| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Colorectal cancer with resectable liver metastases |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bowel which has spread to the liver (secondaries) |
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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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Currently some patients with colorectal cancer that has spread to the liver can be treated surgically and a significant number will effectively be cured. A prior study has shown that chemotherapy improves the survival of these patients if it is given both before and after the liver surgery. However this causes an increase in the complications of surgery. In this trial we are trying to find out if giving all the chemotherapy after surgery is possible, hence potentially avoiding this problem of complications. If this approach is feasible a larger trial will be undertaken to see if this approach is equivalent in terms of the long term survival of these patients. |
|
| E.2.2 | Secondary objectives of the trial |
| We are interested to know whether patients will accept the chemotherapy to be given after the liver operation. We also want to know how much chemotherapy can actually be given, bearing in mind that a liver operation is a major procedure. We want to know how the quality of life in patients differs between the two approaches. As with all studies we will collect tissue from the removed liver and also from the patient’s blood to “bank” for future studies. Such studies may determine the suitability of different patients for different forms of treatment. These samples will be given a code so that they cannot be easily linked with the donor. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| • Confirmed colorectal adenocarcinoma: o either previous or current histologically confirmed primary adenocarcinoma of colon or rectum, together with clinical or radiological evidence of advanced and / or metastatic disease. o or radiologically confirmed primary adenocarcinoma of colon or rectum, together with clinical or radiological evidence of advanced and / or metastatic disease. Histological evidence of primary colorectal cancer should be sought wherever possible but liver metastases should not be biopsied. • Presence of potentially resectable colorectal cancer liver metastases without detectable extra-hepatic tumour that cannot be completely resected. The consulting surgeon and the radiologist, according to local practice, will determine resectability (see appendix VI for guideline). The following patients are eligible: o Patients with rectal cancer who would be suitable for short course radiotherapy as an adjuvant treatment. o Patients who have had long course chemoradiation and R0 surgery for rectal cancer o Patients with metachronous metastases having undergone complete resection of the primary tumour without gross or microscopic evidence of residual disease (R0). o Patients with synchronous metastases who have undergone R0-resection of the primary tumour more than one month before randomisation. o Patients with synchronous metastases for whom there is sufficient evidence (for example by CT scan or diagnostic laparoscopy) that both the primary tumour and the liver metastases can be completely resected during the same procedure and that resection of primary cancer can be delayed for 3 to 4 months. o Unidimensionally measurable disease (RECIST criteria, see appendix V) to measure pre-operative response. o Patients with previously resected liver metastases for whom surgery was performed ≥ 1 year previously. • No previous systemic chemotherapy for metastatic disease o adjuvant chemotherapy with 5FU +/- FA, capecitabine or oxaliplatin may have been given, if completed > 6 months prior to trial entry. o rectal chemoradiotherapy may have been given, if completed > 1 month prior to trial entry. • ECOG performance status ≤2. • Patients who are considered by responsible consultant to be fit to undergo combination chemotherapy and surgery. • Baseline laboratory tests (within 1 week prior to randomisation): o neutrophils ≥ 1.5 x10 to the power of 9/l and platelet count ≥ 100 x10 to the power of 9/l o serum bilirubin ≤ 1.25 x upper limit of normal (ULN), alkaline phosphatase ≤ 5 x ULN, and serum transaminase (either AST or ALT) ≤ 2.5 x ULN o estimated creatinine clearance (Cockcroft; appendix VIII) >50ml/min or measured GFR (EDTA clearance) >50 ml/min. • All patients must be aged 18 years or older. • For women of childbearing potential, negative pregnancy test and adequate contraceptive precautions. Adequate contraception for men. • Written informed consent. • Consent to allow surplus pathological material to be analysed for translational research projects (patients may decline participation in this supplementary component and still participate in the main trial). |
|
| E.4 | Principal exclusion criteria |
| • Patients in whom there is an indication for chemotherapy to facilitate a R0 resection. • Patients in whom radio frequency ablation is felt to be an essential component of treatment. • Patients who are unfit for the chemotherapy regimens in this protocol or subsequent surgery, e.g.: o severe uncontrolled concurrent medical illness (including poorly-controlled angina or very recent MI, i.e. in previous 3 months) likely to interfere with protocol treatments. o Any psychiatric or neurological condition which is felt likely to compromise the patient's ability to give informed consent or to comply with oral medication. o Partial or complete bowel obstruction. o Pre-existing neuropathy (> grade 1). • Patients requiring ongoing treatment with a contraindicated concomitant medication. • Patients with another previous or current malignant disease which, in the judgement of the treating investigator, is likely to interfere with EPOC B treatment or assessment of response. • Patients with known hypersensitivity reactions to any of the components of the study treatments. • Patients with a second metastatic site. • Female patients who are pregnant or lactating. • Patients with a personal or family history suggestive of dihydropyrimidine dehydrogenase (DPD) deficiency or with known DPD deficiency. • Patients who are known to have tumours which are K-ras wild type. • Partial or complete bowel obstruction. • Chronic diarrhoea or inflammatory bowel disease. • Gilbert’s syndrome or other congenital abnormality of biliary transport (e.g. Crigler-Najjar syndrome, Dubin-Johnson syndrome). • Previous transplant surgery, requiring immunosuppressive therapy (due to interaction of cyclosporin-A with irinotecan). • Patients with ≥ grade 1 residual neurotoxicity following oxaliplatin as adjuvant may be offered irinotecan and 5FU instead of oxaliplatin and fluoropyrimidine. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To determine whether it is feasible to recruit to a trial of peri-operative vs post operative chemotherapy. |
|
| E.5.2 | Secondary end point(s) |
| o The proportion of chemotherapy received. o Peri-operative surgical mortality (within 30 days of surgery). o Treatment related toxicity. o The effects of treatment on quality of life (QoL) - QoL data will be collected using EORTC QLQ-C30 (version 3), EORTC QLQ – LMC21, EuroQol Questionnaire (EQ-5D). o Overall survival (OS) for each treatment arm - OS will be determined by flagging and clinical review. o Length of stay. o Progression free survival. |
|
| 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) | 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 | 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 | 18 |
| 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
|
| For assessment of feasibility, the trial will end approximately 9 months post resection of patient 78. At this point a decision will be made to determine whether to progress to the phase III study based on the primary endpoint criteria. If this trial is found to be feasible and it progresses to phase III, to ensure patients in this trial can be included in the phase III trial, the phase III trial will end once the last recruited patient has received treatment and 5 years of follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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