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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2016-002766-31
    Sponsor's Protocol Code Number:BI1200.277
    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:2021-08-03
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-002766-31
    A.3Full title of the trial
    A phase 2, single arm, European multi-center trial evaluating the efficacy of afatinib as first-line or later-line treatment in advanced chordoma.
    Studio di fase 2, a braccio singolo, multicentrico europeo finalizzato a valutare l’efficacia di afatinib in prima o ulteriore linea nel trattamento dei cordomi in fase avanzata.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Afatinib in patients with advanced chordoma.
    Studio con afatinib nel cordoma avanzato
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberBI1200.277
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03083678
    A.5.4Other Identifiers
    Name:Boehringer Ingelheim protocol numberNumber:1200.277
    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 SponsorLeids Universitair Medisch Centrum
    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 supportBoehringer Ingelheim
    B.4.1Name of organisation providing supportChordoma Fundation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointResearch secretary
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2300 RC
    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. name Giotrif
    D. of the Marketing Authorisation holderBoehringer Ingelheim
    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 nameAfatinib
    D.3.2Product code [Afatinib]
    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.3.9.2Current sponsor codeAfatinib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20 to 40
    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. cell therapy medicinal product Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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
    Metastatic or unresectable chordoma
    Cordoma metastatico o non resecabile
    E.1.1.1Medical condition in easily understood language
    Advanced chordoma
    Cordoma avanzato
    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 10008747
    E.1.2Term Chordoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To evaluate the treatment efficacy by progression free survival (PFS) according to RECIST 1.1.
    Quality of life
    - PFS mediano in corso di afatinib = 12 mesi in prima linea e = 9 mesi in linee successive di trattamento.
    - Modificazioni rispetto al baseline del questionario EORTC QLC-30/ Brief pain inventory score.
    E.2.2Secondary objectives of the trial
    - To evaluate the treatment efficacy by growth modulation index
    - To evaluate the safety and tolerability of afatinib in chordoma
    - To determine the overall survival after start of treatment
    - Growth modulation index ( tempo alla progressione in corso di trattamento con afatinib (TTP2) / tempo alla progressione prima di iniziare il trattamento (TTP1)
    - Tossicità definita secondo i criteri CTCAE (v 4.03)
    - Overall survival dall’inizio del trattamento con afatinib
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Optional translational study aimed to evaluate biological prognostic markers

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sotto studio biologico opzionale su tessuto tumorale e sangue per la valutazione di marker prognostici di risposta
    E.3Principal inclusion criteria
    - Locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies
    - Patients of 18 years and up
    - Documented radiographic progression of disease according to RECIST 1.1 criteria in last 6 months
    - ECOG Performance status = 2
    - Adequate bone marrow function (Hb = 6.0 mmol/L, absolute neutrophil count = 1.5 x 109/L, platelets = 75 x 109/L)
    - An adequate renal function with GFR = 45 ml/min calculated by Cockroft-Gault formula
    - Total Bilirubin = 1.5 times upper limit of normal (ULN) (Patients with Gilbert’s syndrome total bilirubin must be =4 times institutional upper limit of normal).
    - Aspartate amino transferase (AST) or alanine amino transferase (ALT) = 3 times ULN (if related to liver metastases = 5 times ULN)
    - Ability to swallow medication
    - Recovered from any previous therapy related toxicity to = grade 1 at study entry (except for stable sensory neuropathy = grade 2 and alopecia)
    - Availability of archival tumor material for central review (if not please obtain a new tumor biopsy)
    - Written signed informed consent
    - Ability to adhere to the study visits and all protocol requirements
    - Diagnosi di cordoma, EGFR positivo, in fase avanzata di malattia (localmente avanzato o metastatico non suscettibile di trattamento locale)
    - Età > 18 anni
    - Evidenza di progressione sec RECIST 1.1 nei 6 mesi precedenti l’avvio del trattamento
    - ECOG Performance status =2
    - Funzione midollare normale (Hb = 6.0 mmol/L, neutrofili = 1.5 x 109/L, piastrine = 75 x 109/L)
    - Funzionalità renale conservata (GFR = 45 ml/min definito secondo la formula di Cockroft-Gault)
    - Bilirubina totale = 1.5 volte il valore normale (nei pazienti con sindrome di Gilbert sono consentiti valori di bilirubina tot =4 volte il limite superiore considerato normale (ULN)).
    - Aspartato amino transferasi (AST) or alanina amino transferasi (ALT) = 3 volte ULN (in caso di elevati valori associati alla presenza di metastasi epatiche = 5 volte ULN)
    - Capacità di deglutire il farmaco
    - Risoluzione di qualsiasi tossicità farmaco-relata a = grado 1, nel momento dell’ingresso in studio (eccezioni: neuropatia sensitiva stabile e = grado 2; alopecia)
    - Disponibilità di tessuto tumorale per la revisione patologica centralizzata (di archivio o ottenuto con biopsia)
    - Consenso informato scritto firmato
    - Capacità di aderire a tutte le visite e procedure richieste dallo studio
    E.4Principal exclusion criteria
    - Life expectancy of less than 3 months
    - No measurable lesions according to RECIST 1.1
    - Known hypersensitivity to afatinib
    - Major surgery less than 4 weeks prior to start of treatment
    - Previous treatment with any other investigational agents within 14 days of first day of study drug dosing
    - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of = 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to inclusion.
    - Known pre-existing interstitial lung disease
    - Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, chronic diarrhea, malabsorption)
    - Known active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.
    - Systemic anti-cancer therapy within 28 days prior to the first dose of study drug , or radiotherapy to an index (or target)lesion within 21 days prior to the first dose of study drug
    - Requiring treatment with any of the prohibited concomitant medications listed in Section 6.3.9 that cannot be stopped for the duration of trial participation
    - Pregnant or lactating women
    - Other invasive malignancies diagnosed within the last 5 years, except non-melanoma skin cancer and localized cured prostate and cervical cancer
    - Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient’s ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug
    Criteri di esclusione:
    - Aspettativa di vita < 3 mesi
    - Assenza di malattia misurabile secondo i RECIST 1.1
    - Ipersensibilità nota ad afatinib
    - Chirurgia maggiore entro le 4 settimane dall’avvio del trattamento
    - Trattamento con qualsiasi altro farmaco sperimentale nei 14 giorni precedenti alla prima assunzione di afatinib
    - Storia pregressa o presenza clinicamente rilevante di alterazioni cardiovascolari come ipertensione non controllata, scompenso cardiaco congestizio (NYHA = 3), angina instabile, aritmia poco controllata (a giudizio del medico sperimentatore). Infarto miocardico nei 6 mesi antecedenti l’inclusione in studio
    - Malattia polmonare interstiziale preesistente nota
    - Storia precedente o presenza di disturbi gastointestinali non controllati che potrebbero interferire con l’assorbimento del farmaco in studio (es morbo di Crohn. Colite ulcerosa, diarrea cronica, malassorbimento)
    - Epatite B cronica in fase attiva (definita dalla presenza di HBVe Ag e/o di HBV DNA), epatite C in fase attiva (definita dalla presenza di HCV RNA) e/o infezione da HIV.
    - Trattamento oncologico sistemico nei 28 giorni prima della prima dose del farmaco in studio, o radioterapia a livello di una delle lesioni target entro i 21 giorni prima della prima dose di afatinib.
    - Trattamento concomitante con uno qualsiasi dei farmaci non permessi indicati nella sezione 6.3.9
    - Gravidanza o allattamento
    - Diagnosi di qualsiasi altra neoplasia maligna nei 5 anni precedenti all’ingresso in studio con l’eccezione di tumori della pelle non-melanoma, carcinoma della cervice uterina o della prostata localizzato e guarito.
    - Storia precedente o concomitanza di qualsiasi condizione che a giudizio dello sperimentatore potrebbe compromettere la compliance del paziente a quanto richiesto dallo studio
    E.5 End points
    E.5.1Primary end point(s)
    - PFS = 12 months in first line treatment and = 9 months in further line treatment
    - Change from baseline in EORTC QLQ-C30 questionnaire / Brief pain inventory score
    - PFS a 12 mesi per il trattamento di prima linea e a 9 mesi in caso di afatinib impiegato in linee successive alla prima
    - Variazione rispetto al basale dei questionarii EORTC QLQ-C30 e Brief pain inventory score
    E.5.1.1Timepoint(s) of evaluation of this end point
    - PFS is evaluated at time point of progressive disease (goal PFS > 12 months for first-line treatment and > 9 months for later-line treatment, imaging every 12 weeks), evaluation throughout complete study
    - Questionnaire scores measured every 8 weeks during afatinib treatment compared to baseline, until progression / withdrawal (no set time limit), evaluation after 1 year
    PFS i è valutato al tempo della progressione (goal PFS > 12 mesi per la prima linea e > 9 mesi per le linee successiva-rivalutazione per immagin ogni 12 settimane) valutazione durante tutto lo studio
    Punteggi ai questionari somminsitrati ogni 8 settimane nel corso di trattamento e confrontati con il basale, fino a PD/dicontinuazione, e ad un anno post-trattamento
    E.5.2Secondary end point(s)
    - Time to progression during afatinib treatment (TTP2) divided by time to progression before start of this treatment TTP1 (= growth modulation index)
    - Toxicity determined by CTCAE v 4.03 criteria
    - Overall survival from start of afatinib treatment

    Exploratory endpoints
    - EGFR pathway and dimerization analysis in archival tumor tissue
    - Genome sequence analysis of available tumor samples
    - Analysis of circulating biomarkers in patients pre and post treatment
    - Observed afatinib plasma levels, administered afatinib doses and time between afatinib doses and sampling. Used to construct:
    o a population PK / PD / PG model
    o a limited sampling model for afatinib exposure
    o a time to event model
    o tumor imaging data in relationship to afatinib exposure and genetic data of the tumor.
    Secondary endpoints
    - Tempo alla progressione in corso di trattamento con afatinib (TTP2) diviso per il tempo alla progressione prima di inizio del trattamento TTP1 (= growth modulation index)
    - Tossicità secondo CTCAE v 4.03
    - Sopravvivenza globale
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints
    - Growth modulation is evaluated at time point of progressive disease (imaging every 12 weeks, , evaluation throughout complete study)
    - Toxicity evaluated continuously during study (every 4 weeks), until progression / withdrawal
    - Overall survival evaluated at time of death (during trial and during follow-up period every 3 months for total 3 years follow-up)

    Translational research endpoints:
    - Blood samples and requesting archival tumor tissue and optinal extra tumor biopsy at baseline, during study blood withdrawals for circulating biomarkers and tumor DNA at baseline, cycle 4 day 1 (C4D1), C7D1 and at progression / withdrawal.

    Pharmacokinetic endpoints:
    - PK withdrawals at C1D1, C1D15, C3D1, C5D1 (total 12 withdrawals)
    - Growth modulation valutato al trempo della PD (imaging ogni12 settimane per tutto il corso dello studio)
    - Tossicità valutata continuativamente durante tutto lo studio ogni 4 settimane fino a PD/discontinuazione
    - Overall survival valutato al tempo di decesso durante tutto lo studio e per un periodo di fup di 3 anni condotto ogni 3 mesi
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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. 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 No
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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 considered to be the last visit of the last patient on-study. Patients will be followed for an additional 3 years for survival.
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 23
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 43
    F.4.2.2In the whole clinical trial 43
    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)
    At the EOT patients will be treated according the chordoma treatment guidelines
    I pazienti al termine del trattamento verranno trattati secondo quanto previsto dalle linee guida di patologia e verranno seguiti per 3 anni per il fup di malatia
    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 Decision2019-04-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-26
    P. End of Trial
    P.End of Trial StatusOngoing
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