Combination Chemotherapy With or Without Cetuximab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer

September 16, 2013 updated by: Velindre NHS Trust

A Three-Arm Randomised Controlled 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 (COIN)

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether combination chemotherapy and cetuximab are more effective than combination chemotherapy alone in treating colorectal cancer.

PURPOSE: 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.

Study Overview

Status

Unknown

Conditions

Colorectal Cancer

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

Compare the overall survival of patients with metastatic colorectal adenocarcinoma treated with continuous combination chemotherapy comprising oxaliplatin, leucovorin calcium, and fluorouracil (OxMdG) or oxaliplatin and capecitabine (XELOX) with vs without cetuximab vs intermittent combination chemotherapy with OxMdG or XELOX as first-line therapy.

Secondary

Compare time of disease control and progression- and failure-free survival of patients treated with these regimens.
Compare response in patients treated with these regimens.
Compare the toxicity of these regimens in these patients.
Compare the cost effectiveness of these regimens in these patients.
Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a multicenter, open label, randomized, controlled study. Patients are randomized to 1 of 3 treatment arms.

Arm I (continuous chemotherapy): Patients receive 1 of the following combination chemotherapy regimens of their choice (or as per participating center):
- OxMdG: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1 and 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
- XELOX: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Arm II (continuous chemotherapy and cetuximab): Patients receive OxMdG or XELOX as in arm I. Patients also receive cetuximab IV over 1-2 hours on days 1 and 8 (for patients receiving OxMdG) OR days 1, 8, and 15 (for patients receiving XELOX). Treatment with OxMdG and cetuximab repeats every 14 days in the absence of disease progression or unacceptable toxicity. Treatment with XELOX and cetuximab repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Arm III (intermittent chemotherapy): Patients receive OxMdG or XELOX as in arm I. Treatment with OxMdG repeats every 14 days for up to 6 courses (12 weeks). Treatment with XELOX repeats every 21 days for up to 4 courses (12 weeks). Patients with disease progression after 12 weeks of therapy are removed from study treatment. Patients with stable or responding disease after 12 weeks of therapy stop treatment and undergo clinical evaluation at least every 6 weeks (treatment break) until disease progression or clinical deterioration. Upon evidence of disease progression or clinical deterioration, patients restart treatment with OxMdG or XELOX as before and continue to alternate 12 weeks of treatment with treatment breaks in the absence of disease progression or unacceptable toxicity Quality of life is assessed at baseline, 6 weeks, 12 weeks, and then every 12 weeks thereafter.

After completion of study treatment, patients are followed every 12 weeks for survival.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 2,421 patients (807 per treatment arm) will be accrued for this study within 3.5 years.

Study Type

Interventional

Enrollment (Anticipated)

2421

Phase

Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Ireland
- - Cork, Ireland
    - Mercy University Hospital
  - Dublin, Ireland, 9
    - Beaumont Hospital
  - Dublin, Ireland, 7
    - Mater Misericordiae University Hospital
  - Dublin, Ireland, 4
    - St. Vincent'S University Hospital
  - Dublin, Ireland, 7
    - Mater Private Hospital
  - Dublin, Ireland, 24
    - Adelaide and Meath Hospital, Dublin Incorporating the National Children's Hospital
  - Dublin, Ireland, 8
    - St. James'S Hospital
  - Galway, Ireland
    - Galway University Hospital
  - Limerick, Ireland, 0009
    - Mid-Western Cancer Centre at Mid-Western Regional Hospital
  - Waterford, Ireland
    - Waterford Regional Hospital
United Kingdom
- England
  - Basingstoke, England, United Kingdom, RG24 9NA
    - North Hampshire Hospital
  - Birmingham, England, United Kingdom, B12 2TH
    - Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
  - Blackpool, England, United Kingdom, FY3 8NR
    - Blackpool Victoria Hospital
  - Bournemouth, England, United Kingdom, BH7 7DW
    - Royal Bournemouth Hospital NHS Trust
  - Bradford, England, United Kingdom, BD9 6RJ
    - Bradford Royal Infirmary
  - Brighton, England, United Kingdom, BN2 5BE
    - Sussex Cancer Centre at Royal Sussex County Hospital
  - Bristol, England, United Kingdom, BS2 8ED
    - Bristol Haematology and Oncology Centre
  - Burton-upon-Trent, England, United Kingdom, DE13 0RB
    - Queen's Hospital
  - Bury St. Edmunds, England, United Kingdom, IP33 2QZ
    - West Suffolk Hospital
  - Cambridge, England, United Kingdom, CB2 0QQ
    - Addenbrooke's Hospital
  - Carlisle, England, United Kingdom, CA2 7HY
    - Cumberland Infirmary
  - Cheltenham, England, United Kingdom, GL53 7AN
    - Cheltenham General Hospital
  - Colchester, England, United Kingdom, C03 3NB
    - Essex County Hospital
  - Derby, England, United Kingdom, DE1 2QY
    - Derbyshire Royal Infirmary
  - Dorchester, England, United Kingdom, DT1 2JY
    - Dorset County Hospital
  - Eastbourne, England, United Kingdom, BN21 2UD
    - Eastbourne District General Hospital
  - Essex, England, United Kingdom, CM20 1QX
    - Princess Alexandra Hospital
  - Guildford, England, United Kingdom, GU2 7XX
    - St. Luke's Cancer Centre at Royal Surrey County Hospital
  - Huddersfield, West Yorks, England, United Kingdom, HD3 3EA
    - Huddersfield Royal Infirmary
  - Hull, England, United Kingdom, HU8 9HE
    - Princess Royal Hospital at Hull and East Yorkshire NHS Trust
  - Huntingdon, England, United Kingdom, PE18 6NT
    - Hinchingbrooke Hospital
  - Leeds, England, United Kingdom, LS16 6QB
    - Cookridge Hospital
  - Liverpool, England, United Kingdom, L9 7AL
    - Aintree University Hospital
  - London, England, United Kingdom, SW17 0QT
    - St. George's Hospital
  - London, England, United Kingdom, EC1A 7BE
    - Saint Bartholomew's Hospital
  - London, England, United Kingdom, SW3 6JJ
    - Royal Marsden - London
  - London, England, United Kingdom, W6 8RF
    - Charing Cross Hospital
  - London, England, United Kingdom, W12 OHS
    - Hammersmith Hospital
  - London, England, United Kingdom, W2 1NY
    - St. Mary's Hospital
  - London, England, United Kingdom, NW1 2PG
    - University College of London Hospitals
  - London, England, United Kingdom, SE18 4QH
    - Queen Elizabeth Hospital - Woolwich
  - London, England, United Kingdom, SE5 9NU
    - Cancer Research UK Clinical Groups at Guy's King's & St. Thomas' Hospitals
  - London, England, United Kingdom, N18 1QX
    - Helen Rollason Cancer Care Centre at North Middlesex Hospital
  - London, England, United Kingdom, NW3 2PF
    - Royal Free and University College Medical School
  - Merseyside, England, United Kingdom, CH63 4JY
    - Southport and Formby District General Hospital
  - Newport, England, United Kingdom, PO30 5TG
    - St. Mary's Hospital
  - North Shields, England, United Kingdom, NE29 8NH
    - North Tyneside Hospital
  - Northampton, England, United Kingdom, NN6 8BJ
    - Northampton General Hospital NHS Trust
  - Northwood, England, United Kingdom, HA6 2RN
    - Mount Vernon Cancer Centre at Mount Vernon Hospital
  - Nottingham, England, United Kingdom, NG5 1PB
    - Nottingham City Hospital NHS Trust
  - Peterborough, England, United Kingdom, PE3 6DA
    - Peterborough Hospitals Trust
  - Plymouth, England, United Kingdom, PL6 8DH
    - Derriford Hospital
  - Poole Dorset, England, United Kingdom, BH15 2JB
    - Poole Hospital NHS Trust
  - Portsmouth Hants, England, United Kingdom, PO3 6AD
    - Portsmouth Oncology Centre at Saint Mary's Hospital
  - Prescot Merseyside, England, United Kingdom, L35 5DR
    - Whiston Hospital
  - Preston, England, United Kingdom, PR2 9HT
    - Royal Preston Hospital
  - Saint Leonards-on-Sea, England, United Kingdom, TN37 7RD
    - Conquest Hospital
  - Salisbury, England, United Kingdom, SP2 8BJ
    - Salisbury District Hospital
  - Scarborough, England, United Kingdom, YO12 6QL
    - Scarborough General Hospital
  - South Shields, England, United Kingdom, NE34 0PL
    - South Tyneside District Hospital
  - Southampton, England, United Kingdom, SO16 6YD
    - Southampton General Hospital
  - Stoke-On-Trent, England, United Kingdom, ST4 7LN
    - University Hospital of North Staffordshire
  - Sunderland, England, United Kingdom, SR4 7TP
    - Sunderland Royal Hospital
  - Sutton, England, United Kingdom, SM2 5PT
    - Royal Marsden - Surrey
  - Swindon, England, United Kingdom, SN3 6BB
    - Great Western Hospital
  - Torquay, England, United Kingdom, TQ2 7AA
    - Torbay Hospital
  - Truro, Cornwall, England, United Kingdom, TR1 3LJ
    - Royal Cornwall Hospital
  - Walsall, England, United Kingdom, WS2 9PS
    - Walsall Manor Hospital
  - West Midlands, England, United Kingdom, B75 7RR
    - Good Hope Hospital Trust
  - Winchester, England, United Kingdom, SO22 5DG
    - Royal Hampshire County Hospital
  - Worcester, England, United Kingdom, WR5 1DD
    - Worcester Royal Hospital
  - Worthing, England, United Kingdom, BN11 2DH
    - Worthing Hospital
  - Yeovil, England, United Kingdom, BA21 4AT
    - Yeovil District Hospital
- Northern Ireland
  - Belfast, Northern Ireland, United Kingdom, BT8 8JR
    - Belfast City Hospital Trust Incorporating Belvoir Park Hospital
- Scotland
  - Aberdeen, Scotland, United Kingdom, AB25 2ZN
    - Aberdeen Royal Infirmary
  - East Kilbride, Scotland, United Kingdom, G75 8RG
    - Hairmyres Hospital
  - Edinburgh, Scotland, United Kingdom, EH4 2XU
    - Edinburgh Cancer Centre at Western General Hospital
  - Inverness, Scotland, United Kingdom, 1V2 3UJ
    - Raigmore Hospital
- Wales
  - Cardiff, Wales, United Kingdom, CF14 2TL
    - Velindre Cancer Center at Velindre Hospital
  - Rhyl, Denbighshire, Wales, United Kingdom, LL 18 5UJ
    - Glan Clwyd Hospital
  - Swansea, Wales, United Kingdom, SA2 8QA
    - South West Wales Cancer Institute
  - Wrexham, Wales, United Kingdom, LL13 7TD
    - Wrexham Maelor Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

Diagnosis of colorectal adenocarcinoma, defined by 1 of the following:
- Histologically confirmed primary adenocarcinoma of the colon or rectum with clinical or radiological evidence of advanced and/or metastatic disease
- Histologically or cytologically confirmed metastatic adenocarcinoma with clinical or radiological evidence of primary colorectal tumor
Unidimensionally measurable disease
Inoperable metastatic or locoregional disease
- Ineligible for hepatic resection after first-line combination chemotherapy
No brain metastases

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

WHO 0-2

Life expectancy

Not specified

Hematopoietic

Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3

Hepatic

Bilirubin ≤ 1.25 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 5 times ULN
AST or ALT ≤ 2.5 times ULN

Renal

Creatinine clearance or glomerular filtration rate ≥ 50 mL/min

Cardiovascular

No poorly controlled angina
No myocardial infarction within the past 3 months

Other

Not pregnant
Negative pregnancy test
Fertile patients must use effective contraception
Must be considered fit to undergo combination chemotherapy
No psychiatric or neurological condition that would preclude study compliance or giving informed consent
No partial or complete bowel obstruction
No other malignant disease that would preclude study treatment
No preexisting neuropathy > grade 1
No known hypersensitivity reaction to any of the components of study drugs
No known DPD deficiency or personal or family history suggestiv of DPD deficiency
No other severe uncontrolled medical illness that would preclude study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

No prior systemic palliative chemotherapy for metastatic disease
No prior oxaliplatin
More than 1 month since prior adjuvant fluorouracil (5-FU) (with or without leucovorin calcium), capecitabine, or irinotecan
More than 1 month since prior rectal chemoradiotherapy with 5-FU (with or without leucovorin calcium) or capecitabine

Endocrine therapy

Not specified

Radiotherapy

See Chemotherapy

Surgery

Not specified

Other

No concurrent brivudine or sorivudine (for patients receiving capecitabine on study)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival at 2 years

Secondary Outcome Measures

Outcome Measure
Progression-free survival at 2 years
Failure-free survival at 2 years
Response by RECIST criteria at 12 and 24 weeks
Toxicity by NCI Common Toxicity Criteria version 3 throughout treatment and at follow-up
Time of disease control at 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Velindre NHS Trust

Investigators

Study Chair: Timothy Maughan, MD, Velindre NHS Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. doi: 10.1016/S1470-2045(11)70102-4. Epub 2011 Jun 5.
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. doi: 10.1016/S0140-6736(11)60613-2. Epub 2011 Jun 5.
Adams RA, Meade AM, Madi A, Fisher D, Kay E, Kenny S, Kaplan RS, Maughan TS. Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience. Br J Cancer. 2009 Jan 27;100(2):251-8. doi: 10.1038/sj.bjc.6604877.
Maughan T: Cetuximab (C), oxaliplatin (Ox) and fluoropyrimidine (Fp): toxicity during the first 12 weeks of treatment for the first 804 patients entered into the MRC COIN (CR10) trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-4070, 2007.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2005

Primary Completion (Anticipated)

May 1, 2009

Study Registration Dates

First Submitted

September 15, 2005

First Submitted That Met QC Criteria

September 15, 2005

First Posted (Estimate)

September 16, 2005

Study Record Updates

Last Update Posted (Estimate)

September 17, 2013

Last Update Submitted That Met QC Criteria

September 16, 2013

Last Verified

December 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

CDR0000440085
UKM-MRC-COIN-CR10
EU-20516
EUDRACT-2004-002951-16
ISRCTN27286448

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.