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    Summary
    EudraCT Number:2015-003385-84
    Sponsor's Protocol Code Number:GO40782(RXDX-101-02)
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-15
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-003385-84
    A.3Full title of the trial
    AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 BASKET STUDY OF ENTRECTINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS THAT HARBOR NTRK1/2/3, ROS1, OR ALK GENE REARRANGEMENTS
    Studio basket, in aperto, multicentrico, globale, di fase II, sull'uso di entrectinib nel trattamento di pazienti con neoplasie solide localmente avanzate o metastatiche che ospitano riarrangiamenti dei geni NTRK1/2/3, ROS1 o ALK
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Tumor Alterations Responsive to Targeting Receptor Kinases-2
    Studio sulle alterazioni tumorali responsive alle terapie mirate contro le chinasi recettoriali-2
    A.3.2Name or abbreviated title of the trial where available
    STARTRK-2
    STARTRK-2
    A.4.1Sponsor's protocol code numberGO40782(RXDX-101-02)
    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 SponsorIGNYTA, INC.
    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. Hoffman-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. Hoffman-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124, Basel
    B.5.3.2Town/ citySwitzerland
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number000000
    B.5.5Fax number000000
    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]
    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.3.9.1CAS number 1108743-60-7
    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.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
    Locally Advanced or Metastatic Solid Tumors that Harbor NTRK1/2/3, ROS1,
    or ALK Gene Rearrangements
    Neoplasie solide localmente avanzate o metastatiche che ospitano riarrangiamenti dei geni NTRK1/2/3, ROS1, o ALK.
    E.1.1.1Medical condition in easily understood language
    Cancer that arises from organs and solid tissues which has spread to
    other organs
    Tumore che origina in organi e tessuti solidi che si è diffuso in altri organi
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the objective response rate of entrectinib, as assessed by BICR, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement
    Determinare il tasso di risposta obiettiva di entrectinib, valutato mediante BICR, in ciascun basket di popolazione di pazienti con neoplasie solide che ospitano un riarrangiamento dei geni NTRK1/2/3, ROS1 o ALK
    E.2.2Secondary objectives of the trial
    To determine the duration of response, time to response, and clinical benefit rate of entrectinib, in each patient population basket of solid tumors
    To determine the intracranial tumor response of entrectinib and CNS progression-free survival in patients presenting with measurable brain metastases at baseline, , as assessed by BICR using RANO or RANO-BM, as applicable
    To estimate the progression-free survival and overall survival of patients with solid tumors treated with entrectinib
    To evaluate the safety and tolerability of entrectinib when administered at the RP2D
    To assess the population pharmacokinetics (PK) of Entrectinib and to explore correlations between PK, response, and/or safety findings
    To evaluate the effect of entrectinib on ventricular repolarization
    To assess treatment-related symptoms and general health status using validated instruments of patient reported outcomes
    Determinare la durata della risposta,tempo risposta,tasso d beneficio clinico d entrectinib,in ogni basket d popolazione d pz cn neoplasie solide.Deter. la risposta tumorale endocranica a entrectinib e sopravvivenza libera da progressione nell'SNC nei pz che presentano metastasi cerebrali misurabili al basale,mediante BICR con i criteriRECISTv1.1 e RANO o RANO-BM,per i pazienti conCNSmetastasi oppureRANO per tumoriCNSprimari,a seconda del caso.Stimare la sopravvivenza libera da progressione e sopravvivenza complessiva dei pazienti cn neoplasie solide trattati cn entrectinib.Valutare sicurezza e tollerabilità di entrectinib quando somministrato alla RP2D.Valutare la farmacocinetica(PK)di popolazione di entrectinib e analizzare le correlazioni traPK,risposta e/orisultati di sicurezza.Valutare l'effetto di entrectinib sulla ripolarizzazione ventricolare. Valutare i sintomi correlati al trattamento e le condizioni di salute generali utilizzando strumenti convalidati per esiti riferiti
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically- or cytologically-confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement that is predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively, without a concomitant second oncodriver as determined by Ignyta's CAP/CLIA laboratory or by any nucleic acidbased diagnostic testing method performed at a local CLIA-certified or equivalently-accredited diagnostic laboratory.
    Note: Patients diagnosed with anaplastic large cell lymphoma harboring a gene earrangement of interest may be eligible provided they meet all other inclusion/exclusion criteria.
    2. For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Ignyta’s CLIA laboratory post-enrollment
    3. Measurable disease as assessed locally using RECIST v1.1. Note: Patients with non-measurable disease will be eligible for enrollment in the "non-evaluable for the primary endpoint" basket and will mainly contribute to assessment of safety, PK, and other secondary endpoints.
    4. Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previouslytreated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment. If patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used. Moderate inducers of CYP450 may be used at the discretion of the Investigator. Steroids can be used at stable or decreasing for at least 2 weeks prior to the start of treatment
    5. Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK(non-NSCLC patients only inhibitors in patients who have tumors that harbor those respective gene rearrangements). Note: There is no basket for ALK-rearranged NSCLC who are naïve to ALK inhibitors; however, ALK- or ROS1-rearranged NSCLC patients previously treated with crizotinib only (and no other ALK or ROS1 inhibitor) are eligible, if they present with CNS-only progression and extracranial stable disease.
    6. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of Entrectinib treatment.
    7. At least 4 weeks must have elapsed since completion of antibody-directed therapy at the time of the start of Entrectinib treatment.
    8. Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. 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.
    9. Age = 18 years.
    10. Eastern Cooperative Oncology Group performance status = 2, and minimum life expectancy of at least 4 weeks.
    11. Adequate organ function as defined by the following criteria:
    Serum aspartate transaminase and serum alanine transaminase = 3.0 × upper limit of normal; = 5.0 × ULN if liver metastases are present
    Total serum bilirubin = 2.0 × ULN; patients with a known history of Gilbert’s syndrome and/or isolated elevations of indirect bilirubin are eligible
    Serum creatinine within normal limits or creatinine clearance = 30 mL/min
    12. Females of childbearing potential must have a negative serum pregnancy test during Screening and must not be breastfeeding or intending to become pregnant during the study. Female patients will be considered to be of childbearing potential unless they have undergone permanent contraception or are postmenopausal.
    1.Diagnosi istologicamente o citologicamente confermata di neoplasia solida localmente avanzata o metastatica che ospiti un riarrangiamento dei geni NTRK1/2/3, ROS1 o ALK, che si prevede possa tradursi in una proteina di fusione con dominio chinasico funzionale TrkA/B/C, TOS1 o ALK, rispettivamente, senza un secondo driver oncologico concomitante, determinato dal laboratorio CAP/CLIA di Ignytia o in base ad analisi con metodiche diagnostiche basate su acidi nucleici, effettuate presso un laboratorio diagnostico locale con certificazione CLIA o equivalente.
    Nota: i pazienti con diagnosi di linfoma anaplastico a grandi cellule che ospita uno dei riarrangiamenti genici di interesse potrebbero essere idonei a condizione che soddisfino tutti gli altri criteri di inclusione/esclusione.
    2. Per pazienti arruolati con un’analisi molecolare effettuata localmente, è necessario inviare un campione archiviato o fresco di tessuto tumorale per un’analisi molecolare centrale indipendente presso il laboratorio di Ignyta dopo l’arruolamento
    3. Malattia misurabile, valutata localmente secondo i criteri RECIST v1.1. Nota:
    i pazienti con malattia non misurabile saranno ritenuti idonei per l’arruolamento nel basket "Non valutabili per l'endpoint primario" e contribuiranno principalmente alla valutazione di sicurezza, PK e altri endpoint secondari.
    4. È consentito l’arruolamento di pazienti con coinvolgimento del SNC. L’uso di una profilassi anticonvulsivante è consentito solo se i pazienti assumano farmaci antiepilettici non-inducenti l’enzima. I pazienti trattati con EIAED che ne devono interrompere l’assunzione da 2 settimane dall’inizio del trattamento con entrectinib. Se i pazienti necessitano di un farmaco antiepilettico, si può utilizzare un non-EIAED induttore del CYP3A4
    Gli induttori moderati del CYP450, possono essere utilizzati a discrezione dello sperimentatore.
    I pazienti possono assumere steroidi solo a dose stabile o in riduzione da almeno 2 settimane dall’inizio del trattamento
    5. Sono consentite precedenti terapie antitumorali (esclusi gli inibitori autorizzati o sperimentali di Trk, ROS1 o ALK (solo pazienti non affetti da NSCLC)
    Nota: non è previsto un basket per i pazienti affetti da NSCLC che presentano riarrangiamenti di ALK che sono naïve agli inibitori di ALK; tuttavia, i pazienti affetti da NSCLC che presentano riarrangiamenti di ALK o ROS1 precedentemente trattati con crizotinib in monoterapia sono idonei se presentano sola progressione a carico dell’SNC e malattia extracranica stabile.
    6. Al momento dell’inizio del trattamento con entrectinib devono essere trascorse almeno 2 settimane o 5 emivite, da una precedente chemioterapia o terapia mirata con agenti a piccole molecole.
    8. Una precedente radioterapia è consentita se trascorsi più di 14 giorni dalla conclusione del trattamento. I pazienti che hanno ricevuto una precedente irradiazione cerebrale devono aver completato la radioterapia panencefalica almeno 14 giorni prima e/o la radiochirurgia stereotassica almeno 7 giorni prima dell’inizio del trattamento con entrectinib.
    9. Età = 18 anni.
    10. Stato di validità secondo l’Eastern Cooperative Oncology Group = 2,
    11. Adeguata funzionalità d’organo, definita dai seguenti criteri:
    Aspartato transaminasi sierica e alanina transaminasi sierica = 3,0 × limite superiore della norma
    (ULN); = 5,0 × ULN in presenza di metastasi epatiche.
    Bilirubina sierica totale = 2,0 × ULN; i pazienti con anamnesi nota di sindrome di Gilbert e/o rialzi isolati della bilirubina indiretta sono idonei
    Creatinina sierica nei limiti della norma o clearance della creatinina = 30 ml/min
    12. Le donne fertili devono avere un risultato negativo al test di gravidanza sul siero effettuato durante lo screening e non devono allattare né programmare una gravidanza durante lo studio
    13. Capa
    E.4Principal exclusion criteria
    1. Current participation in another therapeutic clinical trial.
    2. Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements.
    Note: In cases where the patient was intolerant to prior Trk, ROS1, or
    ALK inhibitors, please discuss with the Sponsor.
    In addition, prior treatment with crizotinib is permitted ONLY in ALK- or
    ROS1-rearranged NSCLC patients presenting with CNS-only progression.
    Other ALK or ROS1 inhibitors are prohibited in that scenario.
    3. History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy. Note: Patients presenting with dual primary cancers may enroll in the
    "non-evaluable for the primary endpoint" basket if at least one of the
    cancers harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement as per
    Inclusion Criterion 1.
    4. Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib.
    5. Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication.
    6. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs performed at least 24 hours apart).
    7. History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).
    8. Peripheral neuropathy Grade = 2.
    9. Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral, including human immunodeficiency virus positive).
    10. Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.
    11. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. Note: Radiation-induced
    lung disorders are not included in this exclusion criterion.
    12. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
    1. Attuale partecipazione ad altra sperimentazione clinica terapeutica.
    2. Precedenti terapie con inibitori autorizzati o sperimentali di Trk, ROS1 o ALK nei pazienti che hanno tumori che ospitano i rispettivi riarrangiamenti genici.
    Nota: nei casi in cui il paziente aveva presentato intolleranza alle precedenti terapie con inibitori Trk, ROS1 o ALK, discuterne con lo sponsor.
    Inoltre, il precedente trattamento con crizotinib è consentito SOLO nei pazienti affetti da NSCLC che presentano riarrangiamenti di ALK o ROS1 e sola progressione a carico dell’SNC. In tale situazione, sono proibiti altri trattamenti con inibitori ALK o ROS1
    3. Anamnesi di altra precedente neoplasia che interferirebbe con la determinazione della sicurezza o dell’efficacia di entrectinib in termini di qualificazione della neoplasia solida. Nota: i pazienti che presentano tumori primari doppi possono arruolarsi al basket “non valutabile per l'endpoint primario” se almeno uno dei tumori ospita un riarrangiamento dei geni NTRK1/2/3, ROS1 o ALK secondo il criterio di inclusione 1.
    4. Recupero incompleto da qualsiasi intervento chirurgico prima dell’inizio del trattamento con entrectinib che potrebbe interferire con la determinazione della sicurezza o dell’efficacia di entrectinib.
    5. Qualsiasi patologia (negli ultimi 3 mesi) che potrebbe interferire con la determinazione della sicurezza o dell’efficacia di entrectinib: infarto del miocardio, angina instabile, bypass aortocoronarico/periferico, insufficienza cardiaca congestizia sintomatica, accidente cerebrovascolare o attacco ischemico
    transitorio, ictus, bradicardia sintomatica, o aritmie incontrollate che necessitano di farmaci.
    6. Anamnesi di intervallo QTc prolungato non indotto farmacologicamente (per es. ripetuta dimostrazione di un intervallo QTc > 500 millisecondi in ECG effettuati a distanza di almeno 24 ore l’uno dall’altro).
    7. Anamnesi di fattori di rischio supplementari per la torsione di punta (per es. anamnesi familiare di sindrome del QT lungo).
    8. Neuropatia periferica di grado = 2.
    9. Note infezioni attive che potrebbero interferire con la valutazione della sicurezza o dell’efficacia di entrectinib (batteriche, fungine o virali, inclusa positività per il virus dell’immunodeficienza umana).
    10. Malattia gastrointestinale attiva (per es. Malattia di Crohn, colite ulcerativa o sindrome dell’intestino corto) o altre sindromi da malassorbimento che potrebbero ragionevolmente influire sull’assorbimento del farmaco.
    11. Nota pneumopatia interstiziale, fibrosi interstiziale o anamnesi di polmonite indotta da inibitori della tirosin chinasi. Nota: le pneumopatie indotte da radiazioni non sono incluse in questo criterio di esclusione.
    12. Altra grave patologia medica o psichiatrica acuta o cronica o anomalia negli esami di laboratorio che potrebbe aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco dello studio, o che potrebbe interferire con l’interpretazione dei risultati dello studio e che, secondo il parere dello sperimentatore, renderebbe il paziente inadatto all’inclusione in questo studio o che potrebbe compromettere gli obiettivi del protocollo secondo il parere dello sperimentatore e/o dello sponsor.
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response Rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR)
    Tasso di risposta oggettivo (Objective Response Rate, ORR), definito come la percentuale di pazienti con risposta completa (Complete Response, CR) o risposta parziale (Partial Response, PR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumor assessments will be performed at Screening, at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), every 8 weeks (+/- 7 days) thereafter, regardless of treatment delays resulting from toxicity, and at the End of Treatment (if more than 4 weeks have passed since the last imaging assessment).
    Le valutazioni del tumore dovranno essere effettuate durante lo screening, al termine del ciclo 1 (giorno 1 del ciclo 2 +/- 2 giorni), in seguito ogni 8 settimane circa (+/- 7 giorni), indipendentemente dai ritardi di trattamento derivanti dalla tossicità, e alla conclusione del trattamento (se sono trascorse più di 4 settimane dall’ultima valutazione di diagnostica per immagini).
    E.5.2Secondary end point(s)
    1.Duration of Response (DOR), 2.Time to Response (TTR), 3.Clinical Benefit Rate (CBR), 4.Intracranial tumor response in patients with measurable brain metastases, as determined by BICR using RANO-BM as applicable 5.CNS Progression-Free Survival (CNS-PFS) in patients with measurable CNS disease, 6.Progression-Free Survival (PFS), 7.Overall Survival (OS), 8.Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities 9.Population PK 10.Ventricular repolarization 11.Quality-of-life and health status
    1. Durata della risposta (Duration of Response, DOR), 2. Tempo di risposta (Time to Response,TTR), 3. Tasso di beneficio clinico (Clinical Benefit Rate, CBR), 4.Risposta tumorale endocranica in pazienti con metastasi cerebrali misurabili, determinata mediante BICR utilizzando i criteri RANO-BM, a seconda del caso 5. Sopravvivenza libera da progressione nel SNC (SNC-PFS) in pazienti con malattie del SNC 6. Sopravvivenza libera da progressione (Progression-Free Survival, PFS), 7. Sopravvivenza complessiva (Overall Survival, OS), 8. Tipo, incidenza, gravit¿, momento di insorgenza, serietà e rapporto con il farmaco dello studio degli eventi avversi e delle anomalie negli esami di laboratorio. 9. Farmacocinetica (PK) di popolazione 10. Ripolarizzazione ventricolare 11. Qualit¿ della vita e condizioni di salute
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor assessments will be performed at Screening, at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), every 8 weeks (+/- 7 days) thereafter, regardless of treatment delays resulting from toxicity, and at the End of Treatment (if more than 4 weeks have passed since the last imaging assessment). Clinical Benefit Rate - 6 months after the first dose of entrectinib
    Le valutazioni del tumore dovranno essere effettuate durante lo screening, al termine del ciclo 1 (giorno 1 del ciclo 2 +/- 2 giorni), in seguito ogni 8 settimane circa (+/- 7 giorni), indipendentemente dai ritardi di trattamento derivanti dalla tossicit¿, e alla conclusione del trattamento (se sono trascorse pi¿ di 4 settimane dall¿ultima valutazione di diagnostica per immagini). Tasso di beneficio clinico - 6 mesi dopo la prima dose di entrectinib
    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 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) 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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Studio basket su entrectinib per ii trattamento di pazienti con tumori solidi
    NA
    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
    fase II
    fase II
    E.8.2.4Number of treatment arms in the trial1
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA72
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Singapore
    Spain
    Switzerland
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met, if the study is not terminated beforehand per recommendation of DMC
    Se lo studio non sarà interrotto prematuramente in seguito alle raccomandazioni del DMC, la conclusione della sperimentazione in tutti i Paesi partecipanti coincidere con il raggiungimento dell'endpoint secondario della OS.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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: 275
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 125
    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 80
    F.4.2.2In the whole clinical trial 400
    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)
    None
    Nessuno
    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 Decision2016-06-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-24
    P. End of Trial
    P.End of Trial StatusOngoing
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