E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary rectal cancer with high risk of failing locally and/or
systemically |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038038 |
E.1.2 | Term | Rectal cancer |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To increase the disease-free survival after 3 years follow-up. |
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E.2.2 | Secondary objectives of the trial |
To describe the toxicity profile of the combined modality treatment in schedule.
- To determine the completion rate of the neo-adjuvant treatment.
- To determine the fraction of patients with a radical resection (negative CRM)
- To determine the pathological complete response rate (pCR).
- To determine the postoperative complications
- To describe the local recurrence rate after 3 years follow-up.
- To evaluate quality of life.
- To evaluate functional outcome.
- To increase overall survival after 5 years of follow-up. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Primary tumour characteristics
- Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumour less than 16 cm from the anal verge using a rigid rectoscope or flexible endoscope.
- Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:
- Clinical stage (c) T4a, i.e. overgrowth to an adjacent organ or structure like the
prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to
TNM version 5).
- cT4b, i.e. peritoneal involvement.
- Extramural vascular invasion (EMVI+).
N2, i.e. four or more lymph nodes in the mesorectum showing morphological
signs on MRI indicating metastatic disease. Four or more nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient.
- Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal
fascia.
- Metastatic lateral nodes, > 1 cm (lat LN+)., see appendix G
General
- Staging done within 5 weeks before randomization.
- No contraindications to chemotherapy, including adequate blood counts:
- white blood count > or = 4.0 x 109/L
- platelet count > or =100 x 109/L
- clinically acceptable haemoglobin levels
- creatinine levels indicating renal clearance of > or =50 ml/min
- bilirubin < 35 μmol/l.
- ECOG performance score < or = 1, see appendix B.
- Patient is considered to be mentally and physically fit for chemotherapy as judged by the oncologist.
- Age > or = 18 years
- Written informed consent
- Adequate potential for follow-up |
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E.4 | Principal exclusion criteria |
- Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
- Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn’s disease or active ulcerative Colitis.
- Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
- Known DPD deficiency.
- Any contraindications to MRI (e.g. patients with pacemakers).
- Medical or psychiatric conditions that compromise the patient’s ability to give informed consent.
- Concurrent uncontrolled medical conditions.
- Any investigational treatment for rectal cancer within the past month.
- Pregnancy or breast feeding.
- Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
- Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
- Patients with symptoms or history of peripheral neuropathy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease-free survival after 3 years follow-up is the primary endpoint. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease-free survival will be computed as the time between randomization and either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. Patients lost to follow-up will be censored the last date of patient visit. |
La supervivencia sin enfermedad se calculará como el tiempo transcurrido entre la
aleatorización y la recidiva local o a distancia o la muerte causada por el carcinoma
rectal, lo que ocurra antes. En el caso de muerte relacionada con un cáncer no rectal, se censurará a los pacientes fallecidos en la fecha de su muerte. En el caso de un segundo tumor primario, se censurará a los pacientes en la fecha del diagnóstico del segundo tumor primario. Los pacientes perdidos para el seguimiento serán censurados en la fecha de la última visita del paciente. |
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E.5.2 | Secondary end point(s) |
Treatment associated toxicity, including surgical morbidity
Completion rate of neo-adjuvant treatment
Negative CRM (margin > 1 mm)
pCR
Postoperative complications
Local recurrence at 3 years
Overall survival
Functional outcome
Quality of life |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Toxicity:All patients will be evaluable for toxicity from the time of their first treatment.
Fraction of radical resection (CRM > 1 mm): will be evaluated according the pathology protocol described by Quirke et al.
Complete pathological response (pCR):is done by the method described in section 6.
Local recurrence: is described as relapse of tumour in the pelvic region.
Distant relapse: is described as relapse of tumour outside the pelvic region.
Local control: will be computed as the time between randomization and local relapse.
Overall survival: will be computed as the time between randomization and all causes of death.
Quality of Life (QoL):including functional outcome will be studied as described in Chapter 8 |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Proteomics, genomics, and circulating tumour cell analyses of plasma and tumour tissue along the treatment schedule may provide insight in biomarkers associated with response and prognosis. A tissue block (or two-three cores for tissue microarray, TMA) will be collected from the preoperative biopsy (if sufficient material is available) and from the operative specimen. |
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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 | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 | 0 |