| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic esophagogastric cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic esophagogastric cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 assess the relative efficacy of S-1 de-escalation therapy vs. continuation of chemotherapy after induction therapy in patients with metastatic esophagogastric cancer in terms of overall survival. |
|
| E.2.2 | Secondary objectives of the trial |
To compare S-1 de-escalation vs. continuation of chemotherapy after induction therapy with respect to
• Safety/toxicity
• Progression-free-survival
• Quality of life
|
|
| 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 |
The translational part of this trial aims to identify a subgroup of patients with a sustained, beneficial response to chemotherapy, especially to S-1 based maintenance therapy.
Blood samples will be analysed for DNA polymorphisms of the fluoropyrimidine pathway, cytokine patterns and microRNA levels. Tumor tissue will be analysed using Gene Expression Profiling and Whole Genome Methylation Analyses.
|
|
| E.3 | Principal inclusion criteria |
1. Signed written informed consent incl. participation in translational research
2. Male or female patient 18 years or older
3. Histologically confirmed metastatic or locally advanced unresectable gastric adenocarcinoma or adenocarcinoma of the esophagus or the esophagogastric junction (Her-2/neu negative or with unknown Her-2/neu status)
4. Measurable disease as per RECIST 1.1 criteria
5. Adjuvant/neoadjuvant or perioperativechemotherapy or (chemo-)radiotherapy must have been finished at least 6 months before study entry
6. No previous systemic treatment (i.e.chemotherapy) for metastatic disease
7. ECOG Performance Score 0-1 (Karnofsky Performance status >= 80%)
8. Ability for oral intake of the study drug, patients with tumor-related problems with oral intake might be registered if the symptom is expected to be improved during induction therapy (e.g. due to a tumor stenosis)
9. Female patient of childbearing potential (i.e.did not undergo surgical sterilization – hysterectomy, bilateral tubal ligation, or bilateral oophorectomy - and is not post-menopausal for at least 24 consecutive months) with a negative pregnancy test
10. Hematology and biochemistry laboratory results within the limits normally expected for the patient population, defined by the following:
• Absolute neutrophil count ≥1500/µl
• Platelet count ≥100000/µl
• Leukocyte count > 3000/µl
• Hemoglobin ≥ 9 g/dL or 5.59 mmol/l, previous transfusions (>3 days) of erythrocytes are allowed
• Total bilirubin ≤ 1.5times the upper limit of normal (ULN), in patients with known Meulengracht syndrom ≤3 x ULN
• AST ≤ 3xULN in absence of liver metastases, or ≤5xULN in presence of liver metastases
• ALT ≤ 3xULN in absence of liver metastases, or ≤5xULN in presence of liver metastases
• Creatinine clearance ≥30 mL/min according to Cockcroft-Gault formula
|
1. Consentement éclairé écrit signé, y compris la participation à la recherche translationnelle
2. Patient homme ou femme âgé de 18 ans ou plus
3. Adénocarcinome gastrique métastatique confirmé à l’histologie ou non résécable localement avancé ou adénocarcinome de l’oesophage ou de la jonction oesophago-gastrique (Her-2/neu négatif ou avec statut Her-2/neu inconnu)
4. Maladie mesurable selon les critères RECIST 1.1
5. La chimiothérapie adjuvante/néoadjuvante ou périopératoire ou (chimio-)radiothérapie doit être achevée depuis au moins 6 mois avant l’inclusion dans l’étude
6. Aucun traitement systémique antérieur (c’est-à-dire chimiothérapie) pour maladie métastatique
7. Score de performance ECOG 0-1 (statut de performance Karnofsky >= 80%)
8. Capacité à prendre oralement le médicament de l’étude, les patients avec problèmes de prise orale liés à la tumeur peuvent être inclus si l’on s’attend à ce que le symptôme s’améliore pendant la thérapie d’induction (par exemple, en raison d’une sténose causée par la tumeur)
9. Femme en âge de procréer (c’est-à-dire n’ayant pas subi de stérilisation chirurgicale – hystérectomie, ligature bilatérale des trompes ou oophorectomie bilatérale – et n’étant pas ménopausée depuis 24 mois consécutifs au moins) avec un test de grossesse négatif
10. Résultats de laboratoire d’hématologie et de biochimie dans les limites normalement attendues pour la population de patients, définies par les valeurs suivantes:
• Numération absolue des neutrophiles ≥ 1500/μl
• Numération plaquettaire ≥ 100000/μl
• Numération leucocytaire > 3000/μl
• Hémoglobine ≥ 9 g/dl ou 5,59 mmol/l, les transfusions antérieures (> 3 jours) d’érythrocytes sont autorisées
• Bilirubine totale ≤ 1,5 fois la limite supérieure de la normale (LSN) chez des patients avec syndrome de Meulengracht connu ≤ 3 x LSN
• AST ≤ 3 x LSN en l’absence de métastases hépatiques, ou ≤5 x LSN en présence de métastases hépatiques
• ALT ≤ 3 x LSN en l’absence de métastases hépatiques, ou ≤ 5 x LSN en présence de métastases hépatiques
• Clairance de la créatinine ≥ 30 ml/min selon la formule de Cockcroft-Gault |
|
| E.4 | Principal exclusion criteria |
1. Previous major sugery within the last 28 days before the start of the induction treatment. The implantation of a central venous access (e.g. porth-a cath system) is allowed.
2. History of other malignant tumors within the last 5 years, except basal cell carcinoma or curatively excised cervical carcinoma in situ
3. Known brain metastases
4. Concurrent radiotherapy involving target lesions used for this study. Concurrent palliative radiation for non-target lesions is allowed if other target lesions are available outside the involved field; previous radiotherapy including target lesions must have been finished at least 28 days before start of induction treatment.
5. Previous systemic treatment (i.e. chemotherapy) for metastatic disease
6. Known active HBV, HCV infection or documented HIV infection
7. Serious concomitant disease or medical condition that by judgment of the Investigator renders the patient at high risk of treatment complications
8. Clinically relevant coronary artery disease (NYHA functional angina classification III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the last 3 months, or high risk of uncontrolled arrhythmia
9. Female patient pregnant or breast feeding
10. Female patient of childbearing potential (i.e. did not undergo surgical sterilization – hysterectomy, bilateral tubal ligation, or bilateral oophorectomy - and is not post-menopausal for at least 24 consecutive months) not willing to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the end of treatment. Male patient not willing to use an adequate method of contraception to avoid conception throughout the study and for up to 26 weeks after the end of treatment in such a manner that the risk of pregnancy is minimized.
11. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 60 days prior to start of induction
12. Chronic diarrhea or short bowel syndrome
13. Known hypersensitivity to S-1, other fluoropyrimidines or platinum compounds.Contraindication to receive S-1 or the polychemotherapy (induction & arm B) chosen for this patient as per current Summary of Product Characteristics. Known DPD decifiency
14. Grade ≥2 peripheral neuropathy
15. Known drug abuse/alcohol abuse
|
1. Chirurgie majeure préalable dans les 28 jours avant le début de la thérapie d’induction. L’implantation d’un accès veineux central (par ex. système porth-a cath) est autorisée
2. Antécédents d’autres tumeurs malignes dans les 5 dernières années, sauf carcinome à cellules basales ou carcinome cervical in situ excisé de manière curative
3. Métastases connues au cerveau
4. Radiothérapie concurrente impliquant les lésions cibles utilisées pour cette étude. L’irradiation palliative concurrente de lésions non cibles est autorisée si d’autres lésions cibles sont disponibles en dehors du champ impliqué; la radiothérapie antérieure incluant des lésions cibles doit avoir été achevée au moins 28 jours avant le début du traitement d’induction
5. Traitement systémique préalable (c’est-à-dire chimiothérapie) pour maladie métastatique
6. Infection par VHB ou VHC connue et active ou infection par VIH documentée
7. Maladie concomitante grave ou maladie qui, de l’avis de l’investigateur, expose le patient à un risque élevé de complications lors du traitement
8. Coronaropathie cliniquement importante (classification de l’angor fonctionnel NYHA III/IV), insuffisance cardiaque congestive (NYHA III/IV), cardiomyopathie cliniquement importante, antécédents d’infarctus du myocarde dans les 3 derniers mois ou risque élevé d’arythmie incontrôlée
9. Femme enceinte ou allaitante
10. Femme en âge de procréer (c’est-à-dire n’ayant pas subi de stérilisation chirurgicale – hystérectomie, ligature bilatérale des trompes ou oophorectomie bilatérale – et n’étant pas ménopausée depuis 24 mois consécutifs au moins) ne voulant pas utiliser une méthode de contraception adéquate afin d’éviter une grossesse pendant toute la durée de l’étude et pendant une durée allant jusqu’à 26 semaines après la fin du traitement. Homme ne voulant pas utiliser une méthode de contraception adéquate afin d’éviter une conception pendant toute la durée de l’étude et pendant une durée allant jusqu’à 26 semaines après la fin du traitement de manière à minimiser le risque de grossesse
11. Traitement concomitant par d’autres substances expérimentales ou participation à un autre essai clinique avec toute substance expérimentale dans les 60 jours avant le début de l’induction
12. Diarrhée chronique ou syndrôme de l’intestin court
13. Hypersensibilité connue à S-1, à d’autres fluoropyrimidines ou aux composés du platine. Contre-indication pour recevoir S-1 ou la polychimiothérapie (induction & bras B) choisie pour ce patient, selon le Résumé des Caractéristiques du Produit en vigueur. Déficit connu en DPD
14. Neuropathie périphérique de grade ≥ 2
15. Abus connu de drogue/d’alcool |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival defined as the time from randomization until death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assuming that 10 patients can be randomized per month, with 297 randomized patients (198 treated with S-1 and 99 treated with continued polychemotherapy), the total study duration (accrual plus follow-up) to reach the required number of deaths will be approximately 39 months (30 months accrual period plus 9 months follow-up). |
|
| E.5.2 | Secondary end point(s) |
• Adverse Events according to the CTCAE Criteria (Version 4.03)
• Progression-free-survival defined as the time from randomization until disease progression or death from any cause
• Quality of life according to the EORTC QLQ-C30and QLQ-STO22
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assuming that 10 patients can be randomized per month, with 297 randomized patients (198 treated with S-1 and 99 treated with continued polychemotherapy), the total study duration (accrual plus follow-up) to reach the required number of deaths will be approximately 39 months (30 months accrual period plus 9 months follow-up). |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
The translational part of this trial aims to identify a subgroup of patients with a sustained, beneficial response to chemotherapy, especially to S-1 based maintenance therapy.
Blood samples will be analysed for DNA polymorphisms of the fluoropyrimidine pathway, cytokine patterns and microRNA levels. Tumor tissue will be analysed using Gene Expression Profiling and Whole Genome Methylation Analyses.
|
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| polychemotherapy as during induction therapy |
|
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | 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 number of events (deaths) required for this study is expected to be reached approximately 9 months after end of accrual period. However,in case that the required number of deaths is reached earlier than anticipated follow-up of each patient will continue until approximately 6 months after the last patient entered the Maintenance Phase to ensure maturity of clinical data. |
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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 | |
| E.8.9.1 | In the Member State concerned months | 39 |
| E.8.9.1 | In the Member State concerned days | |
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