| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The principal reasearch question is whether in MRI-defined operable rectal cancer patients, it is feasible to treat for eight weeks with oxaliplatin/5-Fluorouracil chemotherapy and then give a short course of preoperative radiotherapy (SCPRT)immediately before surgical removal of the tumour. This will be measured by calculating the proportion of patients successfully completing surgery. |
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| E.2.2 | Secondary objectives of the trial |
| 1. To assess treatment compliance and recruitment rates. 2. To determine whether the approach is safe by carefully monitoring any side-effects that the patients have and grading them according to a very specific set of toxicity criteria: the NCI Common Terminology Criteria for Adverse Events. Late toxicity assessment will also be monitored 1 year following radiotherapy. 3. The stage of a cancer is really how large it is and whether it has spread to the lymph nodes or another part of the body (metastasis). One of the secondary objectives of this study is to work out whether giving chemotherapy with oxaliplatin/5-Flourouracil prior to the radiotherapy and surgery is able to shrink the primary tumour such that it can be given a lower stage grading than would have been possible had the patient not received chemotherapy prior to radiotherapy and immediate surgery. We will also look at disease free, local recurrence free, distant metastasis free and overall survival rates. |
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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 |
| There is a translational research sub-study called T-COPERNICUS which is integral to the main COPERNICUS trial protocol. T-COPERNICUS does not therefore have a separate title or version number. Patients will be given the opportunity to consent into T-COPERNICUS and in doing so, will provide blood and biopsy samples. |
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| E.3 | Principal inclusion criteria |
| All of the following criteria must apply for patients to be included in the trial: 1.Patient 18 years old or older 2.Tumour biopsy with histopathologic confirmation of rectal adenocarcinoma 3.Inferior aspect of tumour is > 4 cm from anal verge on digital examination and pelvic MRI scan 4.Superior aspect of tumour is not higher than the anterior aspect of the S1/S2 interspace on pelvic sagittal MRI scan 5.Further MRI defined inclusion criteria include: (i) Mesorectal fascia is not threatened or involved (tumour > 1mm from mesorectal fascia) (ii) Primary tumour is: • T3a-b (mesorectal primary tumour invasion seen ≤ 5 mm beyond muscularis propria) in the presence of either: extra-mural vascular invasion or mesorectal tumour deposit(s) with irregular border and mixed signal intensity •any T3c (primary tumour invasion seen >5mm beyond muscularis propria)-T4a (invasion of visceral peritoneum for tumours with a component above peritoneal reflection) • Low tumours should not involve levator ani (>1 mm gap between tumour and levator ani) or anal sphincters 6.No evidence of distant metastases 7.Patient with measurable disease at the baseline visit 8.A defunctioning colostomy or ileostomy is permitted to relieve impending rectal obstruction or severe local bowel symptoms 9.Candidate for systemic therapy with OxMdG according to the opinion of the primary oncologist treating the patient 10.ECOG Status: 0-1 11.Bloods: Adequate bone marrow, hepatic, renal and metabolic function (assessed within 14 days prior to study entry): • Haemoglobin ≥ 9 g/dL, leucocyte count ≥ 3 x 109/L, neutrophil count ≥1.5 x109/L and platelet count ≥100 x109/L • Total bilirubin ≤ 1.5 x ULRR, alkaline phosphatase ≤ 5 x ULRR, and serum transaminase (either AST or ALT) ≤2.5 x ULRR • Estimated creatinine clearance ≥ 50 mL/min (calculated according to Cockroft and Gault). (Confirmed with 24 hour urine creatinine clearance or EDTA if estimated creatinine clearance < 50 ml/min) • Magnesium and calcium ≥LLRR 12.No known significant impairment of intestinal absorption (e.g. chronic diarrhoea, inflammatory bowel disease) 13.Baseline ECG showing no evidence of established or acute ischaemic heart disease (e.g. left bundle branch block, pathological q waves, ST elevation or ST-segment depression) and normal clinical cardiovascular assessment |
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| E.4 | Principal exclusion criteria |
| If any of the following criteria apply, patients cannot be included in the trial: 1.Disease threatening mesorectal fascia (disease ≤ 1 mm from mesorectal fascia whether this is primary tumour, extra-mural vascular invasion or tumour deposit with irregular border and mixed signal intensity) 2.Stage T4b cancer with invasion into adjacent organs or structures 3.Enlarged pelvic sidewall lymph nodes 4.Distant metastases 5.Severe local bowel symptoms of tenesmus, frequency (at least baseline grade 3 diarrhoea) or incontinence that have not been relieved by a defunctioning colostomy/ileostomy 6.Pelvic sepsis 7.Metallic colonic/ rectal stent in situ 8.Patient who has received previous pelvic radiotherapy 9.Patient with an uncontrolled infection 10.Pregnant, breast feeding or trying to conceive 11.Previous treatment with another investigational antitumoral therapy in the 30 days prior to beginning treatment (including chemotherapy, irradiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloproteinase inhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibodies, or other experimental drugs) 12.Patients with another previous or current malignant disease which in the judgement of the treating investigator is likely to interfere with treatment or assessment of response 13.Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrollment/randomization 14.History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan 15.Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment 16.Previous malignancies in the preceding five years except for: •In situ cancer of the uterine cervix •Adequately treated basal cell skin carcinoma •Any early stage malignancy |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To assess whether or not it is feasible to introduce eight weeks of oxaliplatin/5-FU (OxMdG) chemotherapy prior to SCPRT then immediate surgery. This will be measured by calculating the proportion of patients who commence neoadjuvant chemotherapy who then undergo surgical resection of their rectal cancer. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint is the proportion of patients which undergo surgical resection and is assessed at resection. |
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| E.5.2 | Secondary end point(s) |
| Secondary end points include the following; • Feasibility: • Achieved dose intensity for chemotherapy and radiotherapy [assessed at end of treatment] • Patient recruitment in terms of refusal rates of eligible patients to enter the trial [assessed at registration] • Safety: • NCI CTCAE version 4 toxicities including postoperative complication rate (up to 30 days postoperatively) [assessed at end of treatment] • Late toxicity assessment at 1 year following radiotherapy • Activity: • Histological assessment of downstaging efficacy in the resected specimen including the percentage of patients exhibiting a pathological complete response (pCR), T and N stage compared to the pre-treatment MRI scan, tumour regression grade and tumour cell density measurement [assessed at resection] • Radiological assessment of downstaging efficacy comparing baseline MRI with 9-week post-chemotherapy MRI including T and N stage and tumour regression grade [assessed at 9 week MRI] • Local recurrence-free, distant metastasis-free, disease-free, and overall survival at 12 months following surgery |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 15 |
| 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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| For the purpose of the MHRA, the end of the trial is defined as the date of the last protocol treatment visit for the last participant undergoing protocol treatment. The protocol treatment phase will be followed by a follow-up period which will continue for one year after surgery.For the purposes of the Research Ethics Committee approval, the study end date is deemed to be the date of last data capture. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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