| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive advanced gastroesophageal junction/gastric cancer |
| Carcinoma metastatico dello stomaco o della giunzione gastroesofagea HER2 positivo |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2-positive advanced gastroesophageal junction/gastric cancer |
| Carcinoma metastatico dello stomaco o della giunzione gastroesofagea HER2 positivo |
|
| 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 | PT |
| E.1.2 | Classification code | 10061968 |
| E.1.2 | Term | Gastric neoplasm |
| 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 compare overall survival (OS) in patients treated with pertuzumab in addition to Herceptin (trastuzumab) plus fluoropyrimidine plus cisplatin (TFP) versus patients treated with placebo in addition to TFP. |
| Confrontare la sopravvivenza globale (OS) in pazienti trattati con pertuzumab in associazione ad Herceptin (trastuzumab), fluoropirimidina e cisplatino (TFP) rispetto a pazienti trattati con placebo in associazione a TFP. |
|
| E.2.2 | Secondary objectives of the trial |
| . To compare investigator-assessed PFS, ORR, duration of objective response (DoR), and clinical benefit rate (CBR) between the two treatment arms • To compare the safety profile between the two treatment arms • To assess the pharmacokinetics of pertuzumab • To compare the patient-reported outcomes (PROs) of health-related quality of life (HRQoL), GC, and treatment-related symptoms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 scale and its GC module, the QLQ-STO22, for patients in each treatment arm. |
| . Confrontare il periodo libero da malattia (PFS), il tasso di risposta obiettiva (ORR), la durata della risposta obiettiva (DoR), il tasso di beneficio clinico (CBR) valutati dallo sperimentatore tra i due bracci di trattamento. · Confrontare il profilo di sicurezza dei due bracci di trattamento. · Valutare la farmacocinetica di pertuzumab. · Confrontare gli esiti riferiti dai pazienti (PRO) in termini di qualità della vita relativa alle condizioni di salute, al tumore gastrico (GC), ai sintomi del trattamento misurati attraverso la scala EORTC QLQ-C30 e relativo modulo sul carcinoma gastrico (QLQ-STO22), per i pazienti nei due bracci di trattamento. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Disease-Specific Inclusion Criteria 1. Histologically confirmed (by enrolling center) metastatic adenocarcinoma of the stomach or GEJ 2. HER2-positive tumor defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed by a sponsor-designated central laboratory on a primary or metastatic tumor Note: ISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of signals for chromosome 17 centromere (CEP17). For IHC scoring, the cutoffs as approved by the Food and Drug Administration (FDA) in the context of ToGA apply. Availability of formalin-fixed paraffin-embedded (FFPE)representative tumor tissue for central confirmation of HER2 is mandatory. (See Section 4.5.1.1 for further details.) 3. Measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1; see Appendix 3. 4. Eastern Cooperative Oncology Group (ECOG) PS 0 or 1 5. Life expectancy ≥ 3 months General Inclusion Criteria 6. Age≥ 18 years 7. Ability to comply with requirements of the protocol, as assessed by the investigator 8. Signed Informed Consent document |
| Criteri di inclusione correlati alla neoplasia: 1. Adenocarcinoma dello stomaco o della giunzione gastroesofagea confermato istologicamente dal centro. 2. Tumore HER2-positivo definito IHC3+ o IHC2+, quest’ultimo anche ISH+, in seguito all’analisi fatta da un laboratorio centralizzato designato dallo Sponsor su un campione di tessuto di tumore primario o metastatico Nota: la positività per ISH è definita come il rapporto ≥ 2.0 del numero di copie geniche di HER2 rispetto al numero di segnali per il centromero del cromosoma 17 (CEP17). Per il punteggio di ISH si applicano i limiti approvati dalla Food and Drud Administration (FDA) per lo studio ToGA. La disponibilità di tessuto tumorale rappresentativo fissato in formalina e incluso in paraffina (FFPE) per la conferma centrale dello status di HER2 è obbligatoria (vedi la sezione 4.5.1.1 per ulteriori dettagli)3. Malattia misurabile, o non misurabile ma valutabile dallo sperimentatore, secondo i criteri RECIST v1.1 (Response Evaluation Criteria in Solid Tumors, versione 1.1); vedi Appendice 3 4. Performance status ECOG di 0 o 1 5. Aspettativa di vita > 3 mesi Criteri di inclusione generali 6. Età pari o superiore a 18 anni 7. Capacità di rispettare le richieste del protocollo, su giudizio dell’investigatore 8. Firma del consenso informato |
|
| E.4 | Principal exclusion criteria |
| Cancer-Related Exclusion Criteria 1. Previous systemic cytotoxic chemotherapy for advanced (metastatic) disease 2. History of exposure to the following cumulative doses of anthracyclines: a. Epirubicin > 720 mg/m2 b. Doxorubicin or liposomal doxorubicin > 360 mg/m2 c. Mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2 d. Other (e.g., liposomal doxorubicin or other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin) e. If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin. 3. Evidence of disease progression documented within 6 months after completion of prior neoadjuvant or adjuvant cytotoxic chemotherapy, or both, or radiotherapy for gastric or GEJ adenocarcinoma 4. Previous treatment with any HER2-directed therapy, at any time, for any duration 5. Previous exposure to any investigational treatment within 30 days before the first dose of study treatment 6. Radiotherapy within 30 days before the first dose of study treatment (within 2 weeks if given as palliation to peripheral bone metastases, if recovered from all toxicities) 7. History or evidence of brain metastasis 8. Clinically significant active GI bleeding (Grade ≥ 2 according to NCI CTCAE v4.03) 9. Residual toxicity resulting from previous therapy (e.g., hematologic, cardiovascular, or neurologic toxicity that is Grade ≥ 2). Alopecia is permitted. 10. Other malignancy (in addition to GC) occurring within 5 years before enrollment, except for carcinoma in situ of the uterine cervix or squamous or basal cell carcinoma of the skin that has been previously treated with curative intent Clinical Laboratory Exclusion Criteria (must be confirmed within 7 days before first dose of study treatment) 11. Absolute neutrophil count (ANC) < 1.5 × 109/L 12. Platelet count < 75 × 109/L 13. Hemoglobin < 9.0 g/dL 14. Creatinine CL< 60 mL/min/1.73 m2 (Cockcroft-Gault Formula, see Appendix 6) 15. Serum bilirubin (total) > 1.5 × upper limit of normal (ULN) of laboratory normal range; in case of known Gilbert disease a total bilirubin of up to 2 × ULN is permitted. General Exclusion Criteria 19. Documented history of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria (see Appendix 5) 20. Angina pectoris requiring treatment 21. Myocardial infarction within the past 6 months before the first dose of study treatment 22. Clinically significant valvular heart disease or uncontrollable highrisk cardiac arrhythmia (i.e., atrial tachycardia with a heart rate >100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block) 23. History or evidence of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure >100 mmHg) 24. Baseline LVEF value < 55%, assessed by echocardiogram [ECHO], multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI) scan25. Dyspnea at rest due to complications of advanced malignancy or other disease or requirement of supportive oxygen therapy 26. Any significant uncontrolled intercurrent systemic illness (e.g., active infection, poorly controlled diabetes mellitus) 27. Previous major surgery within 30 days before the first dose of study treatment, unless completely recovered 28. Known infection with HIV, hepatitis B virus, or hepatitis C virus that requires active treatment. |
| Criteri correlati alla neoplasia 1. Precedente chemioterapia sistemica citotossica per carcinoma gastrico localmente avanzato o metastatico 2. Esposizione alle seguenti dosi cumulative di antracicline: a. Epirubicina > 720 mg/m2 b. Doxorubicina o doxorubicina liposomiale > 360 mg/m2 c. Mitoxantrone > 120 mg/m2 ed idarubicina > 90 mg/m2 d. Altre (es. doxorubicina liposomiale od altra antraciclina maggiore dell’equivalente di 360 mg/m2 di doxorubicina) e. Se più di una antraciclina è stata utilizzata, le dosi cumulative non devono superare il limite equivalente di 360 mg/m2 di doxorubicina 3. Evidenza documentata di progressione di malattia entro 6 mesi dopo il completamento di chemioterapia citotossica precedente neoadiuvante o adiuvante, o entrambe, o radioterapia per carcinoma dello stomaco o della giunzione gastroesofagea. 4. Precedente esposizione a qualsiasi trattamento sperimentale mirato contro HER2, in qualsiasi periodo, per qualsiasi durata di trattamento 5. Esposizione a qualsiasi altro trattamento sperimentale nei 30 giorni precedenti alla prima dose di trattamento 6. Radioterapia nei 30 giorni precedenti alla dose iniziale di trattamento (nelle 2 settimane precedenti se è trattamento palliativo per metastasi ossee periferiche, e se non permane tossicità) 7. Storia o evidenza di metastasi cerebrali 8. Sanguinamento gastrointestinale attivo (significativo o non controllato) (Grado ≥2 secondo i criteri NCI CTCAE v 4.03) 9. Rilevante tossicità residua risultante dalla terapia precedente (tossicità ematologica, cardiaca, neurologica di grado ≥ 2 [NCI CTCAE]), ad eccezione di alopecia 10.Anamnesi di altra neoplasia negli ultimi 5 anni, fatta eccezione per carcinoma in situ della cervice o carcinoma cutaneo a cellule squamose o basalioma precedentemente trattati con intento curativo..Criteri di esclusione per valori di laboratorio (devono essere confermati entro 7 giorni prima della dose iniziale di trattamento) 11.Conta assoluta dei neutrofili (ANC) < 1.5 x 109/L 12.Conta piastrinica < 75 x 109/L 13.Emoglobina < 9.0 g/dL 14.Clearance della creatinina (CL) < 60 mL/min/1.73m2 (Cockcroft-Gault Formula) 15.Bilirubina totale sierica >1.5 volte il limite superiore di normalità (upper limit of normal, ULN) oppure, per i pazienti con sindrome di Gilbert accertata, è accettata bilirubina totale sierica fino a 2 ×ULN. Criteri di esclusione generali 19.Storia documentata di insufficienza cardiaca congenita secondo qualsiasi criterio della New York Heart Association [NYHA] (vedi Appendice 5) 20.Angina pectoris che necessita di terapia 21.Infarto del miocardio nei 6 mesi antecedenti la prima dose del trattamento in studio 22.Cardiopatia valvolare clinicamente significativa o aritmie non controllate ad alto rischio, come tachicardia atriale con una frequenza cardiaca > 100/min a riposo, aritmia ventricolare significativa (tachicardia ventricolare) o blocco atrioventricolare (AV) di grado superiore (blocco AV di secondo grado tipo 2 [Mobitz II] o blocco AV di terzo grado) 23.Storia o evidenza di ipertensione scarsamente controllata (es. pressione arteriosa sistolica > 180 mmHg o pressione arteriosa diastolica > 100 mmHg) 24.Valore basale della frazione di eiezione ventricolare sinistra (LVEF) < 55%, valutata tramite ecocardiogramma (ECHO), scansione MUGA o risonanza magnetica cardiaca (MRI) 25.Dispnea a riposo secondaria a complicazioni della neoplasia maligna avanzata o di un’altra malattia, o necessità di ossigenoterapia di supporto 26.Grave malattia sistemica non controllata intercorrente (es. infezioni attive o diabete scarsamente controllato) 27.Intervento di chirurgia maggiore nelle 4 settimane precedenti l’inizio del trattamento in studio, in mancanza di recupero completo. 28.Nota infezione attiva da HIV, virus dell’epatite B o virus dell’epatite C che richiede trattamento attivo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable, OS, is the time from the date of randomization to the date of death from any cause. For patients who are still alive on the date of clinical data cutoff for the OS analysis, the last date when the patient is known to be alive on or prior to the clinical cutoff date will be used to determine the censoring date. Patients who do not have any postbaseline data (e.g., dosing records, imaging dates, visit dates) will be censored at the date of randomization plus 1 day. |
| Sopravvivenza globale (OS), definita come tempo trascorso dalla randomizzazione al decesso per qualsiasi causa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be assessed approx. 50 months after FPI when 502 deaths will have occurred – which is expected to happen in approx. JUL2017. However, if the interim efficacy analysis (351 deaths) provided significant and meaningful treatment benefit and an acceptable safety profile can be seen, then the study could be stopped early. The interim analysis is expected to take place in approx. AUG2016 |
| Sarà valutato approssimativamente 50 mesi dopo che il primo paziente sarà entrato in studio, quando saranno avvenuti circa 502 decessi - che sarà atteso approssimativam. entro Luglio 2017. Tuttavia, se l'analisi ad interim dell'efficacia (351 decessi) identificherà un beneficio significativo al trattamento e un profilo di sicurezza accettabile, lo studio potrà essere concluso in anticipo. L'analisi ad interim è attesa approssimativamente per Agosto 2016. |
|
| E.5.2 | Secondary end point(s) |
| Investigator-assessed progression-free survival (PFS), objective response rate (ORR), duration of objective response (DoR), and clinical benefit rate (CBR). |
| Sopravvivenza libera da progressione (PFS), tasso di risposta globale (ORR), durata della risposta obiettiva (DOR), e il tasso di beneficio clinico (CBR). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These will be analysed together with the primary endpoint. |
| Verrà valutato nello stesso momento dell'endpoint primario. |
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life, exploratory biomarker assessments |
| Qualità della vita, valutazioni esplorative dei biomarcatori |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 |
| European Union |
| Australia |
| Bosnia and Herzegovina |
| Brazil |
| Canada |
| China |
| Croatia |
| El Salvador |
| Guatemala |
| Hong Kong |
| India |
| Japan |
| Kazakhstan |
| Korea, Democratic People's Republic of |
| Korea, Republic of |
| Macedonia, the former Yugoslav Republic of |
| Malaysia |
| Mexico |
| Panama |
| Peru |
| Russian Federation |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| 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
|
| This study will end when the targeted number of events for the final analysis of OS (n = 502) is reached and the last patient who received study treatment has completed 5 years of cardiac safety follow up thereafter or when the study is terminated by the Sponsor, whichever occurs first. |
| Si concluderà a n° di eventi attesi per l'analisi finale di OS(n=502) e l'ultimo paz che ha ricevuto il trattamento avrà completato 5 aa di fw-up per la sicurezza cardiaca o quando lo studio sarà interrotto dallo Sponsor,quale si verifichi per primo |
|
| 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 | 106 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 106 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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