A Phase III trial comparing either COntinuous chemotherapy plus cetuximab or INtermittent chemotherapy with standard continuous palliative combination chemotherapy with oxaliplatin and a fluoropyrimidine in first line treatment of metastatic colorectal cancer

ISRCTN	ISRCTN27286448
DOI	https://doi.org/10.1186/ISRCTN27286448
EudraCT/CTIS number	2004-002951-16
ClinicalTrials.gov number	NCT00182715
Secondary identifying numbers	CR10

Submission date: 09/08/2004
Registration date: 22/10/2004
Last edited: 19/10/2018

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/a-trial-looking-at-treatment-for-advanced-bowel-cancer

Study website

Contact information

Prof Tim Maughan
Scientific

Wales Cancer Network Co-ordinating Office
Velindre Hospital
Whitchurch
Cardiff
CF4 7XL
United Kingdom

Study information

Study design	Randomised controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Scientific title	A Phase III trial comparing either COntinuous chemotherapy plus cetuximab or INtermittent chemotherapy with standard continuous palliative combination chemotherapy with oxaliplatin and a fluoropyrimidine in first line treatment of metastatic colorectal cancer
Study acronym	COIN
Study objectives	This randomized phase III trial is studying combination chemotherapy and cetuximab to see how well they work compared to combination chemotherapy alone as first-line therapy in treating patients with metastatic colorectal cancer. More details can be found at: http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=10
Ethics approval(s)	Not provided at time of registration.
Health condition(s) or problem(s) studied	Metastatic colorectal cancer
Intervention	Chemotherapy The Oxaliplatin regimens used in the trial can be selected on a per patient basis, but prior to knowledge of the treatment randomisation. This conforms with the NICE guidance regarding allowing patient choice with respect to oral or intravenous (IV) therapy. Some centres may be subject to practical constraints such that only one of the regimens will be feasible. In this case the centre may make a policy that all patients treated in that centre will receive one or other regimen. There is no data yet to indicate that one regimen is superior to the other. The regimen will be either: OxMdG: a combination of folinic acid (200 mg/m^2 IV over 2 h), concurrent administration of Oxaliplatin (85 mg/m^2 IV over 2 h) plus bolus 5FU (400 mg/m^2) followed by a 46 hour IV infusion of 5FU 2400 mg/m^2 repeated every 2 weeks. or: XELOX: a combination of Capecitabine plus Oxaliplatin: Oxaliplatin 130 mg/m^2 IV over 2 hours day 1, plus Capecitabine 1000 mg/m^2 twice a day (bd), orally (po) days 1-14 repeated 3 weekly. Treatment duration and breaks Arm A: Continuous chemotherapy (Control Arm): These patients will continue the chemotherapy regimen (with dose reductions as required) until progressive disease is identified on radiological grounds (RECIST), or the development of cumulative toxicity or because of patient choice to stop chemotherapy. Patients in this arm should continue on treatment with no more than a three week interval off treatment for any reason. The cumulative toxicity that is most likely to occur is the neuropathy associated with Oxaliplatin, which increases in incidence from about 7 months duration of therapy. If this occurs, patients may continue on the fluoropyrimidine component of the regimen with dose increment until evidence of disease progression. If the neuropathy resolves to < grade 1 the Oxaliplatin may be reintroduced cautiously at the investigator's discretion. These patients will be evaluated with 12 weekly computed tomography (CT) scans to assess radiological evidence of progression. Arm B: Continuous chemotherapy plus Cetuximab: These patients will continue chemotherapy plus Cetuximab as Arm A above. Cetuximab will be continued if chemotherapy is stopped because of toxicity or patient choice, but should be discontinued on evidence of disease progression or unacceptable Cetuximab toxicity. These patients will be evaluated with 12 weekly CT scans to assess radiological evidence of progression. Arm C: Intermittent chemotherapy: These patients will be treated for 12 weeks. Chemotherapy will then stop and they will be monitored clinically, at least 6 weekly, and with CT scans at 12 weekly intervals. On evidence of progression of disease using RECIST criteria or on clinical evidence of deterioration, the same chemotherapy will be restarted, for a further 12 weeks course. At that point treatment will again be interrupted. Patients with chemo-sensitive disease may have an unlimited number of 12-week treatments alternating with treatment breaks. When the patient demonstrates resistance to this treatment as evidenced by progressive disease during a period on chemotherapy or clinical choice, they will move on to second-line therapy or supportive care.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase III
Drug / device / biological / vaccine name(s)	Various
Primary outcome measure	Not provided at time of registration.
Secondary outcome measures	Not provided at time of registration.
Overall study start date	01/08/2003
Completion date	01/08/2005

Eligibility

Participant type(s)	Patient
Age group	Not Specified
Sex	Both
Target number of participants	Added 10/03/2011: 2421 (2015 achieved)
Key inclusion criteria	1. Confirmed colorectal adenocarcinoma: - either previous or current histologically confirmed primary adenocarcinoma of colon or rectum, together with clinical or radiological evidence of advanced and/or metastatic disease - or histologically/cytologically confirmed metastatic adenocarcinoma, together with clinical and/or radiological evidence of colorectal primary tumour 2. Inoperable metastatic or locoregional disease. Patients who are currently eligible for combination first-line chemotherapy prior to liver resection under National Institute for Clinical Excellence (NICE) guidance are ineligible for this study. 3. Unidimensionally measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST]) 4. No previous systemic palliative chemotherapy for metastatic disease 5. Adjuvant chemotherapy with 5-Fluorouracil (5FU) +/- folinic acid (FA), Capecitabine or irinotecan may have been given, if completed >6 months prior to trial entry 6. Rectal chemoradiotherapy with 5FU +/- FA may have been given, if completed >1 month prior to trial entry 7. World Health Organistion (WHO) performance status (PS) 0, 1 or 2 and considered by responsible consultant to be fit to undergo combination chemotherapy 8. Baseline laboratory tests (within 1 week prior to randomisation): White blood cell count (WBC) ≥4 x 10^9/l, neutrophils ≥1.5 x 10^9/l and platelet count >150 x 10^9/l. Serum bilirubin ≤1.25 x upper limit of normal (ULN), alkaline phosphatase ≤5 x ULN, and serum transaminase (either aspartate transaminase [AST] or alanine transaminase [ALT]) ≤3 x ULN. Estimated creatinine clearance >50 ml/min or measured glomerular filtration rate (GFR) (ethylene diamine tetraacetic acid [EDTA] clearance) >50 ml/min. 9. For women of childbearing potential, negative pregnancy test and adequate contraceptive precautions 10. Consent to allow surplus pathological material to be analysed for epidermal growth factor receptor (EGFR) testing
Key exclusion criteria	1. Patients who are unfit for the chemotherapy regimens in this protocol e.g. Severe uncontrolled concurrent medical illness (including poorly-controlled angina or very recent myocardial infarction [MI], i.e. in previous 3 months) likely to interfere with protocol treatments 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 Partial or complete bowel obstruction Pre-existing neuropathy (>grade 1) 2. Patients requiring ongoing treatment with a contraindicated concomitant medication 3. Patients with another previous or current malignant disease which, in the judgement of the treating investigator, is likely to interfere with COIN treatment or assessment of response
Date of first enrolment	01/08/2003
Date of final enrolment	01/08/2005

Locations

Countries of recruitment

United Kingdom
Wales

Study participating centre

Wales Cancer Network Co-ordinating Office

Cardiff
CF4 7XL
United Kingdom

Sponsor information

Medical Research Council (UK)
Research council

20 Park Crescent
London
W1B 1AL
United Kingdom

Phone	+44 (0)20 7636 5422
Email	clinical.trial@headoffice.mrc.ac.uk
"ROR"	https://ror.org/03x94j517

Funders

Funder type

Charity

The trial is funded by Cancer Research UK and Medical Research Council (MRC), via the Clinical Trials Advisory and Awards Committee (CTAAC). The CRUK grant award reference number is C1210-A4528

No information available

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

Study outputs

Output type	Details	Date created	Peer reviewed?	Patient-facing?
Plain English results			No	Yes
Other publications	review	01/08/2008	Yes	No
Results article	toxicity results	27/01/2009	Yes	No
Results article	phase 3 results	18/06/2011	Yes	No
Results article	results	25/09/2012	Yes	No

Editorial Notes

19/10/2018: Cancer Research UK lay results summary link added to Results (plain English)