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    Summary
    EudraCT Number:2017-002359-27
    Sponsor's Protocol Code Number:D5161C00003
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2018-02-05
    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 number2017-002359-27
    A.3Full title of the trial
    A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients with EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated with Osimertinib
    Studio multicentrico, in aperto, a singolo braccio per l’analisi del profilo molecolare di pazienti affetti da NSCLC con mutazione EGFR positiva, localmente avanzato o metastatico trattati con osimertinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A molecular profiling study of osimertinib in patients with EGFR mutated lung cancer who have not yet received any drug therapy for advanced lung cancer
    Studio per l'analisi del profilo molecolare di osimertinib in pazienti con carcinoma polmonare con mutazione EGFR che non hanno ancora ricevuto alcuna terapia farmacologica per il carcinoma polmonare in stadio avanzato.
    A.3.2Name or abbreviated title of the trial where available
    ELIOS
    ELIOS
    A.4.1Sponsor's protocol code numberD5161C00003
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorASTRAZENECA AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street AddressUSA
    B.5.3.2Town/ cityUSA
    B.5.3.3Post codeUSA
    B.5.3.4CountryUnited States
    B.5.4Telephone number0
    B.5.5Fax number0
    B.5.6E-mailinformation.centre@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TAGRISSO™
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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 nameosimertinib
    D.3.2Product code AZD9291
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOsimertinib
    D.3.9.2Current sponsor codeAZD9291
    D.3.9.3Other descriptive nameOsimertininb mesylate; AZD9291 mesylate
    D.3.9.4EV Substance CodeSUB176340
    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: 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 Yes
    D.2.1.1.1Trade name TAGRISSO™
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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 nameosimertinib
    D.3.2Product code AZD9291
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOsimertinib
    D.3.9.2Current sponsor codeAZD9291
    D.3.9.3Other descriptive nameOsimertininb mesylate; AZD9291 mesylate
    D.3.9.4EV Substance CodeSUB176340
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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
    EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer not amenable to curative surgery or radiotherapy
    Carcinoma polmonare non a piccole cellule con mutazione EGFR positiva, localmente avanzato o metastatico, non sottoponibile a chirurgia curativa o radioterapia
    E.1.1.1Medical condition in easily understood language
    Specific type of lung cancer called non-small cell lung cancer (NSCLC)
    Tipologia specifica di tumore al polmone, chiamato carcinoma polmonare non a piccole cellule (NSCLC).
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029521
    E.1.2Term Non-small cell lung cancer stage IIIB
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    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 examine the genetic and proteomic profile at the point of disease progression in patients receiving osimertinib as first-line EGFR TKI therapy for EGFRm+ locally advanced or metastatic NSCLC compared to the profile prior to initiation of treatment
    Esaminare il profilo genetico e proteomico al momento della progressione della malattia in pazienti trattati con osimertinib come terapia di prima linea con inibitore della tirosinchinasi di EGFR per il carcinoma polmonare non a piccole cellule con mutazione EGFR positiva, localmente avanzato o metastatico, rispetto al profilo precedente all’inizio del trattamento.
    E.2.2Secondary objectives of the trial
    1) To assess the efficacy of osimertinib as first line EGFR TKI therapy for patients with EGFRm+ locally advanced or metastatic NSCLC.
    2) To assess the efficacy of osimertinib in patient subgroups defined by molecular profile, including but not limited to:
    • Positive pre-treatment T790M mutation
    • EGFR Ex19del or L858R mutation
    • EGFR Ex19del or L858R detectable in plasma-derived circulating tumour deoxyribonucleic acid (ctDNA).
    3) To further assess the efficacy of osimertinib post progression.
    4) To summarize the safety and tolerability profile of osimertinib as first-line EGFR tyrosine kinase inhibitor therapy for patients with EGFR mutation-positive locally advanced or metastatic NSCLC
    1) Valutare l’efficacia di osimertinib come terapia di prima linea con inibitore della tirosinchinasi di EGFR per pazienti con carcinoma polmonare non a piccole cellule, con mutazione EGFR positiva, localmente avanzato o metastatico
    2) Valutare l’efficacia di osimertinib in sottogruppi di pazienti definita dal profilo molecolare, tra cui, a titolo meramente esemplificativo:
    - Mutazione T790M positiva precedente al trattamento
    - Mutazione Ex19del o L858R di EGFR
    - Ex19del o L858R di EGFR rilevabile nell’acido desossiribonucleico tumorale circolante nel plasma
    3) Valutare ulteriormente l’efficacia post-progressione di osimertinib
    4) Riassumere il profilo di sicurezza e di tollerabilità di osimertinib come terapia di prima linea con inibitore della tirosinchinasi di EGFR per pazienti affetti da carcinoma polmonare non a piccole cellule, con mutazione EGFR positiva, localmente avanzato o metastatico
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of informed consent prior to any study specific procedures (signed and dated informed consent form).
    2. Patients aged 18 years or older.
    3. Patients with histological confirmation of locally advanced or metastatic, non squamous NSCLC who are not candidates for local curative treatment.
    4. Patients with M1 stage according to the Tumour, Node, and Metastasis Classification of Malignant Tumours (TNM) version 7 including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease that is not a candidate for curative treatment (including patients who progress after chemo radiotherapy in stage III disease).
    5. Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be associated with EGFR TKI sensitivity before treatment by local assessment.
    6. Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients with asymptomatic and stable central nervous system (CNS) metastases are eligible for the study; treatment with low dose corticosteroids is allowed, but is not a requirement for eligibility. Patients with history of CNS metastasis or compression of the spinal cord are eligible if they have received local final treatment (e.g., radiotherapy, stereotactic surgery) and if they have remained clinically stable without using anticonvulsants and increasing doses of corticosteroids for a minimum of 2 weeks prior to the first day of study treatment.
    7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the primary tumour or metastatic tumour tissue, within the 60 days prior to study entry and at or after RECIST 1.1defined progression.
    8. WHO performance status 01.
    9. Life expectancy ≥12 weeks.
    10. Adequate coagulation: international normalised ratio (INR) ≤1.5 for patients on anticoagulation therapy.
    11. Capacity to swallow.
    12. Patients able to complete study and within geographical proximity allowing for adequate follow up.
    13. Resolution of all acute toxic effects of previous anticancer therapy (which can only be adjuvant or neoadjuvant) or surgical interventions to grade 1 according to the National Cancer Institute (NCI) CTCAE version 4.0 (except for alopecia or other side effects that the Investigator does not consider to be a risk to patient safety).
    14. Female patients should be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of nonchildbearing potential by fulfilling one of the following criteria at screening:
    Postmenopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments;
    Female patients under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range for the institution;
    Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation;
    15. Male patients should be willing to use barrier contraception.
    1. Prestazione del consenso informato prima di qualsiasi procedura specifica dello studio (modulo di consenso informato firmato e datato).
    2. Pazienti di età ≥18 anni.
    3. Pazienti con conferma istologica di NSCLC non squamoso localmente avanzato o metastatico non candidati a trattamento locale con intento curativo.
    4. Pazienti con malattia in stadio M1, incluso lo stadio M1a (effusione maligna) o M1b (metastasi a distanza), in base alla Classificazione di tumori, linfonodi e metastasi nelle neoplasie maligne (TNM) versione 7, oppure localmente avanzata non candidata a trattamento con intento curativo (inclusi i pazienti che presentano progressione post chemio-radioterapia con malattia in stadio III).
    5. Pazienti con delezione o mutazione nota di EGFR (in base alla biopsia tumorale o all’analisi del plasma) risultata associata, in base a valutazione locale, a sensibilità agli EGFR TKI pre-trattamento.
    6. Presenza di malattia misurabile o valutabile (in base ai criteri RECIST 1.1). I pazienti con metastasi asintomatiche e stabili a carico del sistema nervoso centrale (SNC) sono idonei per lo studio; il trattamento con corticosteroidi a basse dosi è consentito, ma non costituisce requisito di idoneità. I pazienti con storia di metastasi a carico del SNC o compressione del midollo spinale sono considerati idonei se sottoposti a trattamento locale risolutivo (per es. radioterapia, chirurgia stereotassica) e rimasti clinicamente stabili senza uso di anticonvulsivanti e dosi crescenti di corticosteroidi per almeno 2 settimane precedenti il primo giorno di trattamento in studio.
    7. Possibilità di ottenere un campione di tessuto tumorale sufficiente, mediante biopsia o resezione chirurgica del tumore primitivo o del tessuto tumorale metastatico, nei 60 giorni precedenti l’ingresso nello studio e alla progressione o successivamente come definita in base ai criteri RECIST 1.1.
    8. Indice di performance OMS pari a 01.
    9. Aspettativa di vita ≥12 settimane.
    10. Coagulazione adeguata: rapporto internazionale normalizzato (INR) ≤1,5 per pazienti in terapia anticoagulante.
    11. Capacità di deglutizione.
    12. Pazienti in grado di completare lo studio e a distanza ragionevole dal centro per consentire un follow-up adeguato.
    13. Risoluzione al grado 1 (in base ai criteri CTCAE del National Cancer Institute (NCI) versione 4.0) di tutte le tossicità acute della precedente terapia oncologica (che può essere solo adiuvante o neoadiuvante) o dei precedenti interventi chirurgici (esclusi alopecia o altri effetti indesiderati che lo Sperimentatore non considera costituire un rischio per la sicurezza del paziente).
    14. Le pazienti di sesso femminile, se in età fertile, devono usare metodi contraccettivi altamente efficaci e risultare negative a un test di gravidanza effettuato prima di iniziare il trattamento; alternativamente non devono essere in età fertile come dimostrato dal soddisfacimento di uno dei seguenti criteri allo screening:
    stato di post-menopausa definito come età >50 anni e assenza di mestruazioni da almeno 12 mesi dopo l’interruzione di tutti i trattamenti ormonali esogeni;
    le pazienti di sesso femminile sotto i 50 anni saranno considerate in post-menopausa se in assenza di mestruazioni da ≥12 mesi dopo l’interruzione di trattamenti ormonali esogeni e con livelli di ormone luteinizzante e ormone follicolo stimolante nell’intervallo della norma per la post-menopausa secondo i range di riferimento del centro;
    documentazione di sterilizzazione chirurgica irreversibile mediante isterectomia, ovariectomia bilaterale o salpingectomia bilaterale ma non legatura delle tube.
    15. I pazienti di sesso maschile devono essere disposti a utilizzare metodi contraccettivi di barriera
    E.4Principal exclusion criteria
    1. Locally advanced lung cancer candidate for curative treatment through radical surgery and/or radio(chemo)therapy.
    2. Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with predominantly squamous cell cancer, or with any small-cell lung cancer component.
    3. Patients with an EGFR exon 20 insertion.
    4. Patients with just one measurable or evaluable tumour lesion that has been resected or irradiated prior to their enrolment in the study.
    5. Second active neoplasia.
    6. Treatment with an investigational drug within five half-lives of the compound.
    7. Participation in another clinical study with an investigational product (IP) during the last 3 weeks before the first day of study treatment.
    8. Patients who have received prior immunotherapies.
    9. Patients who have received prior EGFR treatments for lung cancer.
    10. Patients who have received prior treatment with an EGFR TKI including in the adjuvant setting.
    11. Patients who have received previous treatment for metastatic or stage IV disease.
    12. Prior treatment with cytotoxic chemotherapy for advanced NSCLC (neoadjuvant/adjuvant chemotherapy is permitted if at least 6 months have elapsed between the end of chemotherapy and the first day of study treatment).
    13. Patients with a history of cancer that has been completely treated, with no evidence of malignant disease currently cannot be enrolled in the study if their chemotherapy was completed less than 6 months prior and/or have received a bone marrow transplant less than 2 years before the first day of study treatment
    14. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
    15. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
    16. Patients who have had a surgical procedure unrelated to the study within 14 days or major surgery within 1 month prior to the administration of the study drug; patients with a significant traumatic lesion (as judged by the Investigator that would risk patient safety) during the 4 weeks prior to starting the administration of the study drug; patients who have not recovered from the side effects of any major surgery; or patients who might need major surgery during the course of the study.
    17. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required corticosteroid treatment, or any evidence of clinically active interstitial lung disease.
    18. Any of the following cardiac criteria:
    - Mean resting QT interval corrected for heart rate (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value;
    - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block;
    - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
    19. Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or leptomeningeal disease indicated by known clinical symptoms, cerebral oedema and/or progressive neoplasia.
    20. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
    21. Inadequate bone marrow reserve or organ function as demonstrated by the laboratory values.
    22. Female patients who are breastfeeding.
    23. Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4 (at least 3 weeks prior). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
    24. Patient unwilling to undergo a biopsy at the time of disease progression.
    25. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib
    1. Carcinoma polmonare localmente avanzato candidato per trattamento con intento curativo mediante chirurgia radicale e/o radio(chemio)terapia.
    2. Pazienti cui è stato diagnosticato un altro sottotipo di carcinoma polmonare, pazienti con NSCLC misto con carcinoma prevalentemente squamocellulare o con qualsiasi componente di carcinoma polmonare a piccole cellule.
    3. Pazienti con un’inserzione nell’esone 20 di EGFR.
    4. Pazienti con una sola lesione tumorale misurabile o valutabile rimossa o irradiata prima del loro arruolamento nello studio.
    5. Neoplasia attiva secondaria.
    6. Trattamento con un farmaco sperimentale entro cinque emivite del composto.
    7. Partecipazione a un altro studio clinico con un prodotto sperimentale (IP) nelle 3 settimane precedenti il primo giorno di trattamento in studio.
    8. Pazienti sottoposti a precedenti immunoterapie.
    9. Pazienti sottoposti a precedenti trattamenti a base di EGFR per il carcinoma polmonare.
    10. Pazienti sottoposti a precedente trattamento con un EGFR TKI, anche nel contesto adiuvante.
    11. Pazienti precedentemente trattati per malattia metastatica o in stadio IV.
    12. Precedente trattamento con terapia citotossica per il NSCLC avanzato (è consentita la chemioterapia neoadiuvante/adiuvante se sono trascorsi almeno 6 mesi tra la fine della chemioterapia e il primo giorno di trattamento in studio).
    13. Al momento i pazienti con una storia di cancro trattato in via definitiva e senza evidenze di malattia non possono essere arruolati nello studio se la terapia è stata completata meno di 6 mesi prima e/o se sottoposti a trapianto di midollo osseo nei 2 anni precedenti il primo giorno di trattamento in studio.
    14. Qualsiasi tossicità non risolta dalla terapia precedente di grado CTCAE >1 al momento dell’inizio del trattamento in studio, a eccezione di alopecia e neuropatia di grado 2 correlata al precedente trattamento a base di platino.
    15. Qualsiasi evidenza di patologie sistemiche gravi o non controllate, incluse ipertensione non controllata e diatesi emorragiche attive, che nell’opinione dello Sperimentatore rende sconsigliabile la partecipazione del paziente allo studio o che comprometterebbe la compliance al protocollo, oppure infezione attiva, incluse epatite B, epatite C e infezione da virus dell’immunodeficienza umana (HIV). Non è previsto lo screening per malattie croniche.
    16. Pazienti sottoposti a una procedura chirurgica non correlata allo studio o a un intervento di chirurgia maggiore rispettivamente nei 14 giorni o nel mese precedente la somministrazione del farmaco in studio; pazienti interessati da una lesione traumatica significativa (che secondo lo Sperimentatore metterebbe a rischio la sicurezza del paziente) nelle 4 settimane precedenti la somministrazione del farmaco in studio; pazienti non ripresi dagli effetti indesiderati di un qualsiasi intervento di chirurgia maggiore; oppure pazienti per i quali potrebbe essere necessario un intervento di chirurgia maggiore nel corso dello studio.
    17. Storia medica di pneumopatia interstiziale, pneumopatia interstiziale farmaco-indotta, polmonite da radiazioni che ha richiesto trattamento con corticosteroidi o qualsiasi evidenza di pneumopatia interstiziale clinicamente attiva.
    18. Uno qualsiasi dei seguenti criteri cardiaci:
    - intervallo QT medio a riposo corretto per la frequenza cardiaca (QTc) >470 msec, ottenuto da 3 ECG utilizzando il valore QTc misurato allo screening dall’apparecchiatura ECG del centro;
    - qualsiasi anomalia clinicamente importante dell’ECG a riposo in termini di ritmo, conduzione o morfologia, ad es. blocco di branca destra completo e blocco cardiaco di terzo e secondo grado;
    - qualsiasi fattore che aumenti il rischio di prolungamento del QTc o di eventi aritmici, quali insufficienza cardiaca, ipokaliemia, sindrome del QT lungo congenita, storia familiare di sindrome del QT lungo o morte improvvisa inspiegata prima dei 40 anni in parenti di primo grado, o qualsiasi terapia farmacologica concomitante che prolunga l’intervallo QT.
    19. Metastasi a carico del SNC non controllate, attive o sintomatiche, meningite carcinomatosa o malattia leptomeningea indicata da sintomi clinici noti, edema cerebrale e/o neoplasia progressiva.
    20. Nausea e vomito refrattari, malattie gastrointestinali croniche, incapacità di ingerire il prodotto formulato o precedente resezione intestinale significativa che impedirebbe l’assorbimento adeguato di osimertinib.
    21. Riserva di midollo osseo o funzionalità organica inadeguata come dimostrato dai valori di laboratorio.
    22. Pazienti di sesso femminile che allattano al seno.
    23. Pazienti in trattamento corrente (o che non possono interromperne l’uso prima di ricevere la prima dose di trattamento in studio) con farmaci o integratori fitoterapici potenti induttori del citocromo P450 (CYP) 3A4 (il trattamento deve essere interrotto almeno 3 settimane prima). Tutti i pazienti devono evitare l’uso concomitante di qualsiasi farmaco e integratore fitoterapico [...]
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients with a given genetic and proteomic marker (including, but not limited to, EGFR mutations, HER2, and cMET expression and/or amplification) at the point of disease progression as defined by the Investigator
    Percentuale di pazienti con un determinato marcatore genetico e proteomico (incluse, a titolo meramente esemplificativo, le mutazioni EGFR, espressione e/o amplificazione del recettore 2 del fattore di crescita epidermico umano e del proto-oncogene codificante per il recettore del fattore di crescita epatocitario) al momento della progressione della malattia definita dallo Sperimentatore
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the point of disease progression
    Al momento della progressione della malattia
    E.5.2Secondary end point(s)
    Progression-free survival, according to RECIST 1.1 by Investigator assessment, and other selected clinical efficacy endpoints including:
    • Objective response rate
    • Duration of response
    • Disease control rate
    • Tumour shrinkage/depth of response, defined as best change from baseline in target lesion tumour size
    • Time to treatment discontinuation or death
    • Time to first subsequent therapy or death
    Safety Endpoints:
    • Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0
    • Clinical chemistry, haematology and urinalysis
    • Vital signs, physical examination, body weight
    • Electrocardiogram
    • Left ventricular ejection fraction
    • World Health Organization performance status
    • Ophthalmologic assessment
    Sopravvivenza libera da progressione, secondo la valutazione dello Sperimentatore in base ai RECIST 1.1, e altri endpoint di efficacia clinica selezionati, tra cui:
    •Tasso di risposta obiettiva
    •Durata della risposta
    •Tasso di controllo della malattia
    •Restringimento del tumore/entità della risposta, definita come miglior variazione rispetto al basale della dimensione del tumore target
    •Tempo all’interruzione del trattamento o al decesso
    •Tempo alla prima terapia successiva o al decesso
    Endpoint di sicurezza:
    •Eventi avversi classificati dai criteri terminologici comuni per gli eventi avversi versione 4.0
    •Analisi chimico-cliniche ed ematologiche e analisi delle urine
    •Parametri vitali, esame obiettivo, peso corporeo
    •Elettrocardiogramma
    •Frazione di eiezione ventricolare sinistra
    •Stato di validità dell’Organizzazione mondiale della sanità
    •Valutazione oftalmologica
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the trial
    Per tutta la durata dello studio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tollerabilità
    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 No
    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 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 No
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    Italy
    Korea, Republic of
    Malaysia
    Spain
    Taiwan
    United States
    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 the study is defined as when the final analysis of the biopsy data is performed. If the final analysis is performed when over 80% of patients have progressed or died then this analysis may occur 48 months after the first patient in (Q3 2021).
    La fine dello studio è definita come completamento dell'analisi finale dei dati delle biopsie. Se l'analisi finale viene effettuata quando oltre l'80% dei pazienti è progredito o è deceduto, allora l'analisi potrebbe essere effettuata 48 mesi dopo l'arruolamento del primo paziente (Q3 2021).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 116
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 29
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 33
    F.4.2.2In the whole clinical trial 145
    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)
    Patients will be treated in accordance with the regional standard of care
    I pazienti saranno trattati secondo le terapie standard locali.
    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 Decision2017-10-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-20
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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