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    Summary
    EudraCT Number:2019-002869-35
    Sponsor's Protocol Code Number:CAPLAND
    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:2021-02-19
    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 number2019-002869-35
    A.3Full title of the trial
    A randomized, non-comparative, phase II study investigating the best epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sequence in advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR mutations
    Studio di fase II randomizzato, non comparativo, che studia la migliore sequenza di inibitori tirosin-chinasici del recettore del fattore di crescita epidermico (EGFR-TKI) nel carcinoma polmonare non a piccole cellule avanzato o metastatico (NSCLC) con mutazioni dell’EGFR
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized, non-comparative, phase II study investigating the best epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sequence in advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR mutations
    Studio di fase II randomizzato, non comparativo, che studia la migliore sequenza di inibitori tirosin-chinasici del recettore del fattore di crescita epidermico (EGFR-TKI) nel carcinoma polmonare non a piccole cellule avanzato o metastatico (NSCLC) con mutazioni dell’EGFR
    A.3.2Name or abbreviated title of the trial where available
    A randomized, non-comparative, phase II study investigating the best epidermal growth factor recept
    Studio di fase II randomizzato, non comparativo, che studia la migliore sequenza di inibitori tirosi
    A.4.1Sponsor's protocol code numberCAPLAND
    A.5.4Other Identifiers
    Name:CAPLANDNumber:CAPLAND
    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 SponsorFONDAZIONE RICERCA TRASLAZIONALE (FORT)
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer srl
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinical Research Technology
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressVia San Leonardo Traversa Migliaro
    B.5.3.2Town/ citySalerno
    B.5.3.3Post code84131
    B.5.3.4CountryItaly
    B.5.4Telephone number+39089301545
    B.5.5Fax number+390897724155
    B.5.6E-mailcapland@cr-technology.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.2.1.1.1Trade name Vizimpro 45 mg compresse rivestite con film
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namedacomitinib
    D.3.2Product code [NAP]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdacomitinib
    D.3.9.1CAS number 1110813-31-4
    D.3.9.2Current sponsor codePF00299804
    D.3.9.4EV Substance CodeSUB81761
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    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.2.1.1.1Trade name Vizimpro 30 mg compresse rivestite con film
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namedacomitinib
    D.3.2Product code [NAP]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdacomitinib
    D.3.9.1CAS number 1110813-31-4
    D.3.9.2Current sponsor codePF00299804
    D.3.9.4EV Substance CodeSUB81761
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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 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.2.1.1.1Trade name Vizimpro 15 mg compresse rivestite con film
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namedacomitinib
    D.3.2Product code [NAP]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdacomitinib
    D.3.9.1CAS number 1110813-31-4
    D.3.9.2Current sponsor codePF00299804
    D.3.9.4EV Substance CodeSUB81761
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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
    Advanced or metastatic untreated EGFR mutation positive NSCLC
    NSCLC avanzato o metastatico non trattato, positivo alla mutazione dell’EGFR.
    E.1.1.1Medical condition in easily understood language
    Advanced or metastatic untreated EGFR mutation positive NSCLC
    NSCLC avanzato o metastatico non trattato, positivo alla mutazione dell’EGFR
    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 assess the best drug sequencing in patients with advanced or metastatic EGFR mutation positive NSCLC. The study, including patients with classical or uncommon activating EGFR mutations, will allow to investigate the efficacy of dacomitinib or osimertinib in these patients. Patients with asymptomatic or controlled brain metastases are eligible, allowing to define efficacy of dacomitinib in this special population.
    Valutare la migliore sequenza di trattamenti in pazienti con NSCLC avanzato o metastatico, positivo alla mutazione dell’EGFR. Lo studio, includendo i pazienti con mutazioni EGFR attivanti classiche o non comuni, consentirà di studiare l'efficacia di dacomitinib o osimertinib in questa popolazione. La possibilità di arruolare pazienti con metastasi cerebrali asintomatiche o controllate, consente di definire l'efficacia di dacomitinib in questa particolare popolazione.
    E.2.2Secondary objectives of the trial
    • OS in patients treated with osimertinib first followed by dacomitinib and in patients treated with dacomitinib first followed by osimertinib
    • PFS at the time of study second-line therapy failure (PFS2) in patients treated with front-line osimertinib or dacomitinib;
    • PFS in patients treated with osimertinib first or dacomitinib first;
    • Response Rate (RR) with dacomitinib or osimertinib;
    • RR, PFS and OS with osimertinib followed by dacomitinib or with the opposite sequence in patients with uncommon activating EGFR mutations;
    • RR, PFS and OS with dacomitinib given at the time of osimertinib failure;
    • Intracranial RR and intracranial PFS with dacomitinib or osimertinib
    • Safety and incidence of AEs in patients treated with osimertinib followed by dacomitinib or with the opposite sequence.
    • OS nei pazienti trattati prima con osimertinib seguito da dacomitinib e nei pazienti trattati prima con dacomitinib seguito da osimertinib;
    • PFS al momento del fallimento della terapia di seconda linea (PFS2) in pazienti trattati in prima linea con osimertinib o con dacomitinib;
    • PFS in pazienti trattati prima con osimertinib o prima con dacomitinib;
    • Tasso di risposta (RR) con dacomitinib o con osimertinib;
    • RR, PFS e OS con osimertinib seguito da dacomitinib o con la sequenza opposta in pazienti con mutazioni EGFR attivanti non comuni;
    • RR, PFS e OS con dacomitinib somministrato al momento del fallimento di osimertinib;
    • RR intracranico e PFS intracranica con dacomitinib o osimertinib;
    • Sicurezza e incidenza degli eventi avversi in pazienti trattati con osimertinib seguito da dacomitinib o con sequenza opposta;
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Written informed consent;
    2) Male or female patient aged =18 years;
    3) Histologically/cytologically confirmed diagnosis of NSCLC with evidence of activating EGFR mutations including exon 19 deletion, exon 21 L858R or other activating/sensitizing EGFR mutations such as exon 21 L861Q, exon 18 G719S, G719A, G719C, exon 20 S768I and V769L; co-occurrence of de novo T790M is not an exclusion criterion; EGFR status assessed in circulating DNA is allowed;
    4) Patients with brain metastases are allowed provided they are asymptomatic and stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms), and have not received steroids for at least 7 days before randomization;
    5) No evidence of concomitant drivers including KRAS mutations, HER2 mutations, ALK or ROS1 rearrangements, MET mutations, BRAF mutations;
    6) No previous EGFR-TKI therapy; Previous palliative radiotherapy or surgery allowed. Previous neo/adjuvant chemotherapy is allowed as long as therapy was completed at least 6 months before diagnosis of advanced or metastatic NSCLC;
    7) At least one radiological measurable disease according to RECIST criteria version 1.1;
    8) Performance status 0-1 (ECOG PS);
    9) Patient compliance to trial procedures;
    10) Adequate bone marrow function (ANC = 1.5x109/L, platelets =100x109/L, haemoglobin >9 g/dl);
    11) Adequate liver function (AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =5x ULN, bilirubin < grade 2, transaminases no more than 3xULN/<5xULN in presence of liver metastases);
    12) Normal level of alkaline phosphatase, and creatinine;
    13) Female patients should be using adequate contraceptive measures, should not be breastfeeding, until 12 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
    • Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
    • Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
    • Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation.
    14) Male patients should be willing to use barrier contraception, i.e., condoms;
    15) No significant comorbidity that according to the investigator would hamper the participation on the trial;
    1) Consenso informato scritto;
    2) Paziente maschio o femmina di età =18 anni;
    3) Diagnosi istologicamente / citologicamente confermata di NSCLC con evidenza di attivazione di mutazione dell’EGFR tra cui la delezione nell'esone 19, L858R nell’esone 21 o altre mutazioni dell’EGFR attivanti/sensibilizzanti come L861Q nell’esone 21, G719S, G719A, G719C nell’esone 18, S768I e V769L nell’esone 20; la ricorrenza di T790M de novo non è un criterio di esclusione; È consentito lo stato dell’EGFR valutato nel DNA circolante;
    4) I pazienti con metastasi cerebrali sono ammessi a condizione che siano asintomatici e stabili (cioè senza evidenza di progressione mediante imaging per almeno due settimane prima della prima dose del trattamento in studio e senza deterioramento di alcun sintomo neurologico) e non abbiano ricevuto steroidi per almeno 7 giorni prima della randomizzazione;
    5) Nessuna evidenza di driver concomitanti tra cui mutazioni KRAS, mutazioni HER2, riarrangiamenti di ALK o ROS1, mutazioni MET, mutazioni BRAF;
    6) Nessuna precedente terapia EGFR-TKI; È consentita precedente radioterapia palliativa o chirurgia. La chemioterapia neo/adiuvante precedente è consentita fintanto che la terapia sia stata completata almeno 6 mesi prima della diagnosi di NSCLC avanzato o metastatico;
    7) Almeno una malattia misurabile radiologicamente secondo i criteri RECIST versione 1.1;
    8) Performance status 0-1 (ECOG PS);
    9) Compliance del paziente alle procedure dello studio;
    10) Adeguata funzionalità del midollo osseo (ANC = 1,5x109 / L, piastrine =100x109 / L, emoglobina> 9 g / dl);
    11) Funzionalità epatica adeguata (AST (SGOT) / ALT (SGPT) =2,5 x limite superiore istituzionale normale a meno che non siano presenti metastasi epatiche, nel qual caso deve essere =5x ULN, bilirubina <grado 2, transaminasi non più di 3xULN/<5xULN in presenza di metastasi epatiche);
    12) Livelli normali di fosfatasi alcalina e creatinina;
    13) Le pazienti di sesso femminile devono usare adeguate misure contraccettive, non devono allattare al seno, fino a 12 mesi dopo l'ultima dose e devono avere un test di gravidanza negativo (siero o urina) prima della prima dose del farmaco in studio (entro 72 ore); o le pazienti di sesso femminile devono avere una evidenza di non fertilità soddisfacendo uno dei seguenti criteri allo screening;
    • Post-menopausa, definita come di età superiore ai 50 anni e amenorrea per almeno 12 mesi dopo l'interruzione di tutti i trattamenti ormonali esogeni;
    • Le donne di età inferiore a 50 anni verrebbero prese in considerazione in postmenopausa se amenoriche per 12 mesi o più a seguito della cessazione di trattamenti ormonali esogeni e con livelli di ormone luteinizzante (LH) e ormone follicolo-stimolante (FSH) nell'intervallo post-menopausa del Centro;
    • Documentazione di sterilizzazione chirurgica irreversibile mediante isterectomia, bilateral-ooforectomia o salpingectomia bilaterale ma non legatura delle tube;
    14) I pazienti maschi devono essere disposti a usare contraccezione di barriera, cioè preservativi;
    15) Nessuna significativa comorbidità che secondo l'investigatore ostacolerebbe la partecipazione al processo;
    E.4Principal exclusion criteria
    1) Previous therapy with any EGFR-TKI;
    2) Previous systemic anti-cancer therapy for advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug;
    3) Absence of measurable lesions;
    4) Concomitant radiotherapy or chemotherapy;
    5) Symptomatic or immediately requiring therapy brain metastases or carcinomatous meningitis. Subjects with asymptomatic and stable or treated brain metastases may participate
    6) Diagnosis of any other malignancy during the last 3 years, except for in situ carcinoma of cervix uteri and squamous cell carcinoma of the skin;
    7) History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis (but not history of prior radiation pneumonitis);
    8) Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV);
    9) Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of the study drugs;
    10) Any of the following cardiac criteria:
    • Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value;
    • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec or history of episodes of bradycardia (<50 BPM);
    • 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;
    • Abnormal cardiac function: LVEF < 50% (assessed by MUGA or ECHO)
    11) Pregnancy or lactating female;
    12) Other serious illness or medical condition potentially interfering with the study.
    1) Terapie precedenti con qualsiasi EGFR-TKI;
    2) Terapie anticancro sistemica precedente per NSCLC avanzato / metastatico tra cui chemioterapia, terapia biologica, immunoterapia o qualsiasi farmaco sperimentale;
    3) Assenza di lesioni misurabili;
    4) Radioterapia concomitante o chemioterapia;
    5) Metastasi cerebrali sintomatiche o che richiedono immediatamente terapia o meningite carcinomatosa. Possono partecipare soggetti con metastasi cerebrali asintomatiche e stabili o trattate;
    6) Diagnosi di qualsiasi altro tumore maligno negli ultimi 3 anni, ad eccezione del carcinoma in situ dell'utero cervicale e del carcinoma a cellule squamose della pelle;
    7) Storia di presenza diffusa /bilaterale o nota di fibrosi interstiziale di grado 3 o 4 o malattia polmonare interstiziale inclusa anamnesi di polmonite, polmonite da ipersensibilità, polmonite interstiziale, malattia polmonare interstiziale, bronchiolite obliterante e fibrosi polmonare (ma non storia di precedenti polmoniti da radiazioni);
    8) Qualsiasi evidenza di malattie sistemiche gravi o incontrollate, tra cui ipertensione non controllata e diatesi emorragiche attive; o infezione attiva inclusa epatite B, epatite C e virus dell'immunodeficienza umana (HIV);
    9) Nausea e vomito refrattari, malattie gastrointestinali croniche, incapacità di deglutire il prodotto formulato o precedente significativa resezione intestinale che precluderebbe un adeguato assorbimento dei farmaci in studio;
    10) Uno dei seguenti criteri cardiaci:
    • Intervallo QT corretto medio a riposo (QTc)> 470 msec, ottenuto da 3 ECG utilizzando il valore QTcF derivato dalla macchina ECG del Centro locale;
    • Eventuali anomalie clinicamente importanti nel ritmo, nella conduzione o nella morfologia dell'ECG a riposo, ad es. blocco completo di branca sinistra, blocco cardiaco di terzo grado, blocco cardiaco di secondo grado, intervallo PR> 250 msec o storia di episodi di bradicardia (<50 BPM);
    • Qualsiasi fattore che aumenti il rischio di prolungamento dell'intervallo QTc o il rischio di eventi aritmici come insufficienza cardiaca, ipopotassiemia, sindrome congenita del QT lungo, storia familiare del QT lungo o morte improvvisa inspiegabile sotto i 40 anni in parenti di primo grado o farmaci concomitanti noti per prolungare l'intervallo QT;
    • Funzione cardiaca anormale: LVEF <50% (valutata da MUGA o ECHO)
    11) Gravidanza o allattamento;
    12) Altre gravi malattie o condizioni mediche che potrebbero interferire con lo studio.
    E.5 End points
    E.5.1Primary end point(s)
    OS in patients treated with osimertinib first or dacomitinib first
    OS nei pazienti trattati prima con osimertinib o prima con dacomitinib.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Continuous - Every 8 weeks
    continuativo - ogni 8 settimane
    E.5.2Secondary end point(s)
    • OS in patients treated with osimertinib first followed by dacomitinib and in patients treated with dacomitinib first followed by osimertinib
    • PFS at the time of study second-line therapy failure (PFS2) in patients treated with front-line osimertinib or dacomitinib;
    • PFS in patients treated with osimertinib first or dacomitinib first;
    • Response Rate (RR) with dacomitinib or osimertinib;
    • RR, PFS and OS with osimertinib followed by dacomitinib or with the opposite sequence in patients with uncommon activating EGFR mutations;
    • RR, PFS and OS with dacomitinib given at the time of osimertinib failure;
    • Intracranial RR and intracranial PFS with dacomitinib or osimertinib
    • Safety and incidence of AEs in patients treated with osimertinib followed by dacomitinib or with the opposite sequence.
    • OS nei pazienti trattati prima con osimertinib seguito da dacomitinib e nei pazienti trattati prima con dacomitinib seguito da osimertinib;
    • PFS al momento del fallimento della terapia di seconda linea (PFS2) in pazienti trattati in prima linea con osimertinib o con dacomitinib;
    • PFS in pazienti trattati prima con osimertinib o prima con dacomitinib;
    • Tasso di risposta (RR) con dacomitinib o con osimertinib;
    • RR, PFS e OS con osimertinib seguito da dacomitinib o con la sequenza opposta in pazienti con mutazioni EGFR attivanti non comuni;
    • RR, PFS e OS con dacomitinib somministrato al momento del fallimento di osimertinib;
    • RR intracranico e PFS intracranica con dacomitinib o osimertinib;
    • Sicurezza e incidenza degli eventi avversi in pazienti trattati con osimertinib seguito da dacomitinib o con sequenza opposta;
    E.5.2.1Timepoint(s) of evaluation of this end point
    • 24 years from LPFV
    • continuous - every 8 weeks
    • continuous - every 8 weeks
    • continuous - every 8 weeks and 24 years from LPFV
    • continuous - every 8 weeks and 24 years from LPFV
    • continuous - every 8 weeks
    • continuous
    • 24 mesi dalla LPFV
    • continuativo - ogni 8 settimane
    • continuativo - ogni 8 settimane
    • continuativo - ogni 8 settimane
    • continuativo - ogni 8 settimane e 24 mesi dalla LPFV
    • continuativo - ogni 8 settimane e 24 mesi dalla LPFV
    • continuativo - ogni 8 settimane
    • continuativo
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    non comparativo, studia la migliore sequenza di 2 EGFR-TKI
    non-comparative study investigating the best EGFR-TKI sequence
    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 concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Austria
    France
    Germany
    Spain
    Sweden
    Switzerland
    United Kingdom
    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
    24 monhs from Last Patient First Visit
    24 mesi dalla prima visita dell'ultimo paziente
    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.1.1.1In 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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 89
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subject incapable of giving consent for physical reasons or reason linked to their medical condition
    Soggetto incapace di dare il consenso per motivi fisici o motivi legati alla loro condizione medica
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 189
    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)
    If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to radiologic progression, then the patient should still continue to be followed until confirmed objective disease progression.
    Following confirmed progression, patients should continue to be followed up for survival every 3 months (12 weeks) till 2 years from last patient firt fisit
    Se un paziente interrompe il trattamento (e / o riceve una successiva terapia antitumorale) prima della progressione radiologica, allora il paziente deve continuare ad essere seguito fino alla conferma della progressione obiettiva della malattia.
    Dopo la progressione confermata, i pazienti devono continuare a essere seguiti per la sopravvivenza ogni 3 mesi (12 settimane) fino a 2 anni dalla prima visita dell'ultimo paziente
    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 Decision2020-03-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-20
    P. End of Trial
    P.End of Trial StatusOngoing
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