| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SMALL BOWEL ADENOCARCINOMA |
| ADÉNOCARCINOME DE L'INTESTIN GRÊLE |
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| E.1.1.1 | Medical condition in easily understood language |
| SMALL BOWEL ADENOCARCINOMA |
| ADÉNOCARCINOME DE L'INTESTIN GRÊLE |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
The primary oObjective of the trial is to assess:
• the efficacy of observation against 24 weeks of adjuvant post-operative chemotherapy
• the efficacy of 24 weeks of adjuvant post-operative 5-FU/Capecitabine monotherapy versus 5-FU/Capecitabine plus Oxaliplatin
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L’objectif principal est :
1. Évaluation de l'efficacité de la chimiothérapie adjuvante versus l’observation après résection d’un adénocarcinome de l'intestin grêle (AIG) de stade I-III.
2. Évaluation de l'efficacité du traitement adjuvant par fluoropyrimidine en monothérapie versus fluoropyrimidine plus oxaliplatine après résection d’un adénocarcinome de l'intestin grêle (AIG) de stade I-III.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to:
• Assess the toxicity of chemotherapy, the overall survivall, the cost-effectiveness of the treatment alternatives, the quality of life and establish a central tissue bank for patients with this rare cancer.
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| Les objectifs secondaires de l’étude seront : la survie globale, la toxicité de la chimiothérapie, le rapport coût-efficacité des alternatives thérapeutiques, la qualité de vie et de réaliser une collection biologique pour les patients présentant ce cancer rare. |
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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 |
It is planned to have the collection of FFPE blocks and bloods for patients on the BALLAD trial. The aim of collecting this material is to establish a large biobank of SBA tissue and blood with complete and comprehensive trial quality follow-up data which will act as the foundation for many future collaborative research projects and for combined projects with other funded tissue collections. Expected research projects arising will include definition of new prognostic markers in this group of patients and definition of pharmacogenetic markers of 5-FU/capecitabine and oxaliplatin toxicity, particularly high grade diarrhoea and neurotoxicity.
This is a hugely important and integral part of the BALLAD trial that will significantly enhance the potential impact and clinical applicability of the results of the main body of the trial. We are therefore keen that all researchers contribute as much as possible to this part of the trial and encourage their patients to give their consent to allow this to take place.
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La recherche translationnelle biologique est partie intégrante et extrêmement importante de l'étude BALLAD. Elle renforcera significativement l'impact potentiel et l'applicabilité clinique des résultats de la partie principale de l'étude.
Les projets de recherche prévus incluront notamment la détermination de nouveaux marqueurs pronostiques et prédictifs, ainsi que la détermination de marqueurs pharmacogénétiques de la toxicité du 5-FU/capécitabine et de l'oxaliplatine, en particulier les diarrhées et la neurotoxicité de haut grade.
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| E.3 | Principal inclusion criteria |
1. R0 resected stage I, II or III small bowel adenocarcinoma
2. No evidence of residual or metastatic disease at laparotomy and CT/MRI imaging of chest, abdomen and pelvis.
3. Patients must be registered and randomised within 12 weeks of surgery and commence chemotherapy within 14 weeks of surgery
4. ECOG Performance Status of 0 or 1
5. Absolute neutrophil account ≥ 1.5 x109/l
6. Platelet count ≥ 100 x 109/l
7. Haemoglobin ≥90 g/l (previous transfusion is allowed)
8. AST and ALT ≤ 2.5 x upper limit of normal (ULN). (At least one of ALT or AST MUST be performed)
9. Creatinine clearance > 50 ml/min (calculated by Cockcroft Gault or Wright equation) or measured by EDTA
10. Serum bilirubin ≤ 1.5 x ULN
11. Signed and dated informed consent indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrolment.
12. Age ≥ 18 years
13. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.
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1. Adénocarcinome de l’intestin grêle de stade I, II ou III, complètement réséqué (R0)
2. Absence de maladie résiduelle ou métastatique visible par TDM/IRM du thorax, de l'abdomen et du pelvis
3. Patient devant être inscrit et randomisé dans les 12 semaines suivant la chirurgie, et pouvant débuter la chimiothérapie dans les 14 semaines suivant la chirurgie
4. ECOG ≤ 1
5. Âge ≥ 18 ans
6. Bilan biologique : neutrophiles ≥ 1,5 x109/L ; plaquettes ≥ 100 x 109/L ; hémoglobine ≥ 90 g/L (transfusion préalable est possible) et bilirubinémie ≤ 1,5 x la limite supérieure de la normale (LSN).
7. ASAT et ALAT ≤ 2,5 x LSN
8. Clairance de la créatinine > 50 mL/min (calculée par la formule de Cockcroft Gault)
9. Consentement éclairé daté et signé indiquant avant
l'inclusion.
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| E.4 | Principal exclusion criteria |
1. Non-adenocarcinoma histology of small bowel tumour which includes but is not confined to lymphoma, GIST, carcinoid or other neuroendocrine tumour, squamous carcinoma, melanoma or sarcoma.
2. Previous neo-adjuvant chemo(radio)therapy for small bowel adenocarcinoma
3. Clinically significant cardiovascular disease (i.e. active or < 12 months since cerebrovascular accident, myocardial infarction, unstable angina, New York Heart Association [NYHA] grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension)
4. Pregnancy/lactation or of child bearing potential and not using medically approved contraception. (Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential)
5. Previous malignancy other than adequately treated in situ carcinoma of the uterine cervix or basal or squamous cell carcinoma of the skin, unless there has been a disease free interval of at least 3 years and treatment was with curative intent
6. Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency
7. Known untreated coeliac disease (may be enrolled if diet controlled), untreated chronic inflammatory bowel disease or other cause of malabsorption or intestinal obstruction
8. Grade ≥ 2 peripheral neuropathy
9. Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, prior to receiving the first dose of trial treatment.
10. Previous hypersensitivity to platinum salts
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1. Tumeur de l'intestin grêle avec une histologie non adénocarcinome, incluant, mais non exclusivement, les lymphomes, les GIST, les carcinoïdes ou autres tumeurs neuroendocrines, les carcinomes épidermoïdes, les mélanomes et les sarcomes
2. Chimio(radio)thérapie néoadjuvante pour l’AIG
3. Maladie cardiovasculaire cliniquement significative : active ou délai < 12 mois depuis l'accident vasculaire cérébral, l’infarctus du myocarde, l’angor instable, l’insuffisance cardiaque congestive de grade NYHA II ou plus, l’arythmie cardiaque grave requérant un traitement, ou l’hypertension non contrôlée
4. Antécédents de cancer, excepté le carcinome in situ du col utérin traité ou le carcinome basocellulaire ou spinocellulaire de la peau, sauf si traité à visée curative et considéré guéri depuis au moins 3 ans
5. Déficit en dihydropyrimidine déshydrogénase (DPD) connu ou suspecté
6. Maladie cœliaque connue non traitée (possibilité d'inclusion si contrôlé par un régime), maladie inflammatoire chronique de l'intestin non traitée, ou autre cause de malabsorption ou d'occlusion intestinale
7. Neuropathie périphérique de grade ≥ 2
8. Femme enceinte/allaitant ou en âge de procréer n'utilisant pas de contraception médicalement approuvée (Les femmes post-ménopausées doivent être aménorrhéiques depuis au moins 12 mois pour être considérées comme n'étant pas en âge de procréer)
9. Administration de tout autre médicament expérimental dans les 28 jours ou les 5 demi-vies (à la plus longue de ces échéances) avant de recevoir la première dose du traitement de l'étude
10. Incapacité de respecter les visites programmées, les schémas thérapeutiques, les examens biologiques et toutes autres procédures de l'étude
11. Hypersensibilité connue aux sels de platine.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Disease free survival is the primary end point for the trial. This is defined at time from randomisation to the first occurrence of the following events:
• Disease relapse (confirmed by imaging)
• Incidence of a new primary (confirmed by imaging and histology/cytology)
• Death from any cause
Patients who experience none of these events are censored at the last date known to be alive.
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La survie sans maladie (SSM) est le critère d'évaluation principal de l'étude. Elle est définie par le délai entre la randomisation et la première survenue des événements suivants :
• Récidive de la maladie (confirmée par imagerie)
• Apparition d’une nouvelle tumeur primitive (confirmée par imagerie et par histologie/cytologie)
• Décès de toute cause
Les patients ne présentant aucun de ces événements seront censurés à la date de dernières nouvelles.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 3 years after the last patient is randomized |
| 3 ans après la randomisation du dernier patient |
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| E.5.2 | Secondary end point(s) |
Overall survival: The patient’s survival status is determined at each follow-up visit. After the mandated clinic visits survival status data will come from responsible cancer centres, cancer registries and national databases and include long-term passive follow-up data such as that collected through collaboration with the National Cancer Intelligence Network and the Office of National Statistics in the U.K.
Toxicity of chemotherapy: Toxicity will be assessed using CTCAE version 4.0. Only toxicities that are at least grade 2 will be recorded on the CRF
Quality of life: This is assessed using the EORTC QLQ-C30, EORTC QLQ-CR29 v2.1 and EQ-5D scales as per the schedule indicated in section 4.1.5
Health Economics: Assess the cost-effectiveness of 24 weeks adjuvant chemotherapy in comparison to observation alone; and assess the cost-effectiveness of 24 weeks adjuvant 5-FU/Capecitabine monotherapy compared to 5-FU/Capecitabine plus Oxaliplatin. Outcomes will be reported as incremental cost per DFS and incremental cost per QALY.
Establishment of a central tissue bank for patients with SBA – further details on this tissue bank can be found in section 4.2, Translational Research.
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La survie globale : le statut de survie des patients sera déterminé à chaque visite de suivi.
La toxicité de la chimiothérapie : la toxicité sera évaluée en utilisant la classification CTCAE version 4.0. Seules les toxicités de grade 2 minimum seront consignées dans le CRF.
La qualité de vie : elle sera évaluée en utilisant les questionnaires EORTC QLQ-C30, EORTC QLQ-CR29 v2.1 et EQ-5D, conformément au calendrier figurant à la section 4.1.5.
L’économie de la santé : évaluer le rapport coût-efficacité de 24 semaines de chimiothérapie adjuvante comparé à l'observation seule, ainsi que celui de 24 semaines de 5-FU/capécitabine en monothérapie adjuvante comparé au 5-FU/capécitabine plus oxaliplatine. Les résultats seront rapportés en coût différentiel par SSM et en coût différentiel par QALY.
La création d’une banque de tissus centralisée pour les patients atteints d'AIG – des détails complémentaires concernant cette banque de tissus sont fournis à la section 4.2, Recherche translationnelle.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At 3, 5 and 7 years after the last patient is randomized |
| 3, 5 et 7 ans après la randomisation du dernier patient |
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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) | 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 | 4 |
| 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 | 50 |
| 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 | 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
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| LVLS |
| Dernière visite du dernier patient |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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