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    Summary
    EudraCT Number:2011-000391-34
    Sponsor's Protocol Code Number:1200.43
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-03-01
    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 number2011-000391-34
    A.3Full title of the trial
    A randomised, open-label, phase III study to evaluate the efficacy and safety of oral afatinib (BIBW 2992) versus intravenous methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who have progressed after platinum-based therapy
    Studio randomizzato, in aperto, di fase III, per valutare l'efficacia e la sicurezza di afatinib (BIBW 2992) somministrazione orale verso metotressato somministrazione endovenosa in pazienti con carcinoma a cellule squamose del testa-collo ricorrente/metastatico, che sono in progressione dopo terapia a base di platino.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Afatinib (BIBW 2992) versus methotrexate in recurrent and/or metastatic (R/M) head and neck cancer patients who have progressed after chemotherapy
    afatinib (BIBW 2992) verso metotressato in pazienti con carcinoma a cellule squamose del testa-collo ricorrente/metastatico che sono in progressione dopo chemioterapia
    A.3.2Name or abbreviated title of the trial where available
    LUX-Head and Neck 1
    LUX-Head and Neck 1
    A.4.1Sponsor's protocol code number1200.43
    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 SponsorBOEHRINGER ING.
    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 supportBoehringer Ingelheim italia S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    B.5.2Functional name of contact pointQRPE PSC CT Information Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressBinger Strasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55216
    B.5.3.4CountryGermany
    B.5.4Telephone number+1-800-243-0127
    B.5.5Fax number+1-800-821-7119
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.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 nameafatinib
    D.3.2Product code BIBW 2992
    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.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeBIBW 2992
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 nameafatinib
    D.3.2Product code BIBW 2992
    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.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeBIBW 2992
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    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.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 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 nameafatinib
    D.3.2Product code BIBW 2992
    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.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeBIBW 2992
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameafatinib
    D.3.2Product code BIBW 2992
    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.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeBIBW 2992
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    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: 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 Yes
    D.2.1.1.1Trade name -
    D.2.1.1.2Name of the Marketing Authorisation holder-
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Solution for injection
    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 INNmethotrexate
    D.3.9.1CAS number 59-05-2
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB08856MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Recurrent and/or metastatic head and neck squamous cell carcinoma in patients who have progessed after platinum based therapy
    pazienti con carcinoma a cellule squamose del testa-collo (Head & Neck Squamous Cell Carcinoma - HNSCC) ricorrente/metastatico che sono andati in progressione dopo una terapia a base di platino somministrata per il carcinoma a cellule squamose del testa-collo metastatico/ricorrente
    E.1.1.1Medical condition in easily understood language
    Head and neck cancer
    carcinoma del testa-collo
    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 LLT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    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 investigate the efficacy of afatinib versus methotrexate therapy in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who have progressed after platinumbased therapy given for R/M HNSCC
    L'obiettivo dello studio e' di valutare l'efficacia di una terapia con afatinib verso metotressato in pazienti con carcinoma a cellule squamose del testa-collo (Head and Neck Squamous Cell Carcinoma - HNSCC ricorrente/metastatico che sono andati in progressione dopo una terapia a base di platino somministrata per il carcinoma a cellule squamose del testa-collo metastatico/ricorrente
    E.2.2Secondary objectives of the trial
    To investigate the safety of afatinib versus methotrexate therapy in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who have progressed after platinumbased therapy given for R/M HNSCC
    L'obiettivo dello studio e' di valutare la sicurezza di una terapia con afatinib verso metotressato in pazienti con carcinoma a cellule squamose del testa-collo (Head and Neck Squamous Cell Carcinoma - HNSCC) ricorrente/metastatico che sono andati in progressione dopo una terapia a base di platino somministrata per il carcinoma a cellule squamose del testa-collo metastatico/ricorrente
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, which has recurred/metastasised and is not amenable for salvage surgery or radiotherapy. 2.Documented progressive disease based on investigator assessment according to RECIST, following receipt of cisplatin and/or carboplatin (minimum doses described below*) administered for recurrent and/or metastatic disease independent of whether patient progressed during or after platinum based therapy: -Cisplatin, minimum dose: at least two cycles of cisplatin, >=60 mg/m2/cycle or a total cumulative dose of >=120 mg/m2 during eight weeks; -Carboplatin, minimum dose: at least two cycles of carboplatin area under the concentration-time curve (AUC) >=4/cycle or a total cumulative dose of AUC >=8 during eight weeks.*if cisplatin is switched to carboplatin (or vice versa, e.g due to intolerance), the following conversion should be used for calculation of minimum cumulative platinum dose: carboplatin 1 AUC = cisplatin 15 mg/m**2. 3. Measurable disease according to RECIST (version 1.1). 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at the time of randomisation. 5. Male and female patients age >=18 years. 6. Written informed consent that is in compliance with ICH-GCP and local law.
    1.Conferma istologica o citologica di carcinoma a cellule squamose di cavita` orale, orofaringe, ipofaringe o laringe, che ha recidivato/metastatizzato e non e` eleggibile per chirurgia di salvataggio o radioterapia. 2.Documentata progressione di malattia basata sulla valutazione dello sperimentatore secondo i criteri RECIST, a seguito di trattamento con cisplatino e/o carboplatino (dosi minime come descritto sotto*) somministrati per malattia ricorrente e/o metastatica, indipendentemente dal fatto che il paziente sia progredito durante o dopo la terapia a base di platino: -Cisplatino, dose minima: almeno due cicli di cisplatino, &gt;=60 mg/m2/ciclo o dose totale cumulativa &gt;=120 mg/m2 in otto settimane; -Carboplatino, dose minima: almeno due cicli di carboplatino area sotto la curva (AUC) &gt;= 4/ciclo o una dose totale cumulativa di AUC &gt;= 8 in otto settimane. *Se si passa da cisplatino a carboplatino (o viceversa, per esempio a causa di intolleranza), si deve usare la seguente conversione per calcolare la dose minima cumulativa di platino: carboplatino 1 AUC = cisplatino 15 mg/m2. 3.Malattia misurabile secondo i criteri RECIST (versione 1.1). 4.`Eastern Cooperative Oncology Group (ECOG) performance status` 0 o 1 alla randomizzazione. 5.Pazienti maschi e femmine di eta` superiore o uguale a 18 anni. 6.Consenso informato scritto in accordo alle ICH-GCP e alla legislazione locale.
    E.4Principal exclusion criteria
    1. Progressive disease within three months after completion of curatively intended treatment for locoregionally advanced or for metastatic HNSCC. 2. Primary tumour site nasopharynx (of any histology), sinuses, and/or salivary glands. 3. Any other than one previous platinum based systemic regimen given for recurrent and/or metastatic disease. Re-challenge with the first line regimen after a temporary break is considered a second line regimen only in case of progression within the break. 4. Prior treatment with EGFR-targeted small molecules. 5. Treatment with any investigational drug or anti-cancer therapy less than four weeks prior to randomisation (except palliative radiotherapy to bones to alleviate pain). 6. Unresolved chronic toxicity, other than hearing loss, tinnitus or dry mouth, CTCAE grade >2 from previous anti-cancer therapy or unresolved skin toxicities CTCAE grade >1 and/or diarrhoea CTCAE grade >1 caused by prior treatment with EGFR targeted antibodies. 7. Previous tumour bleeding CTCAE grade >=3. 8. Requirement for treatment with any of the prohibited concomitant medications listed in Section 4.2.2. 9. Major surgical or planned procedure less than four weeks prior to randomisation (isolated biopsies are not counted as major surgical procedures). 10. Any other malignancy (except for appropriately treated superficial basal cell skin cancer and surgically cured cervical cancer in situ) unless free of disease for at least five years. 11. Known brain metastasis or signs thereof. 12. Known pre-existing interstitial lung disease (ILD). 13. Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification >III, unstable angina, myocardial infarction within six months prior to randomisation, or poorly controlled arrhythmia. 14. Cardiac left ventricular dysfunction with resting ejection fraction of less than institutional lower limit of normal (LLN) (if no LLN is defined in the institution, the lower limit is 50%). 15. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn`s disease, malabsorption or CTCAE grade >1 diarrhoea of anyaetiology at randomisation. 16. Known HIV, active hepatitis B, active hepatitis C and/or other known severe infections, including but not limited to tuberculosis, as judged by the investigator 17. Other significant disease that in the investigator`s opinion would exclude the subjectfrom the trial. 18. Screening laboratory values based on central laboratory analysis: a) Absolute neutrophil count (ANC) <1.5x109/l b) Platelet count <75x109/l c) Total bilirubin >1.5 times the upper limit of normal (ULN) d) Aspartate amino transferase (AST) or alanine amino transferase (ALT) >3 times the ULN (if related to liver metastases >5 times the ULN) e) Calculated creatinine clearance <50 ml/min (as evidenced by using the Cockcroft-Gault formula, see Appendix 2). 19. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or to use adequate contraception during the trial and for at least six months after end of treatment. Adequate methods of contraception and definition of child-bearing potential are described in Section 5.2.2.2.1. 20. Pregnancy or breast feeding. 21. Known or suspected hypersensitivity to any of the study medications or their excipients. 22. Patients unable to comply with the protocol, in the opinion of the investigator.
    1.Progressione di malattia nei tre mesi dopo il completamento di trattamento con intento curativo per carcinoma squamoso del testa-collo loco-regionalmente avanzato o metastatico 2.Tumori primari di nasofaringe (di qualunque istologia), seni paranasali, e/o ghiandole salivari 3.Qualsiasi altro regime sistemico a base di platino tranne uno, somministrato per malattia ricorrente e/o metastatica. Rechallange con il regime di prima linea dopo una pausa temporanea e` considerato un regime di seconda linea solo se vi e` stata progressione durante l`interruzione 4.Precedente trattamento con piccole molecole che abbiano come target il recettore del fattore di crescita epidermico (Epidermal Growth Factor Receptor, EGFR) 5.Trattamento con qualunque altro farmaco sperimentale o terapia anti-cancro nelle quattro settimane precedenti la randomizzazione (con l’eccezione di radioterapia palliativa alle ossa per alleviare dolore) 6.Tossicita` cronica non risolta, esclusi perdita dell’udito, tinnito auricolare o secchezza delle fauci, di grado CTCAE &gt;2 causata dalla precedente terapia anti-cancro o tossicita' alla pelle non risolte di grado CTCAE &gt;1 e/o diarrea CTCAE grado &gt;1 causate da precedente trattamento con anticorpi anti-EGFR 7.Precedente sanguinamento tumorale di grado CTCAE &gt;=3. 8.Necessita` di trattamento con uno dei farmaci concomitanti vietati elencati nella sezione 4.2.2 del protocollo finale 9.Procedure chirurgiche importanti pianificate nelle quattro settimane prima della randomizzazione (tra queste non sono incluse le biopsie isolate) 10.Qualunque altro tipo di tumore maligno (con l`eccezione di cancro della pelle basale superficiale opportunamente trattato e cancro alla cervice in situ curato chirurgicamente) a meno che non sia libero da malattia da almeno cinque anni 11.Metastasi al cervello note o sintomi delle stesse 12.Pre-esistente malattia polmonare interstiziale nota (Interstitial Lung Disease, ILD) 13.Anormalita` cardiovascolari clinicamente rilevanti, secondo il giudizio dello sperimentatore, come, ma non limitate a, ipertensione incontrollata, insufficienza cardiaca congestizia classe NYHA (New York Heart Association) &gt;III, angina instabile, infarto del miocardio nei sei mesi precedenti la randomizzazione, o aritmia scarsamente controllata 14.Disfunzione cardiaca del ventricolo sinistro con frazione di eiezione a riposo inferiore al limite inferiore di normalita' previsto nel centro sperimentale (se tale limite non definito nella struttura, considerare il limite inferiore pari a 50%) 15.Significativi o recenti disturbi gastrointestinali acuti con diarrea come sintomo principale per esempio morbo di Crohn, malassorbimento o diarrea di grado CTCAE &gt;1 di qualunque eziologia alla randomizzazione. 16.Infezione nota da HIV, epatite B attiva e/o epatite C attiva e/o ogni altra infezione grave nota, inclusa tubercolosi, secondo l`opinione dello sperimentatore. 17.Altre patologie significative che, secondo lo sperimentatore, escluderebbero il soggetto dallo studio 18.Valori di laboratorio allo screening basati sulle analisi del laboratorio centralizzato: a) Conta assoluta dei neutrofili (ANC) &lt;1.5x109/l b) Conta piastrinica &lt;75x109/l c) Bilirubina totale &gt;1.5 volte il limite superiore di normalita' (ULN) d) Aspartato amino transferasi (AST) o alanina amino transferasi (ALT) &gt;3 volte ULN (se correlato a metastasi epatiche &gt;5 volte ULN) e) Clearance calcolata della creatinina &lt;50 ml/min (secondo la formula di Cockcroft-Gault, si veda l`Appendice 1 del protocollo di studio). Per gli altri criteri si faccia riferimento alla sinossi ed alla sezione 3.3.3 del protocol version 2
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival (PFS)
    L`endpoint primario di questo studio e` la sopravvivenza libera da progressione (Progression Free Survival – PFS), definita come il tempo dalla randomizzazione alla progressione valutata secondo i criteri RECIST 1.1 o al decesso per qualunque causa (l`evento che accade per primo).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 364 disease progression events, estimated to be approximately 20 months after start of recruitment.
    Dopo il raggiungimento di 364 eventi di progressione (o fatali) richiesti, stimato approssimativamente 20 mesi dopo l'inizio del reclutamento
    E.5.2Secondary end point(s)
    Key secondary endpoint is Overall Survival (OS). Other secondary enpoints are Objective Response and Health related quality of life (HRQOL).
    L`endpoint secondario chiave e` la sopravvivenza globale (Overall Survival – OS), definita come il tempo dalla randomizzazione al decesso (indipendentemente dalla causa). Altri end points sono: -Risposta oggettiva -Qualita` della vita correlata alla salute (Health Related Quality Of Life – HRQOL)
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 343 death events, estimated to be approximately 26 months after start of recruitment. For the key secondary endpoint OS a futility analysis will be made after approximately 40% of the death events, estimated to be after 14 months after start of recuitment.
    Dopo il raggiungimento di 343 eventi fatali richiesti, approssimativamente 26 mesi dopo l`inizio del reclutamento. Per l`endpoint secondario chiave, la sopravvivenza globale (Overall Survival – OS), verra` eseguita, dopo approssimativamente 40% di eventi fatali, una `futility analisys` stimata dopo 14 mesi dal reclutamento
    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 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) 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 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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA61
    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
    Argentina
    Brazil
    Chile
    Israel
    Japan
    Mexico
    Peru
    Russian Federation
    South Africa
    Switzerland
    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
    The trial is considered completed after all patients have progressed and the required number of death events has occurred.
    Lo studio e' considerato terminato quando tutti i pazienti hanno avuto una progerssione della malattia e si e' raggiunto il numero di casi di morte richiesto
    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 months27
    E.8.9.1In the Member State concerned 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: 534
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 61
    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 state59
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 331
    F.4.2.2In the whole clinical trial 595
    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)
    --
    --
    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 Decision2011-08-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-07-22
    P. End of Trial
    P.End of Trial StatusCompleted
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