor's Protocol Code Number:D0102C00006
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-09-25
    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 number2011-005194-23
    A.3Full title of the trial
    A Phase IIa Multi-centre Randomised Double-Blind Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of AZD8931 in Combination with Paclitaxel versus Paclitaxel alone in Patients with Metastatic, Gastric or Gastro-oesophageal Junction, Cancer who progress following First Line Therapy and are Ineligible for Treatment with trastuzumab by HER2 Status (SAGE)
    Studio di Fase IIa, multicentrico, randomizzato, in doppio cieco, controllato verso placebo, per valutare l'efficacia, la sicurezza e la farmacocinetica di AZD8931 in combinazione con dosi settimanali di Paclitaxel verso Paclitaxel da solo in pazienti con tumore gastrico metastatico o alla giunzione gastro-esofagea che manifestano progressione a seguito di trattamento di Prima Linea e non sono eleggibili al trattamento con trastuzumab sulla base dello status di HER2 (Studio Sage)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase IIa Multi-centre Randomised Double-Blind Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of AZD8931 in Combination with Paclitaxel versus Paclitaxel alone in Patients with Metastatic, Gastric or Gastro-oesophageal Junction, Cancer who progress following First Line Therapy and are Ineligible for Treatment with trastuzumab by HER2 Status (SAGE)
    Studio di Fase IIa,multicentrico,rand ,in doppio cieco,controllato vs placebo,per valutare l’efficacia,la sicurezza e la farmacocinetica di AZD8931 in combinazione con dosi settimanali di Paclitaxel verso Paclitaxel da solo in pazienti con tumore gastrico metastatico o alla giunzione gastro-esofagea con progressione a seguito di trattamento di Prima Linea e non sono eleggibili al trattamento con trastuzumab sulla base dello status di HER2
    A.3.2Name or abbreviated title of the trial where available
    SAGE
    SAGE
    A.4.1Sponsor's protocol code numberD0102C00006
    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
    B.1.3.4CountryItaly
    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 pointInformation Center
    B.5.3 Address:
    B.5.3.1Street AddressInformation Center - Sweden
    B.5.3.2Town/ cityInformation Center - Sweden
    B.5.3.3Post codeInformation Cen
    B.5.3.4CountryItaly
    B.5.4Telephone numberInformation Center - Sweden
    B.5.6E-mailinformation.center@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 nameAZD8931 film coated tablet 20 mg
    D.3.2Product code AZD8931
    D.3.4Pharmaceutical form Film-coated tablet
    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.3.9.1CAS number 1196531-39-1
    D.3.9.2Current sponsor codeAZD8931difumarate
    D.3.9.3Other descriptive nameAZD8931difumarate
    D.3.9.4EV Substance CodeAZD8931difumara
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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: 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 nameAZD8931 film coated tablet 40mg
    D.3.2Product code AZD8931
    D.3.4Pharmaceutical form Film-coated tablet
    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.3.9.1CAS number 1196531-39-1
    D.3.9.2Current sponsor codeAZD8931 difumarate
    D.3.9.3Other descriptive nameAZD8931 difumarate
    D.3.9.4EV Substance CodeAZD8931 difumar
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic, Gastric or Gastro-oesophageal Junction Cancer
    Tumore gastrico metastatico o della giunzione gastro-esofagea
    E.1.1.1Medical condition in easily understood language
    Metastatic, Gastric or Gastro-oesophageal Junction Cancer
    Tumore gastrico metastatico o della giunzione gastro-esofagea
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the relative efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by comparison of the change in tumour size at 8 weeks
    Valutare l’efficacia di AZD8931 in combinazione con Paclitaxel verso Paclitaxel da solo confrontando i cambiamenti della dimensione del tumore a 8 settimane
    E.2.2Secondary objectives of the trial
    · To assess the relative efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of progression-free survival (PFS) · To investigate the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of objective response rate (ORR) · To assess the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of the percentage of patients without progressive disease (i.e. patients with CR, PR or SD) at 8 weeks · To assess the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of overall survival (OS) · To compare and assess the safety and tolerability of AZD8931 plus paclitaxel compared with paclitaxel alone · To investigate the pharmacokinetics (PK) of AZD8931 and AZD8931 Odesmethyl metabolite in a metastatic, gastric or gastro-oesophageal junction, cancer patient population.
    •Valutare l’efficacia di AZD8931 in combinazione con Paclitaxel vs Paclitaxel da solo tramite la valutazione della sopravvivenza libera da progressione•Valutare l’efficacia di AZD8931 in combinazione con Paclitaxel vs Paclitaxel da solo tramite la valutazione del grado di risposta obiettiva•Valutare l’efficacia di AZD8931 in combinazione con Paclitaxel vs Paclitaxel da solo tramite la valutazione della perce di pazienti senza progressione di malattia a 8 sett •Valutare l’efficacia di AZD8931 in combinazione con Paclitaxel vs Paclitaxel da solo tramite la valutazione della sopravvivenza complessiva •Comparare e valutare la sicurezza e la tollerabilità di AZD8931 in combinazione con Paclitaxel vs Paclitaxel da solo •Studiare la PK di AZD8931 e di O-desmethyl metabolita dell’AZD8931 in pazienti con tumore metastatico gastrico o della giunzione gastro-esofagea.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of signed, written informed consent prior to any study specific procedures 2. Male or female aged 18 years or older (20 years or older in Japan) 3. Histological diagnosis of gastric adenocarcinoma (including adenocarcinoma of the gastro-oesophageal junction) 4. Patients must have radiologically confirmed progression following 1st line fluoropyrimidine and platinum based treatment for metastatic gastric cancer (the date of progression and start of first line treatment to be captured on the database) 5. Suitable for paclitaxel therapy 6. At least one lesion, not previously irradiated and not chosen for a mandatory fresh tumour biopsy during the study screening period, that can be accurately measured at baseline as ≥10mm in longest diameter (except lymph nodes which must have short axis ≥15mm) by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeat assessment i.e. the tumour site chosen for mandatory biopsy will not be deemed measurable and will be classed as a non-target lesion at baseline RECIST 1.1 assessment. 7. World Health Organisation (WHO) performance status 0-1, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose. Investigator has discretion to exclude rapidly progressive gastric cancer (such as those patients with rapid deterioration of performance status, requiring repeated drainage of ascites, patients with low or rapidly decreasing albumin or patients requiring feeding assistance with devices such as PEG) 8. Ineligible for trastuzumab treatment by local assessment. This should include IHC analysis to determine HER2 status with further testing by FISH/CISH for IHC 2+ patients. Eligible patients are those defined as; HER2 IHC 0, HER2 IHC 1+, or HER2 IHC 2+ (FISH –ve) 9. Collection of the original archival diagnostic (or more recent archival) tumour sample for retrospective central HER2 assessment, followed by exploratory retrospective biomarker analysis. Both primary lesion and metastatic sites are acceptable. 10. Women should be using adequate contraceptive measures (see Appendix J), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child bearing potential, or must have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: · Post menopausal defined as: - Aged ≥ 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Aged <50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and with luteinising hormone and follicular stimulating hormone levels in the post menopausal range · Documentation of irreversible surgical sterilization by hysterectomy, and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal ligation For inclusion in the optional PGx sample collection: 11. Provision of informed consent for PGx sample collection For inclusion in the optional fresh tumour biopsy upon RECIST 1.1 defined progression: 12. Provision of informed consent for tumour sample collection If a patient declines to participate in the optional components of the study (PGx or additional tumor sample collection) there will be no penalty or loss of benefit to the patients. The patient will not be excluded from other aspects of the study to which they have consented. 13. Patients must provide fresh baseline (pre-treatment) excisional or core needle tumour biopsies from a suitable and accessible site (other than from a key target lesion site chosen for the primary efficacy assessment [see inclusion criteria 6]).
    1)Firma del consenso informato prima dell’utilizzo delle specifiche proced di studio 2)Maschio o Femmina dai 18 anni in su (20 anni in poi in Giappone)3)Diagnosi istologica di adenocarc gastrico(incluso adenocarcinoma della giunzione gastro-esofagea. 4)I paz devono avere una progressione radiologicamente confermata successiva ad una prima linea di trattamento con fluoro pirimidina e platino per il tratt del tumore gastrico metastatico (la data di progressione e l’inizio del primo trattamento deve essere registrato sul database)5)Idoneo alla terapia con paclitaxel 6)Almeno una lesione, non recedentemente irradiata e non scelta per la biopsia tumorale fresca durante il periodo di pre-screening di studio, che può essere accuratamente misurata fissando a &gt;10 mm il diametro più ampio (escludendo i linfonodi che devono avere l’asse corto &gt;15 mm) mediante TC o MRI ed idonea per accurarate valutazioni, ad esempio il sito tumorale scelto per la biopsia obbligatoria non sarà considerato misurabile e sarà classificato come una lesione non- target con il metodo valutativo RECIST 1.1. 7)Performance Status WHO 0-1, aspettativa di vita minima di 12 settimane dalla data prevista per la prima dose, nessun peggioramento durante le 2 settimane di screening e di prima dose. Lo Sperimentatore ha la facoltà di escludere tumori gastrici con progressione rapida (come quei paz con un rapido peggioramento dello stato di salute, che richiedono ripetuti drenaggi per le asciti, paz con basso o rapido decremento dell’albumina o pazienti che necessitano di alimentazione artificiale con attrezzature quali PEG)8) Inelegibilità per il trattamento con trastuzumab mediante valutazione locale. Questo potrebbe includere l’analisi IHC per determinare lo stato di HER2 comprovato ulteriormente con FISH/CISH per pazienti IHC2 positivi. I pazienti elegibili sono quelli definiti come : HER2 IHC 0, HER2 IHC 1 +, O HER2 IHC 2+ ( FISH- ve) 9)Recupero dei campioni tumorali provenienti dall’archivio originario per la valutazione a livello centrale in maniera retrospettiva di HER2, seguita da un’analisi esplorativa retrospettiva dei biomarkers. Sono accettatabili sia campioni provenienti dalla lesione primaria che dai siti metastatici. 10)Le donne dovrebbero utilizzare delle misure contraccettive adeguate (vedi Appendice J), dovrebbero essere in età non fertile e devono essere negative al test di gravidanza prima dell’inizio della somministrazione della dose se sono potenzialmente fertili, o devono avere prove evidenti di infertilità valutabile mediante uno dei seguenti criteri al momento dello screening: •Post menopausa definita come: -Età &gt; 50 anni ed amenorroiche da almeno 12 mesi successivi alla cessazione di tutti i trattamenti ormonali esogeni. -Età &lt; 50 anni ed amenorroiche da almeno 12 mesi successivamente al termine di tutti i trattamenti ormonali esogeni e con livelli di ormone luteinizzante e ormone follicolo stimolante nel range post-menopausa. •Documentazione di sterilizzazione chirurgica irreversibile mediante isterectomia, e/o ovariectomia e/o salpingectomia bilaterale escludendo però il legamento bilaterale delle tube. Per l’inclusione nello studio sulla raccolta opzionale dei campioni per la farmacogenetica (PGx): 11)Fornitura del consenso informato per la raccolta di campioni PGx Per l’inclusione nello studio sulla raccolta della biopsia fresca del tumore per valutare la progressione mediante RECIST 1.1: 12)Fornitura del consenso informato per la raccolta del campione tumorale. Se il paziente rifiuta di partecipare alle parti opzionali dello studio (PGx o raccolata campione tumorale aggiuntiva) non ci saranno penalità o mancanza di benefici per il paziente. Il paz non sarà escluso dagli altri aspetti dello studio a cui ha acconsentito.13)I paz devono fornire una biopsia fresca basale (effettuata prima del trattamento) ottenuta per eradicaz ...
    E.4Principal exclusion criteria
    1.Have received more than 1 prior chemotherapy regimen for metastatic XML File Identifier: nAVHtDzd4GrnaVYvSFsaUPuVZu8= Page 16/29 gastric cancer. (chemotherapy as adjuvant treatment is permitted). 2.Any prior taxane therapy (at any time from diagnosis of gastric cancer) 3.Any prior therapy with an inhibitor of ErbB1 or ErbB2 (eg, lapatinib) 4.Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count <1.5 x 109/L or platelet count <100 x 109/L 5.Moderate or severe renal impairment. 6.Haemoglobin ≤9 g/dL (5.59 mmol/L), any blood transfusion must be >14 days prior to the determination of the haemoglobin levels 7.Inadequate liver function defined in protocol; 8.Resting ECG with measurable QTc(F) interval of >480 msec at 2 or more time points within a 24 hour period 9.Cardiac ejection fraction outside institutional range of normal or ≤50% (whichever is higher) as measured by echocardiogram 10.Known uncontrolled or symptomatic angina, arrhythmias or congestive heart failure, evidence of transmural infarction on ECG, poorly controlled hypertension (systolic >180 mmHg or diastolic >100 mmHg), significant valvular disease or history of high risk dysrrhythmia (such as ventricular fibrillation or ventricular tachycardia [includes ventricular triplets]) 11.Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease 12.Active or uncontrolled systemic disease which in the investigator's / delegate's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol 13.History or repeated unexplained episodes of syncope/dizziness 14.Medical diagnosis of acne rosacea, psoriasis, severe atopic eczema 15.Concurrent second primary malignancy (except in situ carcinoma of the cervix). Patients with a prior cancer are eligible if they are diseasefree with no evidence of recurrence or relapse in the past 5 years 16.Unresolved toxicity >CTCAE grade 2 (except alopecia) from previous anti-cancer therapy 17.Unable to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation. ...
    1) Hanno seguito precedentemente più di un primo regime chemioterapico per il tumore gastrico metastatico ( la chemioterapia come trattamento adiuvante è consentita) 2) Qualsiasi precedente terapia con taxani (in qualsiasi momento dalla diagnosi di tumore gastrico) 3) Qualsiasi precedente terapia con inibitori di EGFR o HER2 ( Es. lapatinib) 4) Inadeguata riserva di midollo osseo dimostrata da una conta totale di neutrofili &lt; 1.5 x 109 /L o conta piastrinica &lt; 100 x 109 /L 5) Moderata o severa insufficienza renale. Se la Creatina è &gt; 1 x ULN, la clearance di creatinina o la velocità di filtrazione glomerulare (GFR) deve essere calcolata usando la formula di Cockcroft-Gault o MDRD (Modification of Diet in Renal Disease) . La clearance di creatinina o il GFR è &lt; 50 mL/ min. 6) Emoglobina &lt; 9 g/dL (5.59 mmol/L), qualsiasi trasfusione di sangue deve essere antecedente ai 14 giorni prima della determinazione dei livelli di emogobina. 7) Insufficiente funzionalità epatica, definita mediante: - Bilirubina nel siero &gt; 2 x ULN - e ALT o AST &gt; 2.5 x ULN in assenza di note metastasi epatiche, - e ALP &gt;2.5 x ULN in assenza di note metastasi epatiche, - o ALP, AST o ALT &gt; 5.0 x ULN se il Medico giudica i valori correlati a metastasi epatiche. Alti livelli di ALP non sono esclusivamente dovuti alla presenza di metastasi ossee , e la funzionalità epatica è considerata al contrario adeguata secondo il giudizio del Medico. 8) ECG a riposo con intervallo misurabile QTc(F) &gt; 480 msec in 2 o più momenti temporali nell’arco di 24 ore ( vedi sezione 6.4.9.1) 9) Frazione di eiezione cardiaca al di fuori del range istituzionale normale o &lt; 50% ( qualsiasi valore più alto) misurato mediante ecocardiogramma ( angioscintigrafia miocardica (MUGA) se l’ecocardiogramma non è effettuabile o inutile) 10) Storia di angina nota incontrollata o sintomatica, aritmie o insufficienza cardiaca congestizia, evidenza di infarto transmurale rilevabile all’ECG, ipertensione mal controllata ( sistolica &gt; 180 mm Hg o diastolica &gt; 100 mm Hg), significante patologia valvolare o storia di alto rischio di aritmia ( come fibrillazione ventricolare o tachicardia ventricolare[ incluso triplette ventricolari]) 11) Anamnesi di malattia polmonare interstiziale, malattia polmonare interstiziale indotta da farmaci, polmonite da radiazione che ha richiesto trattamento steroideo, o qualsiasi evidenza di malattia polmonare interstiziale clinicamente attiva 12) Patologia sistemica attiva o incontrollata che secondo l’opinione dello sperimentatore / delegato rende la partecipazione allo studio clinico non auspicabile per il paziente o potrebbe compromettere la conformità al protocollo 13) Storia o inspiegati episodi ripetuti di sincope/ vertigini 14) Diagnosi medica di acne rosacea, psoriasi, grave eczema atopico 15) Neoplasie concomitanti secondarie allo stadio primario ( eccetto carcinoma in situ alla cervice). Pazienti con precedente tumore sono elegibili se sono guariti e quindi non si sono verificate ulteriori ricomparse della patologia o ricadute negli utlimi 5 anni. 16) Irrisolta tossicità &gt; CTCAE di grado 2 ( eccetto alopecia) da precedenti terapie anti-tumorali 17) Impossibilità a discontinuare il trattamento con agenti che presentano un alto rischio di sviluppare la “ Torsades de Pointes” per un prolungamento del tratto QT. Una guida sui farmaci da evitare ed i periodi di “washout” sono scritti nell’Appendice G del protocollo ...
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy- Change in tumour size at 8 weeks
    Efficacia - Cambiamento nella dimensione del tumore a 8 settimane
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change in tumour size at 8 weeks
    Cambiamento nella dimensione del tumore a 8 settimane
    E.5.2Secondary end point(s)
    Efficacy- -Progression Free Survival (PFS) -Overall survival (OS) -Objective response rate (ORR) -Percentage of patients without progressive disease at 8 weeks (i.e. patients with CR, PR or SD) Safety- Adverse Events - Deaths - Laboratory findings (clinical chemistry, haematology, urinalysis) - Vital signs - Physical Examination - Ophthalmic assessments Pharmacokinetic - Plasma concentrations of AZD8931 and AZD8931 O-desmethyl metabolite - Pharmacokinetic parameters including (but not restricted to): AZD8931: AUCss, Css,max, Css,min,tssmax, CLss/F and tlast AZD8931 O-desmethyl metabolite : AUC0-t, Cmax, tmax and AUC0-t metabolite:parent ratio - Cardiac assessments (ECG, ECHO/MUGA)
    Efficacia:  Sopravvivenza libera da progressione (PFS)  Sopravvivenza complessiva (OS)  Grado di risposta obiettiva (ORR)  Percentuale di pazienti senza progressione di malattia a 8 settimane (per esempio pazienti con CR,PR o SD) Sicurezza: - Eventi avversi - Morti - Esami di laboratorio (chimica clinica, ematologia, analisi delle urine) - Segni vitali - Esame fisico - Esami oftalmici Farmacocinetica: - Concentrazioni plasmatiche di AZD8931 e del metabolita O-desmethyl dell’ AZD8931 - Parametri farmacocinetici coinvolti (e non unici): AZD8931: AUCss, Css,max, Css,min,tssmax, CLss/F and tlast metabolita O-desmethyl dell’AZD8931: AUC0-t, Cmax, tmax and AUC0-t metabolita:rapporto di concentrazione rispetto al farmaco originale Valutazioni cardiache (ECG, ECHO/MUGA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessment made during trial
    Accertamenti effettuati durante lo studio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    China
    Japan
    Korea, Democratic People's Republic of
    Korea, Republic of
    Taiwan
    E.8.7Trial has a data monitoring committee No
    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
    Patients may continue to receive AZD8931 as long as they are continuing to show clinical benefit, as judged by the investigator, and in the absence of discontinuation criteria
    I pazienti potranno continuare a ricevere AZD8931 fino a beneficio clinico, a giudizio dello sperimentatore, ed in assenza di criteri di discontinuazione
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months15
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months21
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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: 21
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 39
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 60
    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)
    Each patient continues treatment after completion of trial will be chosen at the discretion of the investigator, and according to local practice
    Each patient continues treatment after completion of trial will be chosen at the discretion of the investigator, and according to local practice
    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 Decision2012-09-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-09-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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