E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic or unresectable chordoma |
Cordoma metastatico o non resecabile |
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E.1.1.1 | Medical condition in easily understood language |
Advanced chordoma |
Cordoma avanzato |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008747 |
E.1.2 | Term | Chordoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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
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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
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E.3 | Principal 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 |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary 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
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- 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 |
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E.5.1.1 | Timepoint(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 |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial 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
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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. |
LVLS |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |