A Phase II study of chemotherapy given before radiotherapy as treatment for patients with rectal cancer

ISRCTN	ISRCTN10052456
DOI	https://doi.org/10.1186/ISRCTN10052456
EudraCT/CTIS number	2010-023083-40
ClinicalTrials.gov number	NCT01263171
Secondary identifying numbers	11709

Submission date: 17/05/2012
Registration date: 17/05/2012
Last edited: 24/01/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://cancerhelp.cancerresearchuk.org/trials/trial-looking-chemotherapy-people-rectal-cancer-copernicus

Contact information

Dr Ruby AL-Mokhtar
Scientific

Cardiff University
Neuadd Meirionnydd
Heath Park
Cardiff
CF14 4YS
United Kingdom

Email	al-mokhtarr@cardiff.ac.uk

Study information

Study design	Non-randomised interventional treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	A Phase II study of neoadjuvant chemotherapy given before short course of preoperative radiotherapy (SCPRT) as treatment for patients with MRI-staged operable rectal cancer at high risk of metastatic relapse
Study acronym	COPERNICUS
Study objectives	Approximately 15,000 patients are diagnosed with rectal cancer in the UK per annum, 4800 of which would be considered operable. The current standard of care for these patients, is to deliver a short course of preoperative radiotherapy (SCPRT) followed by immediate surgery and postoperative chemotherapy to prevent relapse. However, several studies have highlighted poor compliance due to postoperative surgical morbidity and reduced performance status. There is thus a strong argument to evaluate pre-operative chemotherapy in patients with operable rectal cancer in order to increase patient tolerance, achievable dose intensity and minimize micrometastases by addressing this issue earlier on in treatment. The overall aim of this study is to assess the feasibility of introducing eight weeks of oxaliplatin/5-Fluorouracil (OxMdG) chemotherapy prior to SCPRT and immediate surgery. Feasibility will be assessed as the percentage of patients undergoing surgery as well as assessing; the dose intensity achieved, treatment toxicities, postoperative morbidity/mortality and activity using histological measures of response in the resected specimen. If deemed to be feasible, the Phase II treatment regime will be taken forward to a Phase III trial where it will be compared against standard practice of SCPRT alone followed by immediate surgery.
Ethics approval(s)	Research Ethics Committee for Wales, ref: 12/WA/0051
Health condition(s) or problem(s) studied	Colorectal cancer
Intervention	Neoadjuvant chemotherapy, Patients who have enrolled into the COPERNICUS study will be treated with four, two weekly cycles of oxaliplatin and fluorouracil prior to short course pre-operative radiotherapy followed by surgical removal of the tumour and adjuvant chemotherapy.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Fluorouracil, oxaliplatin
Primary outcome measure	The proportion of patients who commence neoadjuvant chemotherapy who then undergo surgical resection
Secondary outcome measures	1. Acute and late toxicity 2. Histological assessment of downstaging efficacy
Overall study start date	01/05/2012
Completion date	14/04/2015

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	UK Sample Size: 62
Key inclusion criteria	1. Patient 18 years old or older 2. Tumour biopsy with histopathological confirmation of rectal adenocarcinoma 3. Inferior aspect of disease (primary tumour, mesorectal tumour deposits or extra-mural vascular invasion) is not less than 4 cm from anal verge on digital examination and pelvic MRI scan 4. Superior aspect of disease is not more superior than the anterior aspect of the S1/S2 interspace on pelvic sagittal MRI scan 5. Further MRI defined inclusion criteria include: Mesorectal fascia is not threatened or involved (i.e. tumour is > 1mm from mesorectal fascia) Primary tumour is: T3a-b (mesorectal primary tumour invasion seen = 5 mm beyond muscularis propria) in the presence of either: 5.1. Extra-mural vascular invasion or 5.2. Mesorectal lymph nodes(s)/tumour deposit(s) with irregular border or 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 (i.e. there is >1 mm gap between tumour and levator ani) or anal sphincters 6. No evidence of established metastatic disease on CT of chest and abdomen. (Patients with equivocal lesions determined at MDT are eligible) 7. Patient with measurable disease at the baseline visit 8. The patient is a candidate for systemic therapy with OxMdG chemotherapy in the opinion of the primary oncologist treating the patient 9. ECOG Status: 0-1 10. Bloods: Adequate bone marrow, hepatic, renal and metabolic function (assessed within 14 days prior to consent): 10.1. Haemoglobin = 9 g/dL, leucocyte count = 3 x 109/L, neutrophil count =1.5 x109/L and platelet count =100 x109/L 10.2. Total bilirubin = 1.5 x ULRR, alkaline phosphatase = 5 x ULRR, and serum transaminase (either AST or ALT) =2.5 x ULRR 10.3. 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) 10.4. Calcium =LLRR 11. No known significant impairment of intestinal absorption (e.g. chronic diarrhoea, inflammatory bowel disease) 12. 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 13. Note, a defunctioning colostomy or ileostomy is permitted to relieve impending rectal obstruction or severe local bowel symptoms 14. Lower age limit 18 years
Key exclusion criteria	1. Disease threatening the mesorectal fascia (i.e. disease = 1 mm from mesorectal fascia whether this is primary tumour, extra-mural vascular invasion or tumour deposit with irregular border or mixed signal intensity) 2. Stage T4b cancer with invasion into adjacent organs or structures 3. Enlarged pelvic sidewall (internal iliac) lymph nodes considered to be involved 4. Unequivocal evidence of metastatic disease (includes resectable 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, 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 the 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 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
Date of first enrolment	01/05/2012
Date of final enrolment	01/04/2013

Locations

Countries of recruitment

United Kingdom
Wales

Study participating centre

Cardiff University

Cardiff
CF14 4YS
United Kingdom

Sponsor information

Cardiff University (UK)
University/education

30-36 Newport Road
Cardiff
CF24 0DE
Wales
United Kingdom

Website	http://www.cardiff.ac.uk/
"ROR"	https://ror.org/03kk7td41

Funders

Funder type

Charity

Cancer Research UK
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results				No	No
Results article	results	01/09/2018	11/04/2019	Yes	No
Plain English results			24/01/2022	No	Yes
HRA research summary			28/06/2023	No	No

Editorial Notes

24/01/2022: A link to plain English results was added.
23/07/2019: The overall trial end date has been changed from 01/04/2013 to 14/04/2015.
11/04/2019: Publication reference added.
04/07/2018: Added link to basic results (scientific)