| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced inoperable or metastatic gastro-esophageal adenocarcinoma |
| Adenocarcinoma gastro-esofageo localmente avanzato inoperabile o metastatico |
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| E.1.1.1 | Medical condition in easily understood language |
| Inoperable or metastatic gastric or esophageal cancer |
| Tumore gastrico o esofageo inoperabile o metastatico |
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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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030144 |
| E.1.2 | Term | Oesophageal adenocarcinoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001150 |
| E.1.2 | Term | Adenocarcinoma gastric |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030145 |
| E.1.2 | Term | Oesophageal adenocarcinoma stage IV |
| 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 identify the most efficacious sequence of chemiotherapeutic agents in terms of progression free survival between mDCF for 4 cycles followed by mDCF or by COFFI until progression in patients with gastric or esophageal adenocarcinoma.
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Identificare la sequenza chemoterapica più efficace, in termini di sopravvivenza libera da progressione, tra mDCF per 4 cicli seguito da mDCF oppure COFFI fino a progressione, in pazienti affetti da adenocarcinoma gastrico o esofageo.
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of the chemotherapeutic agents sequences based on tumor objective response;
- To evaluate the overall survival;
- To assess overall tolerability and safety;
- To evaluate the effect of treatments on the quality of life of patients.
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- Valutare l’efficacia delle sequenze chemioterapiche basata sulla risposta obiettiva del tumore;
- Valutare la sopravvivenza globale;
- Determinare la tollerabilità e il profilo di sicurezza globale;
- Valutare l’impatto dei trattamenti sulla qualità della vita dei pazienti
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologic diagnosis for gastric or esophageal adenocarcinoma, stage III inoperable or IV;
2. Age > 18 years and < 75 years;
3. ECOG Performance Status (PS) </=2;
4. Previous adjuvant chemotherapy provided that it is completed at least 6 months before study enrollment;
5. Availability of imaging assessment performed at least 4 weeks before mDCF induction treatment starts, showing that the desease can be evaluated or measured according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria v 1.1.
6. Signed and dated Informed Consent.
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1.Diagnosi istologica di adenocarcinoma gastrico o esofageo, con stadiazione III inoperabile o IV;
2.Età compresa tra i 18 e i 75 anni;
3.ECOG Performance Status (PS) </=2;
4.Precedente chemioterapia adiuvante purché sia terminata almeno 6 mesi prima dell’arruolamento nello studio;
5.Disponibilità degli esami di imaging eseguiti al massimo 4 settimane prima dell’inizio del trattamento d’induzione con mDCF dai quali si evinca la malattia valutabile o misurabile secondo i criteri RECIST (Response Evaluation Criteria in Solid Tumors) v 1.1;
6. Modulo di consenso informato firmato e datato.
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| E.4 | Principal exclusion criteria |
1. Over-expression (+++) of HER2 receptor (by ICH) or HER2 gene amplification (by FISH) in positive cases ++ at ICH;
2. Cerebral metastases not controlled by any therapy;
3. Previous (less than 10 years) or concomitant malignant neoplasm execpt for in situ carcinoma of the cervix, squamous carcinoma and skin basal cell carcinoma, if not resolved;
4) Congestive heart failure (Class III and IV, New York Heart Association [NYHA]), angina pectoris not controlled by therapy or myocardial infarction within 6 weeks prior to enrollment;
5) Clinically significant cardiovascular disease (included myocardial infarction, unstable angina, heart failure, serious arrhythmia not controlled by therapy) within the last 12 months prior to enrollment;
6) Abnormal hematologic and biochemical parameters:
• Alkaline phosphatase >/= 2.5 X ULN
• Total bilirubin >/= 1.5 x ULN
• AST/ALT >/= 2.5 x UNL unless liver metastasis >/= 5 UNL
• creatinine >/= 1.5 x UNL and/or creatinine clearance < 60 ml/min
• Neutrophils <1500/mm3, platelets <100.000/mm3, hemoglobin <10 g/dl
7) Pregnant or breastfeeding women, or pregnancy planned within 6 months from the end of treatment;
8) Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
9) Deficiency of DPD;
10) Previous hypersensitivity to any of the IMP.
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1.Presenza di iperespressione (+++) del recettore HER2 all’immunoistochimica (IHC) o amplificazione del gene HER2 alla Ibridazione fluorescente in situ (FISH) nei casi positivi ++ all’IHC;
2.Presenza di metastasi cerebrali non controllate da alcuna terapia;
3.Precedente (meno di 10 anni) o concomitante presenza di altra neoplasia maligna, eccetto il carcinoma in situ della cervice uterina, il carcinoma squamoso e il basalioma della cute, se non trattati in modo curativo;
4.Insufficienza cardiaca congestizia (classe III e IV, New York Heart Association [NYHA]), angina pectoris non controllata farmacologicamente, o infarto miocardico insorto entro le 6 settimane prima dell’entrata nello studio;
5.Patologia cardiovascolare clinicamente significativa (compreso l’infarto miocardico, l’angina instabile, l’insufficienza cardiaca, le aritmie gravi non controllate farmacologicamente) insorta meno di 1 anno prima dell’entrata nello studio;
6.Parametri ematologici e biochimici non adeguati:
• Fosfatasi alcalina >/=2.5 volte il valore superiore della norma (U.L.N)
• Bilirubina totale >/=1.5 U.L.N
• Transaminasi (ALT/AST) >/=2.5 U.L.N. (in caso di metastasi epatiche >/=5 U.L.N.)
• Creatinina >/=1.5 U.L.N. e/o clearance della creatinina <60 ml/min
• Neutrofili <1500/mm3, piastrine <100.000/mm3, emoglobina <10 g/dl
7.Donne in gravidanza o allattamento, o gravidanza pianificata entro 6 mesi dal termine del trattamento o allattamento in atto;
8.Presenza di condizioni psicologiche, familiari, sociali o geografiche che, a parere dallo Sperimentatore potrebbero interferire con la compliance allo studio o al follow up;
9.Deficit di diidropirimidina deidrogenasi (DPD);
10.Allergia ad uno o più farmaci dello studio.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival - PFS |
| Sopravvivenza libera da progressione |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From randomization date until desease progression at the following assessment points: at the end of induction period, every 8 weeks during treatment, at the end of treatment and every 8 weeks during follow up.
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A partire dalla data di randomizzazione, fino a progressione della malattia ai seguenti tempi di rilevazione: alla fine del periodo di induzione, ogni 8 settimane durante il trattamento, alla fine del trattamento e ogni 8 settimane durante il follow up.
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| E.5.2 | Secondary end point(s) |
1) Overall Response Rate – ORR;
2) Time To Progression - TTP
3) Overall Survival - OS;
4) Safety profile assessed on the base of laboratory and clinic parameters (hematology, biochemistry, ECOG-PS) and on the evaluation of Adverse Events classified per type, frequency, seriousness (NCI, Common Terminology Criteria, Version 4.0 – CTCAE v.4.0), releted to study therapy, duration;
5) Quality of life evaluated through EORTC QLQ-C30 questionnaire.
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1) Tasso di risposta globale (Overall Response Rate – ORR);
2) Tempo alla progressione (Time To Progression - TTP);
3) Sopravvivenza globale (Overall Survival – OS);
4) Profilo di sicurezza determinato sulla base di parametri di laboratorio e clinici (ematologia, biochimica, ECOG-PS) e sulla valutazione degli eventi avversi, classificati in base a tipo, frequenza, gravità (secondo i criteri NCI, Common Terminology Criteria, versione 4.0 – CTCAE v4.0), relazione con la terapia in studio, durata;
5) Qualità della vita misurata utilizzando il questionario EORTC QLQ-C30.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2) From randomization date until desease progression at the following assessment points: at the end of induction period, every 8 weeks during treatment, at the end of treatment and every 8 weeks during follow up;
3) from randomization date to patient’s death for any cause or last date documenting the patient is alive, until 18 months from the date of evaluation of treatment end;
4)-5) All study period including follow up.
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1-2) a partire dalla data di randomizzazione, fino a progressione della malattia ai seguenti tempi di rilevazione: alla fine del periodo di induzione, ogni 8 settimane durante il trattamento, alla fine del trattamento e ogni 8 settimane durante il follow up;
3) dalla data di randomizzazione alla data di morte per qualunque causa o ultima data in cui è documentato che il paziente è in vita, fino al 18° mese dalla data di valutazione di fine trattamento;
4)-5) per tutta la durata dello studio, follow up compreso
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | 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 | 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 | 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 | 9 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 Clinical study is considered completed 18 months after the evaluation of treatment end of the last randomized patient.
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Lo studio si considera terminato 18 mesi dopo la valutazione di fine trattamento dell’ultimo paziente randomizzato
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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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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