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    Summary
    EudraCT Number:2014-002123-10
    Sponsor's Protocol Code Number:1200.120
    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:2015-11-23
    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 number2014-002123-10
    A.3Full title of the trial
    Phase I open label, dose escalation trial to determine the MTD, safety, PK and efficacy of afatinib monotherapy in children aged 2 years to <18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology
    Studio di fase I in aperto, a dosaggio scalare, per determinare la MTD, la sicurezza, la PK e l'efficacia di afatinib in monoterapia nei bambini di età compresa tra 2 anni e <18 anni con tumori recidivanti/refrattari neuroectodermici, rabdomiosarcoma e/o altri tumori solidi con nota deregolazione della via ErbB indipendentemente dalla istologia tumorale.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I trial of afatinib in pediatric tumours
    Studio di fase I con Afatinib in tumori pediatrici
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code number1200.120
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBoehringer Ingelheim Italia S.p.A.
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBoehringer Ingelheim Italia S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    B.5.2Functional name of contact pointQRPE PSC CT Information Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressBinger Strasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55216
    B.5.3.4CountryGermany
    B.5.4Telephone number+18002430127
    B.5.5Fax number+18008217119
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name GIOTRIF
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer International GmbH
    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 nameAfatinib
    D.3.2Product code BIBW 2992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number 850140-72-6
    D.3.9.3Other descriptive nameAFATINIB
    D.3.9.4EV Substance CodeSUB32268
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 GIOTRIF
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer International GmbH
    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 nameAfatinib
    D.3.2Product code BIBW 2992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number 850140-72-6
    D.3.9.3Other descriptive nameAFATINIB
    D.3.9.4EV Substance CodeSUB32268
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 Yes
    D.2.1.1.1Trade name GIOTRIF
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer International GmbH
    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 nameAfatinib
    D.3.2Product code BIBW 2992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number 850140-72-6
    D.3.9.3Other descriptive nameAFATINIB
    D.3.9.4EV Substance CodeSUB32268
    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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name GIOTRIF
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer International GmbH
    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 nameAfatinib
    D.3.2Product code BIBW 2992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number 850140-72-6
    D.3.9.3Other descriptive nameAFATINIB
    D.3.9.4EV Substance CodeSUB32268
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAfatinib
    D.3.2Product code BIBW 2992
    D.3.4Pharmaceutical form Powder and solvent for oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNafatinib
    D.3.9.1CAS number 850140-72-6
    D.3.9.3Other descriptive nameAFATINIB
    D.3.9.4EV Substance CodeSUB32268
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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
    Paediatric patients with recurrent/refractory high grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), low grade astrocytoma, neuroblastoma, ependymoma, medulloblastoma/primitive neuroectodermal tumours (PNET), rhabdomyosarcoma (RMS) and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology
    tumori recidivanti/refrattari neuroectodermici, rabdomiosarcoma e/o altri tumori solidi con nota deregolazione della via ErbB indipendentemente dalla istologia tumorale.
    E.1.1.1Medical condition in easily understood language
    pediatric oncology
    oncologia pediatrica
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10029091
    E.1.2Term Neoplasm of unspecified nature of endocrine glands and other parts of nervous system
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10029006
    E.1.2Term Neoplasm of uncertain behavior of brain and spinal cord
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10029050
    E.1.2Term Neoplasm of uncertain behaviour of connective and other soft tissue
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10028992
    E.1.2Term Neoplasm CNS
    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
    -Establish MTD of afatinib in pediatric patients
    -describe pharmacokinetics of afatinib
    -investigate objective response (OR) to treatment
    Parte sulla determinazione della dose (dose finding part) :
    - Determinare la dose massima tollerata (MTD) di afatinib nei pazienti ≥2 a <18 anni, valutando la tossicità dose-limitante (DLT). L'MTD sarà determinata come la dose massima a cui non più di 1/6 pazienti avranno DLT.
    - Valutare la sicurezza
    - Descrivere la farmacocinetica (PK), dopo la prima dose e allo ”steady state” nei bambini.
    - Indagare la risposta obiettiva (OR) al trattamento
    Coorte di espansione MTD:
    - I pazienti inclusi nella coorte di espansione MTD saranno selezionati per qualsiasi biomarcatore di deregolamentazione ErbB, precedentemente identificato nello studio di prevalenza sui biomarcatori, al di fuori di questo protocollo di sperimentazione clinica
    - Indagare la risposta obiettiva (OR) al trattamento
    - Raccogliere ulteriori dati sulla sicurezza, PK ed efficacia
    E.2.2Secondary objectives of the trial
    -Safety
    -pharmacokinetics
    -efficacy by objective reponse
    - Valutare la qualità della vita relativamente allo stato di salute (HRQoL), soltanto nella coorte di espansione MTD
    - Valutare l'accettabilità del farmaco sperimentale.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Paediatric patients
    - aged ≥2 years - <18 years at the time of informed consent
    - who present with recurrent/refractory disease after they received at least one prior standard treatment regimen and for whom no effective conventional therapy exists
    - Dose finding part: patients with a diagnosis of HGG, DIPG, low grade astrocytoma, neuroblastoma, ependymoma, medulloblastoma/PNET, RMS, and/or solid tumours with known ErbB pathway deregulation regardless of tumour histology.
    - MTD expansion cohort: patients with solid tumours (regardless of histology) selected by any biomarker(s) for ErbB pathway deregulation, which was previously identified in a biomarker prevalence study done outside of this clinical trial protocol
    -Performance status >= 50% (Lansky for =<12ys; Karnofsky for >12ys)
    Fase I “dose finding part”
    1. Pazienti con diagnosi istologica di glioma di alto grado (HGG), glioma pontino intrinseco diffuso (DIPG), astrocitoma di grado basso, medulloblastoma/PNET, ependimoma, neuroblastoma, rabdomiosarcoma e/o altri tumori solidi (indipendentemente dalla istologia tumorale) ma con nota deregolamentazione della via ErbB.
    2. Pazienti con malattia recidivante o refrattaria precedentemente trattati con almeno un regime terapeutico standard
    3. Pazienti di età compresa tra >=2 e <18 anni
    4. Pazienti che abbiano recuperato da qualsiasi tossicità acuta (a CTCAE grado 1 o al basale) derivante da qualsiasi trattamento antitumorale precedente (tranne alopecia)
    5. Mancanza di terapia convenzionale efficace
    6. Assenso scritto del paziente e consenso informato scritto dei genitori/tutore legale in coerenza con la legislazione locale e le linee guida ICH-GCP
    7. Disponibilità di tessuto tumorale fresco/archiviato. Per DIPG, se non disponibili, devono essere resi disponibili i dati della biopsia sulla istologia del tumore e sul profilo tumorale (se applicabile)
    8. Performance status: Lansky >= 50% per pazienti di età <= 12 anni di età o Karnofsky >= 50% per pazienti di età superiore a 12 anni valutati nelle due settimane precedenti l'arruolamento
    9. Pazienti con neoplasie del sistema nervoso centrale neurologicamente stabili per almeno 7 giorni prima dell'inclusione nello studio secondo giudizio dello sperimentatore
    10. Pazienti, sia maschi che femmine, con un potenziale riproduttivo (ragazze post menarca e maschi dopo la prima eiaculazione) e sessualmente attivi devono accettare di praticare efficaci misure contraccettive per la durata della terapia col farmaco in studio e per almeno 28 giorni dopo il completamento della terapia con il farmaco in studio (si veda la Sezione 4.2.3.3 del protocollo per misure efficaci di contraccezione)
    11. Pazienti in grado e disposti a inghiottire/prendere afatinib per via orale una volta al giorno (compresse o soluzione orale) secondo giudizio dello sperimentatore
    12. LVEF >= 50%
    Criteri di inclusione modificati per MTD expansion cohort:
    Criterio inclusione 1 modificato: Pazienti i cui tumori mostrino qualsiasi deregolamentazione della via ErbB, identificata nello studio di prevalenza sui biomarcatori indipendentemente dalla istologia tumorale – l’inclusione sarà basata sulla valutazione dei biomarcatori prima dell’inclusione, determinati attraverso l’analisi di materiale bioptico tumorale, eseguita da un laboratorio di analisi centralizzato.
    I criteri di inclusione 2-12 si applicano come sopra.
    E.4Principal exclusion criteria
    -relevant toxicity from previous treatment
    -known pre-existing relevant cardiac , hepatic, renal, bone marrow dysfunction, ILD, keratitis
    1. Chemioterapia entro 3 settimane prima dell'inizio del trattamento in studio, terapia biologica o con farmaci sperimentali entro 4 settimane prima dell'inizio del trattamento in studio o prima che siano trascorse 5 emivite, per esempio clearance sistemica, o quello che accade prima
    2. Radioterapia entro 2 settimane prima di iniziare il trattamento in studio (la radioterapia palliativa è consentita se non focalizzata su una lesione target)
    3. Chirurgia entro 4 settimane prima di iniziare il trattamento in studio o intervento chirurgico durante il corso dello studio che comprometterebbe la partecipazione alla sperimentazione da parte del paziente, secondo giudizio dello sperimentatore
    4. Ipersensibilità nota ad afatinib o ai suoi eccipienti
    5. Storia o presenza di rilevanti anomalie cardiovascolari, secondo giudizio dello sperimentatore
    6. Pazienti di sesso femminile in età fertile, che allattano o in stato di gravidanza
    7. Qualsiasi storia o condizione concomitante che, a giudizio dello sperimentatore, comprometterebbe la capacità del paziente di rispettare le procedure dello studio o interferisca con la valutazione della efficacia e la sicurezza del farmaco in studio
    8. Trattamento con un farmaco concomitante vietato, elencato nel Protocollo di studio, che non possa essere interrotto per la durata della partecipazione allo studio
    9. Pre-esistente malattia interstiziale polmonare (ILD) nota, o presenza di segni e sintomi indicativi di quest'ultima, secondo il giudizio dello sperimentatore (vedi Sezione 4.2.1)
    10. Qualsiasi storia o presenza di disturbi gastrointestinali scarsamente controllati che potrebbero influenzare l'assunzione/assorbimento del farmaco in studio (ad esempio malattia di Crohn, colite ulcerosa, diarrea cronica, malassorbimento), secondo il giudizio dello sperimentatore
    11. Infezione attiva da epatite B (definita dalla presenza di sAg HepB e/o HepB DNA), infezione attiva di epatite C (definita dalla presenza di RNA Hep C) e/o portatore di HIV noto
    12. Cheratite nota
    13. Funzionalità epatica inadeguata (AST/ALT> 2.5xULN, bilirubina> 1.5xULN, valori aggiustati per l’età)
    14. Funzionalità renale inadeguata, ossia creatinina> 1.5xULN aggiustato per età e/o clearance della creatinina <70 ml/min/1.73m² secondo formula standard per la stima del GFR nei pazienti pediatrici
    15. Funzionalità del midollo osseo inadeguata (ANC <= 1000/mm**3, piastrine <= 100.000/mm**3)
    E.5 End points
    E.5.1Primary end point(s)
    In dose finding part
    1) DLT measured during the first course of treatment
    2) Pharmacokinetics (AUC, Cmax, tmax and accumulation (or effective) half-life)

    In MTD expansion cohort
    3)Objective Response by investigator assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression of disease.
    Dose finding part, per determinare la MTD
    1) tossicità dose-limitante (DLT) misurata nel corso della prima fase di trattamento
    2) Profilo farmacocinetico di afatinib in una popolazione pediatrica (AUC, Cmax, tmax ed emivita di accumulo (o effettiva))

    MTD expansion cohort
    3) Risposta obiettiva, secondo la valutazione da parte dello sperimentatore, come da criteri di riferimento per la valutazione della risposta per ogni determinato tipo di tumore, valutata ogni 8 settimane fino alla progressione della malattia.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1: up to 1 year

    2: up to 1 year

    3: up to 2 years

    1) Fino ad 1 anno
    2) Fino ad 1 anno
    3) Fino a 2 anni
    E.5.2Secondary end point(s)
    In dose finding part
    1) Objective Response by investigator assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression of disease.

    In MTD expansion cohort
    2) Progression free survival (PFS)
    3) Pharmacokinetics (AUC, Cmax, tmax and accumulation (or effective) half-life)
    Dose finding part, per determinare la MTD
    1) Risposta obiettiva, secondo la valutazione da parte dello sperimentatore, come da criteri di riferimento per la valutazione della risposta per ogni determinato tipo di tumore, valutata ogni 8 settimane fino alla progressione della malattia.

    MTD expansion cohort
    2) Sopravvivenza libera da progressione (PFS)
    3) Profilo farmacocinetico di afatinib in una popolazione pediatrica (AUC, Cmax, tmax ed emivita di accumulo (o effettiva))
    E.5.2.1Timepoint(s) of evaluation of this end point
    1: up to 2 years

    2: up to 2 years

    3: up to 2 years
    1) Fino a 2 anni
    2) Fino a 2 anni
    3) Fino a 2 anni
    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 Yes
    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
    efficacy assessment in biomarker preselected patients
    Valutazione dell’efficacia attraverso la presenza di biomarcatori in pazienti preselezionati
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    phase I trial in paediatric population
    Fase I in una popolazione pediatrica
    E.7.2Therapeutic exploratory (Phase II) No
    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 Information not present in EudraCT
    E.8.1.2Open Yes
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Canada
    Denmark
    France
    Germany
    Italy
    Netherlands
    Spain
    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
    LVLS
    LVLS
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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 Yes
    F.1.1Number of subjects for this age range: 60
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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
    minor
    Pazienti minori
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 60
    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)
    No long term safety follow up planned
    nessuno
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Innovative Treatments for Children with Cancer
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-11
    P. End of Trial
    P.End of Trial StatusOngoing
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