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    Summary
    EudraCT Number:2019-003859-11
    Sponsor's Protocol Code Number:MO41552
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-10-12
    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 number2019-003859-11
    A.3Full title of the trial
    RANDOMIZED, OPEN LABEL, MULTICENTER, PHASE III STUDY OF ENTRECTINIB VERSUS CRIZOTINIB IN PATIENTS WITH LOCALLYADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER HARBORING ROS1 GENE REARRANGEMENTS WITH AND WITHOUT CENTRAL NERVOUS SYSTEM METASTASES
    STUDIO DI FASE III, RANDOMIZZATO, IN APERTO E MULTICENTRICO VOLTO A VALUTARE ENTRECTINIB RISPETTO A CRIZOTINIB IN PAZIENTI CON TUMORE POLMONARE NON A PICCOLE CELLULE LOCALMENTE AVANZATO O METASTATICO CHE PRESENTA RIARRANGIAMENTI DEL GENE ROS1 CON E SENZA METASTASI DEL SISTEMA NERVOSO CENTRALE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Entrectinib versus Crizotinib in Patients with Locally-Advanced or Metastatic Non-Small Cell Lung Cancer Harboring ROS1 Gene Rearrangements With and Without Central Nervous System Metastases
    STUDIO DI FASE III, RANDOMIZZATO, IN APERTO E MULTICENTRICO VOLTO A VALUTARE ENTRECTINIB RISPETTO A CRIZOTINIB IN PAZIENTI CON TUMORE POLMONARE NON A PICCOLE CELLULE LOCALMENTE AVANZATO O METASTATICO CHE PRESENTA RIARRANGIAMENTI DEL GENE ROS1 CON E SENZA METASTASI DEL SISTEMA NERVOSO CENTRALE
    A.3.2Name or abbreviated title of the trial where available
    RANDOMIZED, OPEN LABEL, MULTICENTER, PHASE III STUDY OF ENTRECTINIB VERSUS CRIZOTINIB IN PATIENTS WI
    STUDIO DI FASE III, RANDOMIZZATO, IN APERTO E MULTICENTRICO VOLTO A VALUTARE ENTRECTINIB RISPETTO A
    A.4.1Sponsor's protocol code numberMO41552
    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 SponsorF. HOFFMANN - LA ROCHE LTD.
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 nameEntrectinib
    D.3.2Product code [RO7102122 - F04/F06/F10/F14/F24]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEntrectinib
    D.3.9.2Current sponsor codeRO7102122
    D.3.9.4EV Substance CodeSUB177830
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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: 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 nameEntrectinib
    D.3.2Product code [RO7102122 - F08/F09/F11/F20/F25]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENTRECTINIB
    D.3.9.2Current sponsor codeRO7102122
    D.3.9.4EV Substance CodeSUB177830
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name XALKORI
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG - Auth. EU/1/12/793/003-004
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCrizotinib
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcrizotinib
    D.3.9.1CAS number 877399-52-5
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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.2.1.1.1Trade name XALKORI
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG - Auth. EU/1/12/793/001-002
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCrizotinib
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcrizotinib
    D.3.9.1CAS number 877399-52-5
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Non-small cell lung cancer with ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene rearrangements
    Tumore polmonare non a piccole cellule con riarrangiamenti del recettore tirosin-chinasico del proto-oncogene ROS 1 (ROS1)
    E.1.1.1Medical condition in easily understood language
    Non-small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung
    Il tumore polmonare non a piccole cellule è una patologia nella quale le cellule del carcinoma maligno si formano nei tessuti polmonari
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung cancer
    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 evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline
    Valutare l’efficacia di entrectinib rispetto a crizotinib in pazienti con NSCLC positivo per riarrangiamento di ROS1 con metastasi dell’SNC al basale
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC in the whole study population (ITT)
    •To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline
    •To evaluate the safety of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC
    •To evaluate health status utility scores of patients treated with entrectinib to inform pharmacoeconomic modeling using the EuroQol 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and visual analog scale (VAS) scores
    -Valutare l’efficacia di entrectinib rispetto a crizotinib in pazienti con NSCLC positivo per riarrangiamento di ROS1 nell’intera popolazione di studio (ITT)
    -Valutare l’efficacia di entrectinib rispetto a crizotinib in pazienti con NSCLC positivo per riarrangiamento di ROS1 con metastasi dell’SNC al basale
    -Valutare la sicurezza di entrectinib rispetto a crizotinib in pazienti con NSCLC positivo per riarrangiamento di ROS1
    -Valutare i punteggi di utilità per le condizioni di salute nei pazienti trattati con entrectinib per l’elaborazione di modelli di farmacoeconomia in base al punteggio basato sull’indice dell’EuroQol 5-Dimension Questionnaire (versione a 5 livelli; EQ-5D-5L) e al punteggio nella scala analogica visiva (VAS)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Age = 18 years
    •Histologically- or cytologically-confirmed diagnosis of advanced or recurrent (Stage IIIB/C, not amenable for radical treatment) or metastatic (Stage IV) NSCLC that harbors a documented ROS1 gene rearrangement
    •No prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
    •Prior radiotherapy is allowed if more than 14 days have elapsed between the end of treatment and randomization. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment
    •Measurable systemic disease according to RECIST v1.1
    •Patients with measurable and non-measurable CNS lesions per RECIST v1.1, including leptomeningeal carcinomatosis, are eligible, provided that the patient is neurologically stable for at least 1 week prior to the first dose of study treatment
    •Life expectancy of at least 12 weeks
    •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
    •Adequate hematologic, renal, liver function
    •Patients must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
    •Ability to comply with the study protocol, in the investigator’s judgment
    •Ability to swallow entrectinib and crizotinib intact without chewing, crushing, or opening the capsules
    •For women of childbearing potential: agreement to remain abstinent or use contraceptive methods during the treatment period and for up to 5 weeks after the last dose of entrectinib or for at least 90 days after the last dose of crizotinib
    •For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
    Per accedere allo studio, i pazienti dovranno soddisfare i seguenti criteri:
    -Sottoscrizione del modulo di consenso informato.
    - Età = 18 anni al momento della sottoscrizione del modulo di consenso informato.
    - Diagnosi di NSCLC avanzato o recidivante (stadio IIIB/C, non candidabile a trattamento radicale) oppure metastatico (stadio IV) con un riarrangiamento documentato del gene ROS1 confermata dall’esame istologico o citologico.
    -Nessun trattamento precedente con inibitori della tirosin-chinasi diretti contro ROS1, chemioterapie o altre terapie sistemiche per l’NSCLC avanzato o recidivante (stadio IIIB/C non candidabile a trattamento radicale) oppure metastatico (stadio IV).
    - Sono ammesse radioterapie precedenti purché siano trascorsi più di 14 giorni tra la fine del trattamento e la randomizzazione. I pazienti sottoposti a irradiazione cerebrale dovranno aver concluso la radioterapia panencefalica almeno 14 giorni prima, e/o la radiochirurgia stereotassica almeno 7 giorni prima, dell’inizio del trattamento con entrectinib.
    - Malattia sistemica misurabile secondo i criteri RECIST v1.1.
    - I pazienti con lesioni dell’SNC misurabili e non misurabili in base ai criteri RECIST v1.1, tra cui carcinomatosi leptomeningea, saranno ritenuti idonei, a condizione che il paziente sia neurologicamente stabile da almeno 1 settimana prima della prima dose del trattamento in studio
    -Aspettativa di vita di almeno 12 settimane.
    - Performance status secondo l’Eastern Cooperative Oncology Group (ECOG) pari a 0, 1 o 2
    - Adeguata funzionalità ematologica, renale, epatica
    -I pazienti dovranno essersi ristabiliti dagli effetti di eventuali interventi di chirurgia maggiore o lesioni traumatiche significative almeno 28 giorni prima della prima dose del trattamento in studio.
    -Capacità di rispettare il protocollo dello studio secondo il parere dello sperimentatore.
    - Capacità di ingerire entrectinib e crizotinib intatti senza masticare, spezzare o aprire le capsule.
    -Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o ad adottare metodi contraccettivi che garantiscano un tasso di insuccesso ¿ 1% all’anno durante il periodo di trattamento e fino a 5 settimane dopo l’ultima dose di entrectinib o per almeno 90 giorni dopo l’ultima dose di crizotinib.
    -Per gli uomini: consenso a praticare l’astinenza dai rapporti eterosessuali o a far uso di metodi contraccettivi e consenso ad astenersi dalla donazione del seme
    E.4Principal exclusion criteria
    •Current participation in another therapeutic clinical trial
    •Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
    •NCI-CTCAE v5.0 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia, fatigue, nausea and lack of appetite), which have not shown improvement and are strictly considered to interfere with current study medication
    •History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction = 50% observed during screening for the study
    •History of prolonged QTc interval
    •History of additional risk factors for torsades de pointes
    •Peripheral sensory neuropathy = Grade 2
    •Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
    •Previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC)
    •Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy
    •Active GI disease or other malabsorption syndrome that would reasonably impact drug absorption
    •History of prior therapy-induced pneumonitis
    •Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of study treatments
    •Known active infections that would interfere with the assessment of safety or efficacy of study treatments (bacterial, fungal or viral, including human immunodeficiency virus positive)
    •History of hypersensitivity to any of the additives in the entrectinib and/or crizotinib drug formulations
    •Pregnant or lactating women
    •Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness
    •Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study
    •Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry
    - Partecipazione in corso a un’altra sperimentazione clinica terapeutica.
    - Trattamento precedente con inibitori della tirosin-chinasi diretti contro ROS1, chemioterapie o altre terapie sistemiche per l’NSCLC avanzato o recidivante (stadio IIIB/C non candidabile a trattamento radicale) oppure metastatico (stadio IV).
    -Tossicità di grado uguale o superiore a 3 secondo i criteri NCI-CTCAE v5.0 dovute a qualsiasi terapia precedente (ad esclusione di alopecia, affaticamento, nausea e inappetenza) che non hanno evidenziato miglioramenti e che si ritiene interferiscano con l’attuale farmaco in studio in senso stretto.
    - Anamnesi positiva per recente (negli ultimi 3 mesi) insufficienza cardiaca congestizia o frazione di eiezione = 50% sintomatica osservata durante lo screening dello studio.
    - Anamnesi positiva per prolungamento dell’intervallo QTc
    -Anamnesi positiva per altri fattori di rischio per torsione di punta (per es. anamnesi familiare positiva per sindrome del QT lungo).
    - Neuropatia sensoriale periferica di grado = 2.
    - Pneumopatia interstiziale o fibrosi interstiziale nota oppure anamnesi positiva per polmonite indotta da inibitori della tirosin-chinasi.
    -Precedente neoplasia maligna negli ultimi 3 anni (diversa da forme trattate con intento curativo di carcinoma cutaneo basocellulare, tumore gastrointestinale (GI) in stadio iniziale sottoposto a resezione endoscopica, carcinoma in situ della cervice o qualsiasi tumore curato che si ritenga non abbia alcun impatto sulla PFS e sulla OS per l’NSCLC attuale).
    - Recupero incompleto da interventi chirurgici precedenti l’inizio del trattamento in studio che interferirebbe con la determinazione della sicurezza o dell’efficacia.
    - Malattia GI attiva che potrebbe ragionevolmente influire sull’assorbimento del farmaco.
    - Anamnesi positiva per polmonite indotta da terapia.
    -Qualsiasi condizione (negli ultimi 3 mesi) che interferirebbe con la determinazione della sicurezza o dell’efficacia dei trattamenti in studio, per es. infarto del miocardio, angina instabile, bypass aorto-coronarico/di arteria periferica, accidente cerebrovascolare o attacco ischemico transitorio, ictus, bradicardia sintomatica o aritmie incontrollate necessitanti di trattamento farmacologico.
    -Infezioni attive note che interferirebbero con la valutazione della sicurezza o dell’efficacia dei trattamenti in studio (batteriche, micotiche o virali, compresa positività per il virus dell’immunodeficienza umana).
    - Anamnesi positiva per ipersensibilità a uno qualsiasi dei componenti delle formulazioni di entrectinib e/o crizotinib.
    -Donne in gravidanza o in allattamento.
    - Positività per il virus dell’immunodeficienza umana (HIV) o malattia correlata a sindrome da immunodeficienza acquisita (AIDS) nota.
    -Qualsiasi malattia o condizione concomitante clinicamente significativa che potrebbe interferire con, o a causa della quale il trattamento potrebbe interferire con, la conduzione dello studio o l’assorbimento di farmaci orali, oppure che, secondo il parere dello sperimentatore principale, esporrebbe il paziente dello studio a un rischio inaccettabile.
    Qualsiasi condizione psicologica, familiare, sociologica o geografica che potrebbe compromettere il rispetto dei requisiti del protocollo dello studio e/o delle procedure di follow-up; tali condizioni dovranno essere discusse con il paziente prima dell’ingresso nella sperimentazione.
    E.5 End points
    E.5.1Primary end point(s)
    1.Progression-free survival (PFS) in patients with CNS metastases at baseline, defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by a blinded independent review committee (BIRC) using RECIST v1.1
    1. Sopravvivenza libera da progressione (PFS), intesa come il tempo intercorso dalla randomizzazione alla prima progressione documentata della malattia (extracranica o intracranica) o al decesso per qualsiasi causa, a seconda della circostanza che si verifichi per prima, secondo quanto stabilito da un comitato di revisione indipendente in cieco (BIRC) in base ai criteri RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.Up to 7 years
    1. fino a 7 anni
    E.5.2Secondary end point(s)
    1.Progression-free survival in the CNS (CNS-PFS), defined as the time from randomization to the first documented disease progression in the CNS or death from any cause, whichever occurs first, as determined by the BIRC using RECIST v1.1
    2.Overall response rate (ORR), defined as the percentage of patients who attain CR or PR, as assessed by the BIRC and the investigator per RECIST v1.1
    3.Duration of response (DOR), defined as the time from when response (CR or PR) is first documented to disease progression or death, whichever occurs first, as assessed by the BIRC and the investigator per RECIST v1.1
    4.Progression-free survival (PFS), defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by the BICR and investigator using RECIST v1.1
    5.Overall survival (OS), defined as the time from randomization to death from any cause
    6.Impact on functioning, including health-related quality of life, using the Global Health Status/Quality of Life (GHS/QoL), the Physical Functioning (PF) and Role Function (RF) scores, as assessed by the EORTC QLQ-C30 and analyzed as a time to first and confirmed clinically meaningful deterioration
    7.Impact on lung cancer-specific symptoms, as assessed by the EORTC QLQ-LC13
    8.Objective response rate in the CNS (CNS-ORR), defined as the percentage of patients who attain CR or PR for lesions in the CNS, as determined by the BIRC per RECIST v1.1
    9.Duration of response in the CNS (CNS-DOR), defined as the time from when a CNS response (CR or PR) is first documented to disease progression in the CNS, as determined by the BIRC per RECIST v1.1
    10.Incidence, type, timing, relatedness and severity of AEs, including SAEs and AEs leading to dose modifications/interruptions, study drug withdrawal or death, as assessed by the investigator according to the NCI CTCAE v5.0
    11.Health utility from the EQ-5D-5L and pharmacoeconomic model
    1Sopravvivenza libera da progressione nell’SNC (SNC-PFS), intesa come il tempo intercorso dalla randomizzazione alla prima progressione documentata della malattia nell’SNC o al decesso per qualsiasi causa, a seconda della circostanza che si verifichi per prima, secondo quanto stabilito dal BIRC in base ai criteri RECIST v1.1
    2 Tasso di risposta globale (ORR), inteso come la percentuale di pazienti che ottengono una CR o una PR, secondo quanto valutato dal BIRC e dallo sperimentatore in base ai criteri RECIST v1.1
    3 Durata della risposta (DOR), intesa come il tempo intercorso dalla prima risposta (CR o PR) documentata alla progressione della malattia o al decesso, a seconda della circostanza che si verifichi per prima, secondo quanto valutato dal BIRC e dallo sperimentatore in base ai criteri RECIST v1.1
    4 Sopravvivenza libera da progressione (PFS), intesa come il tempo intercorso dalla randomizzazione alla prima progressione documentata della malattia (extracranica o intracranica) o al decesso per qualsiasi causa, a seconda della circostanza che si verifichi per prima, secondo quanto stabilito dal BIRC e dallo sperimentatore in base ai criteri RECIST v1.1
    5 Sopravvivenza globale (OS), intesa come il tempo intercorso dalla randomizzazione al decesso per qualsiasi causa
    6 Impatto sulla funzionalità, compresa la qualità di vita correlata alla salute, in base ai punteggi relativi alle condizioni generali di salute/qualità di vita (GHS/QoL), all’attività fisica (PF) e al ruolo (RF), valutato mediante il questionario EORTC QLQ-C30 e analizzato come tempo al primo peggioramento clinicamente significativo confermato
    7 Impatto sui sintomi specifici del tumore polmonare valutato mediante il questionario EORTC QLQ-LC13
    8Tasso di risposta obiettiva nell’SNC (SNC-ORR), inteso come la percentuale di pazienti che ottengono una CR o una PR per lesioni nell’SNC, secondo quanto stabilito dal BIRC in base ai criteri RECIST v1.1
    9 Durata della risposta nell’SNC (SNC-DOR), intesa come il tempo intercorso dalla prima risposta (CR o PR) documentata nell’SNC alla progressione della malattia nell’SNC, secondo quanto stabilito dal BIRC in base ai criteri RECIST v1.1
    10 Incidenza, tipo, momento di insorgenza, correlazione e severità degli AE, compresi SAE e AE comportanti modifiche della dose/sospensioni del trattamento, interruzione del trattamento con il farmaco in studio o decesso, secondo quanto valutato dallo sperimentatore in base ai criteri NCI CTCAE v5.0
    11 Utilità per le condizioni di salute secondo il questionario EQ-5D-5L e il modello di farmacoeconomia
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-10.Up to 7 years
    11.Baseline (Day 1), Week 4, Week 8, all subsequent visits (every 8 weeks), Post-progression visits on treatment in case of isolated CNS progression (every 8 weeks), Post-Treatment Visit / Safety Follow Up Visit (4 weeks after permanent treatment discontinuation)
    1-10. Fino a 7 anni
    11. Baseline (giorno 1), Settimana 4, Settimana 8, tutte le visite successive (ogni 8 settimane), visite di post-progressione al trattamento in caso di isolata progressione CNS (ogni 8 settimane), Visita di post-trattamento/Visita di sicurezza Follow Up (4 settimane dopo l'interruzione permanente del trattamento).
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    CRIZOTINIB
    CRIZOTINIB
    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 EEA47
    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
    China
    Guatemala
    Jordan
    Lebanon
    Russian Federation
    Turkey
    Croatia
    France
    Germany
    Italy
    Netherlands
    Romania
    Slovakia
    Spain
    Sweden
    Switzerland
    Greece
    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
    The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. The end of the study is expected to occur approximately 24 months after the last patient is enrolled.
    The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 7 years.
    La conclusione della sperimentazione è definita come la data in cui l'ultimo pazientecompleta l'ultima visita o la data in cui l'ultimo dato richiesto per l'analisi statistica o il follow-up safety è ricevuto per l'ultimo paziente, a seconda di quale avviene per ultimo.
    La fine dello studio è attesa approssimativamente 24 mesi dopo l'arruolamento dell'ultimo paziente.
    La durata totale dello studio, dallo screening del primo paziente al termine dello studio, è approssimativamente di 7 anni.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months5
    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: 176
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 44
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 220
    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)
    The Sponsor will offer continued access to entrectinib free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product.
    Lo Sponsor offrirà accesso continuato a entrectinib ai pazienti eliggibili in accordo con le Policy Roche Globali all'accesso continuato agli IMP.
    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 Decision2021-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-22
    P. End of Trial
    P.End of Trial StatusOngoing
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