| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Small Bowel Adenocarcinoma
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| Adenokarcinom I tolvfingertarmen eller tyndtarmen |
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| E.1.1.1 | Medical condition in easily understood language |
| Small Bowel Adenocarcinoma |
| Adenokarcinom I tolvfingertarmen eller tyndtarmen |
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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 | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
To assess the efficacy (in terms of Disease free survival which is defined as time from randomisation to recurrence, development of a new primary or death from any cause) of observation against 24 weeks of adjuvant post-operative chemotherapy in resected stage I-III small bowel adenocarcinoma and to assess the efficacy of 24 weeks of adjuvant post-operative fluoropyrimidine monotherapy versus fluoropyrimidine plus Oxaliplatin combination chemotherapy.
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1. At evaluere effekten af 24-ugers adjuverende kemoterapi efter resektion for stadier I-III adenocarcinom i tolvfingertarmen eller tyndtarmen versus observation.
2. At evaluere effekten af 24-ugers adjuverende fluoropyrimidin (5-FU/capecitabin)”monoterapi” versus fluoropyrimidin plus oxaliplatin kombinationskemoterapi efter resektion for stadier I-III adenocarcinom i tolvfingertarmen eller tyndtarmen versus observation.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are; overall survival, toxicity of chemotherapy, quality of life and the establishment of a central tissue bank for patients with small bowel adenocarcinoma.
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| Samlet overlevelse, omkostningseffektivitet, toksicitet, den klinikopatologiske og molekylære profil af adenocarcinomer i tolvfingertarmen eller tyndtarmen. |
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| E.2.3 | Trial contains a sub-study | No |
| 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 on 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 count of ≥ 1.5 x10(9)/l
6. Platelet count ≥ 100 x 10 (9)/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 ≥ 16 years
13. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.
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1. Patienter som er radikal opereret (R0 reseceret) for stadier I, II eller III adenocarcinom i tolvfingertarmen eller tyndtarmen.
2. Ingen tegn på rest eller metastatisk sygdom ved hverken operation eller CT/MR undersøgelse af thorax, abdomen og pelvis.
3. Patienterne registreres og randomiseres inden for 12 uger efter operationen og skal påbegynde kemoterapi inden for 14 uger efter operationen.
4. ECOG Performance Status 0 eller 1.
5. Blodprøveanalyse: Absolut neutrofiltal ≥ 1,5 x109 / l.
6. Trombocyttal ≥ 100 x 109 / l;
6. Biokemisk analyse: AST og ALT ≤ 2,5 x øvre reference grænse.
7. Kreatininclearance> 50 ml / min (beregnet ved Cockcroft Gault eller målt ved Cr-EDTA)
8. Serum bilirubin ≤ 1,5 x øvre reference grænse.
9. Underskrevet og dateret informeret samtykke.
10. Alder ≥ 18 år
11. Villighed og evne til at overholde planlagte besøg, behandlingsplaner og planlagte undersøgelser.
12. Fertile mænd og kvinder skal benytte effektiv svangerskabsforbyggelse. Fertile kvinder som inkluderes i forsøget, skal anvende p-piller, spiral, depotinjektion af gestagen, subdermal implatation, hormonal vaginal ring eller transdermal depotplaster under hele forsøgsbehandlingen og 6 måneder herefter.
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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
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1. Ikke-adenocarcinom histologi af tyndtarmstumor, dvs. lymfom, GIST, carcinoid eller anden neuroendokrin tumor, planocellulært karcinom, melanom eller sarkom.
2. Tidligere neoadjuverende kemoterapi eller kemoradioterapi.
3. Klinisk signifikant kardiovaskulær lidelse i anamnese (dvs. aktiv eller <12 måneder siden cerebrovaskulære katastrofer, myokardieinfarkt, ustabil angina pectoris, NYHA klasse II eller betydelige kongestivt hjertesvigt, alvorlig hjertearytmi der kræver medicinering, ukontrolleret hypertension)
4. Graviditet/amning eller kvinder i en fertilitetsdygtig alder som ikke anvender medicinsk prævention. (Postmenopausale kvinder skal have amenorré i mindst 12 måneder for at blive betragtet som ikke-fertile)
5. Tidligere kræftsygdomme bortset fra tilstrækkeligt behandlet karcinom in situ i livmoderhalsen eller basal eller planocellulært karcinom i huden, medmindre disse patienter blev behandlet med helbredende sigter og har været sygdomsfri mindst 3 år
6. Kendt eller formodet dihydropyrimidin dehydrogenase (DPD) mangel
7. Kendt ubehandlet cøliaki (kan inkluderes hvis diætstyret), ubehandlet kronisk inflammatorisk tarmsygdom eller anden årsag til malabsorption eller intestinal obstruktion
8. Kendt med Grad ≥ 2 periferisk neuropati
9. Administrering af ethvert andet forsøgslægemiddel inden for 28 dage eller
forsøgslægemiddel som har 5 halveringstider før opstart af forsøgsbehandling.
10. Tidligere overfølsomhed over for platinsalte.
11. Patienter med klinisk signifikante, aktive infektioner eller enhver anden alvorlig medicinsk tilstand, hvor kemoterapi er kontraindiceret.
12. Patienter med ubehandlet vitamin B12-mangel. Dog kan disse patienter modtage capecitabin, eftersom folinsyre ikke er en del af behandlingen.
13. Patienter med klinisk signifikant neurosensorisk hørenedsættelse er udelukket fra at modtage oxaliplatin, men kan være kandidater til at modtage 5FU eller capecitabin monoterapi.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Disease free survival (defined as time from randomisation to recurrence, development of a new primary or death from any cause).
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| Sygdomsfri overlevelse (defineret som tidspunktet fra randomisering til tidspunktet for recidiv af adenocarcinom i tolvfingertarmen eller tyndtarmen, udvikling af ny primær kræft eller død uanset årsag). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients that are randomised to observation only will be seen 3 and 6 months post randomisation with all other follow up being the same as the treatment group.
Patients that are randomised to treatment will be seen prior to every chemotherapy treatment.
All patients will be seen 9, 12, 18, 24, 30 and 36 months post recruitment and then annually for a period of up to 7 years.
At all these time points patients will be accessed for recurrence, development or a new primary. These will be recorded on the CRF. If the patient has died this will also be recorded on the CRF
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Gruppe 1. Patienter,vil blive randomiseret enten til observation eller 6-måneders kemoterapibehandling med fluoropyrimidin (enten 5-FU eller capecitabin), med eller uden oxaliplatin.
Patienter som indgår i kemoterapigruppen kan også bliver randomiseret til enten observation eller 6- måneders kemoterapibehandling med fluoropyrimidin (enten 5-FU eller capecitabin), med eller uden oxaliplatin. Gruppe 2. Patienter, vil blive randomiseret til at modtage 5-FU eller capecitabin, enten med eller uden oxaliplatin i 6 måneder. Patienterne vil blive rekrutteret til forsøget over en periode på 5 år og have en follow-up 9, 12, 18, 24, 30 og 36 måneder efter inklusion; herefter hvert år over en periode på op til 7 år.
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| E.5.2 | Secondary end point(s) |
| Overall survival, cost-effectiveness, toxicity and molecular profiling of SBA |
Samlet overlevelse, omkostningseffektivitet, toksicitet, den klinikopatologiske og molekylære profil af adenocarcinomer i tolvfingertarmen eller tyndtarmen.
|
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cost effectiveness will be accessed using the EQ-5D which will be completed at 3 and 6 months post randomisation and at every subsequent clinic visit.
Any toxicity the patients experiance will be collected at the time of clinic attendence on the CRF.
Patients can consent to their tumour being accessed and an additional blood sample being taken to allow for the molecular profiling of SBA.
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| Omkostningseffektivitet evalueres ved anvendelse af EQ-5D som vil blive udført 3 og 6 måneder efter randomiseringen og ved hvert kliniske besøg. Toksicitetsdata vil blive samlet ved hvert klinisk besøg og dokumenteret i CRF. Adenokarcinomernes molekylære profil vil blive analyseret i tumorvævet og blodet. |
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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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Gruppe 1: observationsgruppe |
| Comparator description: Observation (group 1 patients) |
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| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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 |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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