| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent and/or metastatic head and neck squamous cell carcinoma in patients who have progessed after platinum based therapy |
| pazienti con carcinoma a cellule squamose del testa-collo (Head & Neck Squamous Cell Carcinoma - HNSCC) ricorrente/metastatico che sono andati in progressione dopo una terapia a base di platino somministrata per il carcinoma a cellule squamose del testa-collo metastatico/ricorrente |
|
| E.1.1.1 | Medical condition in easily understood language |
| Head and neck cancer |
| carcinoma del testa-collo |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate the efficacy of afatinib versus methotrexate therapy in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who have progressed after platinumbased therapy given for R/M HNSCC |
| L'obiettivo dello studio e' di valutare l'efficacia di una terapia con afatinib verso metotressato in pazienti con carcinoma a cellule squamose del testa-collo (Head and Neck Squamous Cell Carcinoma - HNSCC ricorrente/metastatico che sono andati in progressione dopo una terapia a base di platino somministrata per il carcinoma a cellule squamose del testa-collo metastatico/ricorrente |
|
| E.2.2 | Secondary objectives of the trial |
| To investigate the safety of afatinib versus methotrexate therapy in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who have progressed after platinumbased therapy given for R/M HNSCC |
| L'obiettivo dello studio e' di valutare la sicurezza di una terapia con afatinib verso metotressato in pazienti con carcinoma a cellule squamose del testa-collo (Head and Neck Squamous Cell Carcinoma - HNSCC) ricorrente/metastatico che sono andati in progressione dopo una terapia a base di platino somministrata per il carcinoma a cellule squamose del testa-collo metastatico/ricorrente |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, which has recurred/metastasised and is not amenable for salvage surgery or radiotherapy. 2.Documented progressive disease based on investigator assessment according to RECIST, following receipt of cisplatin and/or carboplatin (minimum doses described below*) administered for recurrent and/or metastatic disease independent of whether patient progressed during or after platinum based therapy: -Cisplatin, minimum dose: at least two cycles of cisplatin, >=60 mg/m2/cycle or a total cumulative dose of >=120 mg/m2 during eight weeks; -Carboplatin, minimum dose: at least two cycles of carboplatin area under the concentration-time curve (AUC) >=4/cycle or a total cumulative dose of AUC >=8 during eight weeks.*if cisplatin is switched to carboplatin (or vice versa, e.g due to intolerance), the following conversion should be used for calculation of minimum cumulative platinum dose: carboplatin 1 AUC = cisplatin 15 mg/m**2. 3. Measurable disease according to RECIST (version 1.1). 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at the time of randomisation. 5. Male and female patients age >=18 years. 6. Written informed consent that is in compliance with ICH-GCP and local law. |
| 1.Conferma istologica o citologica di carcinoma a cellule squamose di cavita` orale, orofaringe, ipofaringe o laringe, che ha recidivato/metastatizzato e non e` eleggibile per chirurgia di salvataggio o radioterapia. 2.Documentata progressione di malattia basata sulla valutazione dello sperimentatore secondo i criteri RECIST, a seguito di trattamento con cisplatino e/o carboplatino (dosi minime come descritto sotto*) somministrati per malattia ricorrente e/o metastatica, indipendentemente dal fatto che il paziente sia progredito durante o dopo la terapia a base di platino: -Cisplatino, dose minima: almeno due cicli di cisplatino, >=60 mg/m2/ciclo o dose totale cumulativa >=120 mg/m2 in otto settimane; -Carboplatino, dose minima: almeno due cicli di carboplatino area sotto la curva (AUC) >= 4/ciclo o una dose totale cumulativa di AUC >= 8 in otto settimane. *Se si passa da cisplatino a carboplatino (o viceversa, per esempio a causa di intolleranza), si deve usare la seguente conversione per calcolare la dose minima cumulativa di platino: carboplatino 1 AUC = cisplatino 15 mg/m2. 3.Malattia misurabile secondo i criteri RECIST (versione 1.1). 4.`Eastern Cooperative Oncology Group (ECOG) performance status` 0 o 1 alla randomizzazione. 5.Pazienti maschi e femmine di eta` superiore o uguale a 18 anni. 6.Consenso informato scritto in accordo alle ICH-GCP e alla legislazione locale. |
|
| E.4 | Principal exclusion criteria |
| 1. Progressive disease within three months after completion of curatively intended treatment for locoregionally advanced or for metastatic HNSCC. 2. Primary tumour site nasopharynx (of any histology), sinuses, and/or salivary glands. 3. Any other than one previous platinum based systemic regimen given for recurrent and/or metastatic disease. Re-challenge with the first line regimen after a temporary break is considered a second line regimen only in case of progression within the break. 4. Prior treatment with EGFR-targeted small molecules. 5. Treatment with any investigational drug or anti-cancer therapy less than four weeks prior to randomisation (except palliative radiotherapy to bones to alleviate pain). 6. Unresolved chronic toxicity, other than hearing loss, tinnitus or dry mouth, CTCAE grade >2 from previous anti-cancer therapy or unresolved skin toxicities CTCAE grade >1 and/or diarrhoea CTCAE grade >1 caused by prior treatment with EGFR targeted antibodies. 7. Previous tumour bleeding CTCAE grade >=3. 8. Requirement for treatment with any of the prohibited concomitant medications listed in Section 4.2.2. 9. Major surgical or planned procedure less than four weeks prior to randomisation (isolated biopsies are not counted as major surgical procedures). 10. Any other malignancy (except for appropriately treated superficial basal cell skin cancer and surgically cured cervical cancer in situ) unless free of disease for at least five years. 11. Known brain metastasis or signs thereof. 12. Known pre-existing interstitial lung disease (ILD). 13. Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification >III, unstable angina, myocardial infarction within six months prior to randomisation, or poorly controlled arrhythmia. 14. Cardiac left ventricular dysfunction with resting ejection fraction of less than institutional lower limit of normal (LLN) (if no LLN is defined in the institution, the lower limit is 50%). 15. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn`s disease, malabsorption or CTCAE grade >1 diarrhoea of anyaetiology at randomisation. 16. Known HIV, active hepatitis B, active hepatitis C and/or other known severe infections, including but not limited to tuberculosis, as judged by the investigator 17. Other significant disease that in the investigator`s opinion would exclude the subjectfrom the trial. 18. Screening laboratory values based on central laboratory analysis: a) Absolute neutrophil count (ANC) <1.5x109/l b) Platelet count <75x109/l c) Total bilirubin >1.5 times the upper limit of normal (ULN) d) Aspartate amino transferase (AST) or alanine amino transferase (ALT) >3 times the ULN (if related to liver metastases >5 times the ULN) e) Calculated creatinine clearance <50 ml/min (as evidenced by using the Cockcroft-Gault formula, see Appendix 2). 19. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or to use adequate contraception during the trial and for at least six months after end of treatment. Adequate methods of contraception and definition of child-bearing potential are described in Section 5.2.2.2.1. 20. Pregnancy or breast feeding. 21. Known or suspected hypersensitivity to any of the study medications or their excipients. 22. Patients unable to comply with the protocol, in the opinion of the investigator. |
| 1.Progressione di malattia nei tre mesi dopo il completamento di trattamento con intento curativo per carcinoma squamoso del testa-collo loco-regionalmente avanzato o metastatico 2.Tumori primari di nasofaringe (di qualunque istologia), seni paranasali, e/o ghiandole salivari 3.Qualsiasi altro regime sistemico a base di platino tranne uno, somministrato per malattia ricorrente e/o metastatica. Rechallange con il regime di prima linea dopo una pausa temporanea e` considerato un regime di seconda linea solo se vi e` stata progressione durante l`interruzione 4.Precedente trattamento con piccole molecole che abbiano come target il recettore del fattore di crescita epidermico (Epidermal Growth Factor Receptor, EGFR) 5.Trattamento con qualunque altro farmaco sperimentale o terapia anti-cancro nelle quattro settimane precedenti la randomizzazione (con l’eccezione di radioterapia palliativa alle ossa per alleviare dolore) 6.Tossicita` cronica non risolta, esclusi perdita dell’udito, tinnito auricolare o secchezza delle fauci, di grado CTCAE >2 causata dalla precedente terapia anti-cancro o tossicita' alla pelle non risolte di grado CTCAE >1 e/o diarrea CTCAE grado >1 causate da precedente trattamento con anticorpi anti-EGFR 7.Precedente sanguinamento tumorale di grado CTCAE >=3. 8.Necessita` di trattamento con uno dei farmaci concomitanti vietati elencati nella sezione 4.2.2 del protocollo finale 9.Procedure chirurgiche importanti pianificate nelle quattro settimane prima della randomizzazione (tra queste non sono incluse le biopsie isolate) 10.Qualunque altro tipo di tumore maligno (con l`eccezione di cancro della pelle basale superficiale opportunamente trattato e cancro alla cervice in situ curato chirurgicamente) a meno che non sia libero da malattia da almeno cinque anni 11.Metastasi al cervello note o sintomi delle stesse 12.Pre-esistente malattia polmonare interstiziale nota (Interstitial Lung Disease, ILD) 13.Anormalita` cardiovascolari clinicamente rilevanti, secondo il giudizio dello sperimentatore, come, ma non limitate a, ipertensione incontrollata, insufficienza cardiaca congestizia classe NYHA (New York Heart Association) >III, angina instabile, infarto del miocardio nei sei mesi precedenti la randomizzazione, o aritmia scarsamente controllata 14.Disfunzione cardiaca del ventricolo sinistro con frazione di eiezione a riposo inferiore al limite inferiore di normalita' previsto nel centro sperimentale (se tale limite non definito nella struttura, considerare il limite inferiore pari a 50%) 15.Significativi o recenti disturbi gastrointestinali acuti con diarrea come sintomo principale per esempio morbo di Crohn, malassorbimento o diarrea di grado CTCAE >1 di qualunque eziologia alla randomizzazione. 16.Infezione nota da HIV, epatite B attiva e/o epatite C attiva e/o ogni altra infezione grave nota, inclusa tubercolosi, secondo l`opinione dello sperimentatore. 17.Altre patologie significative che, secondo lo sperimentatore, escluderebbero il soggetto dallo studio 18.Valori di laboratorio allo screening basati sulle analisi del laboratorio centralizzato: a) Conta assoluta dei neutrofili (ANC) <1.5x109/l b) Conta piastrinica <75x109/l c) Bilirubina totale >1.5 volte il limite superiore di normalita' (ULN) d) Aspartato amino transferasi (AST) o alanina amino transferasi (ALT) >3 volte ULN (se correlato a metastasi epatiche >5 volte ULN) e) Clearance calcolata della creatinina <50 ml/min (secondo la formula di Cockcroft-Gault, si veda l`Appendice 1 del protocollo di studio). Per gli altri criteri si faccia riferimento alla sinossi ed alla sezione 3.3.3 del protocol version 2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) |
| L`endpoint primario di questo studio e` la sopravvivenza libera da progressione (Progression Free Survival – PFS), definita come il tempo dalla randomizzazione alla progressione valutata secondo i criteri RECIST 1.1 o al decesso per qualunque causa (l`evento che accade per primo). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 364 disease progression events, estimated to be approximately 20 months after start of recruitment. |
| Dopo il raggiungimento di 364 eventi di progressione (o fatali) richiesti, stimato approssimativamente 20 mesi dopo l'inizio del reclutamento |
|
| E.5.2 | Secondary end point(s) |
| Key secondary endpoint is Overall Survival (OS). Other secondary enpoints are Objective Response and Health related quality of life (HRQOL). |
| L`endpoint secondario chiave e` la sopravvivenza globale (Overall Survival – OS), definita come il tempo dalla randomizzazione al decesso (indipendentemente dalla causa). Altri end points sono: -Risposta oggettiva -Qualita` della vita correlata alla salute (Health Related Quality Of Life – HRQOL) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 343 death events, estimated to be approximately 26 months after start of recruitment. For the key secondary endpoint OS a futility analysis will be made after approximately 40% of the death events, estimated to be after 14 months after start of recuitment. |
| Dopo il raggiungimento di 343 eventi fatali richiesti, approssimativamente 26 mesi dopo l`inizio del reclutamento. Per l`endpoint secondario chiave, la sopravvivenza globale (Overall Survival – OS), verra` eseguita, dopo approssimativamente 40% di eventi fatali, una `futility analisys` stimata dopo 14 mesi dal reclutamento |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Chile |
| Israel |
| Japan |
| Mexico |
| Peru |
| Russian Federation |
| South Africa |
| Switzerland |
| United States |
|
| E.8.7 | Trial 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
|
| The trial is considered completed after all patients have progressed and the required number of death events has occurred. |
| Lo studio e' considerato terminato quando tutti i pazienti hanno avuto una progerssione della malattia e si e' raggiunto il numero di casi di morte richiesto |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 27 |
| E.8.9.1 | In the Member State concerned days | 0 |
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