| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| small bowel adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| SMALL BOWEL ADENOCARCINOMA |
|
| 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 objective of the trial is to assess:
• the efficacy of observation against 24 weeks of adjuvant postoperative chemotherapy
• the efficacy of 24 weeks of adjuvant post-operative 5-FU/Capecitabine monotherapy versus 5-FU/Capecitabine plus Oxaliplatin |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to:
• Assess the toxicity of chemotherapy, the overall survival, the cost-effectiveness of the treatment alternatives, the quality of life and establish a central tissue and data bank for patients with this rare cancer |
|
| 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. |
|
| E.3 | Principal inclusion criteria |
1. R0 resected stage I, II, III or IV 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 14 weeks of surgery and commence chemotherapy within 16 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. Female of child bearing potential (Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential) must use a method of contraception during treatment and at least 4 months after stopping treatment; for male
patients this will be during treatment and for at least 6 months after stopping treatment
13. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures. |
|
| 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.adenocarcinoma arising in the appendix or colorectum
3. Previous neo-adjuvant chemo(radio)therapy for small bowel adenocarcinoma
4. 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)
5. 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)
6. Previous invasive or non-invasive malignancy except:
(i) Ductal Carcinoma In Situ (DCIS) of the breast where treatment consisted of resection alone, (ii) Cervical carcinoma in situ where treatment consisted of resection alone, (iii) Basal cell or squamous cell carcinoma where treatment consisted of resection alone or radiotherapy, (iv) Superficial bladder carcinoma where treatment consisted of resection alone or with a single installation of intravesical chemotherapy or with BCG treatment, (v) Other cancers where the patient has been disease-free for at least 3 years and treatment was with curative intent, and (vi) Other cancers with very low potential for recurrence can be discussed with the CI
7. Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency
8. Known untreated coeliac disease (may be enrolled if diet controlled), untreated chronic inflammatory bowel disease or other cause of malabsorption or intestinal obstruction
9. Grade ≥ 2 peripheral neuropathy
10. Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, prior to receiving the first dose of trial
treatment.
11. Previous hypersensitivity to platinum salts
12. Patients with clinically significant, active infections, or any other serious medical condition in which chemotherapy is contraindicated will
be excluded
13. Patients with untreated vitamin B12 deficiency are excluded from receiving folinic acid as part of their chemotherapy regimen. However,
these patients may be eligible for treatment with capecitabine fluoropyrimidine therapy, where no folinic acid is administered as part of
the treatment regimen
14. Patients with clinically significant sensorineural hearing impairment are excluded from receiving oxaliplatin but will be eligible for the
fluoropyrimidine monotherapy provided as a clinician's choice for patients in group 1 randomised to either observation or chemotherapy
15. Any patient receiving treatment with brivudine, sorivudine and analogues |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 3 years after the last patient is randomized |
|
| E.5.2 | Secondary end point(s) |
Overall survival: The patient's survival status is determined at each follow-up visit.
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 QLQCR29 v2.1 and EQ-5D scales as per the schedule indicated in section
4.1.4
Establishment of a central tissue and data bank for patients with SBA – further details on this tissue bank can be found in section 4.2, Translational
Research. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At 3, 5 and 7 years after the last patient is randomized |
|
| 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 | 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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