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

Colorectal Cancer Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00182715
• Other study ID #: CDR0000440085
• Secondary ID: UKM-MRC-COIN-CR1
• Status: Active, not recruiting
• Phase: Phase 3
• First received: September 15, 2005
• Last updated: September 16, 2013
• Start date: March 2005

Study information

• Verified date: December 2007
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 2421
• Est. primary completion date: May 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Biological:
• cetuximab

Drug:
• capecitabine

• fluorouracil

• leucovorin calcium

• oxaliplatin

Locations

Country	Name	City	State
Ireland	Mercy University Hospital	Cork
Ireland	Adelaide and Meath Hospital, Dublin Incorporating the National Children's Hospital	Dublin
Ireland	Beaumont Hospital	Dublin
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	Mater Private Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	St. Vincent's University Hospital	Dublin
Ireland	Galway University Hospital	Galway
Ireland	Mid-Western Cancer Centre at Mid-Western Regional Hospital	Limerick
Ireland	Waterford Regional Hospital	Waterford
United Kingdom	Aberdeen Royal Infirmary	Aberdeen	Scotland
United Kingdom	North Hampshire Hospital	Basingstoke	England
United Kingdom	Belfast City Hospital Trust Incorporating Belvoir Park Hospital	Belfast	Northern Ireland
United Kingdom	Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	Birmingham	England
United Kingdom	Blackpool Victoria Hospital	Blackpool	England
United Kingdom	Royal Bournemouth Hospital NHS Trust	Bournemouth	England
United Kingdom	Bradford Royal Infirmary	Bradford	England
United Kingdom	Sussex Cancer Centre at Royal Sussex County Hospital	Brighton	England
United Kingdom	Bristol Haematology and Oncology Centre	Bristol	England
United Kingdom	Queen's Hospital	Burton-upon-Trent	England
United Kingdom	West Suffolk Hospital	Bury St. Edmunds	England
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United Kingdom	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales
United Kingdom	Cumberland Infirmary	Carlisle	England
United Kingdom	Cheltenham General Hospital	Cheltenham	England
United Kingdom	Essex County Hospital	Colchester	England
United Kingdom	Derbyshire Royal Infirmary	Derby	England
United Kingdom	Dorset County Hospital	Dorchester	England
United Kingdom	Hairmyres Hospital	East Kilbride	Scotland
United Kingdom	Eastbourne District General Hospital	Eastbourne	England
United Kingdom	Edinburgh Cancer Centre at Western General Hospital	Edinburgh	Scotland
United Kingdom	Princess Alexandra Hospital	Essex	England
United Kingdom	St. Luke's Cancer Centre at Royal Surrey County Hospital	Guildford	England
United Kingdom	Huddersfield Royal Infirmary	Huddersfield, West Yorks	England
United Kingdom	Princess Royal Hospital at Hull and East Yorkshire NHS Trust	Hull	England
United Kingdom	Hinchingbrooke Hospital	Huntingdon	England
United Kingdom	Raigmore Hospital	Inverness	Scotland
United Kingdom	Cookridge Hospital	Leeds	England
United Kingdom	Aintree University Hospital	Liverpool	England
United Kingdom	Cancer Research UK Clinical Groups at Guy's King's & St. Thomas' Hospitals	London	England
United Kingdom	Charing Cross Hospital	London	England
United Kingdom	Hammersmith Hospital	London	England
United Kingdom	Helen Rollason Cancer Care Centre at North Middlesex Hospital	London	England
United Kingdom	Queen Elizabeth Hospital - Woolwich	London	England
United Kingdom	Royal Free and University College Medical School	London	England
United Kingdom	Royal Marsden - London	London	England
United Kingdom	Saint Bartholomew's Hospital	London	England
United Kingdom	St. George's Hospital	London	England
United Kingdom	St. Mary's Hospital	London	England
United Kingdom	University College of London Hospitals	London	England
United Kingdom	Southport and Formby District General Hospital	Merseyside	England
United Kingdom	St. Mary's Hospital	Newport	England
United Kingdom	North Tyneside Hospital	North Shields	England
United Kingdom	Northampton General Hospital NHS Trust	Northampton	England
United Kingdom	Mount Vernon Cancer Centre at Mount Vernon Hospital	Northwood	England
United Kingdom	Nottingham City Hospital NHS Trust	Nottingham	England
United Kingdom	Peterborough Hospitals Trust	Peterborough	England
United Kingdom	Derriford Hospital	Plymouth	England
United Kingdom	Poole Hospital NHS Trust	Poole Dorset	England
United Kingdom	Portsmouth Oncology Centre at Saint Mary's Hospital	Portsmouth Hants	England
United Kingdom	Whiston Hospital	Prescot Merseyside	England
United Kingdom	Royal Preston Hospital	Preston	England
United Kingdom	Glan Clwyd Hospital	Rhyl, Denbighshire	Wales
United Kingdom	Conquest Hospital	Saint Leonards-on-Sea	England
United Kingdom	Salisbury District Hospital	Salisbury	England
United Kingdom	Scarborough General Hospital	Scarborough	England
United Kingdom	South Tyneside District Hospital	South Shields	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	University Hospital of North Staffordshire	Stoke-On-Trent	England
United Kingdom	Sunderland Royal Hospital	Sunderland	England
United Kingdom	Royal Marsden - Surrey	Sutton	England
United Kingdom	South West Wales Cancer Institute	Swansea	Wales
United Kingdom	Great Western Hospital	Swindon	England
United Kingdom	Torbay Hospital	Torquay	England
United Kingdom	Royal Cornwall Hospital	Truro, Cornwall	England
United Kingdom	Walsall Manor Hospital	Walsall	England
United Kingdom	Good Hope Hospital Trust	West Midlands	England
United Kingdom	Royal Hampshire County Hospital	Winchester	England
United Kingdom	Worcester Royal Hospital	Worcester	England
United Kingdom	Worthing Hospital	Worthing	England
United Kingdom	Wrexham Maelor Hospital	Wrexham	Wales
United Kingdom	Yeovil District Hospital	Yeovil	England

Sponsors (1)

Lead Sponsor	Collaborator
Velindre NHS Trust

Countries where clinical trial is conducted

Ireland,  United Kingdom, 

References & Publications (4)

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. — View Citation

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 — View Citation

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.

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 Investigat — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival at 2 years			No
Secondary	Progression-free survival at 2 years			No
Secondary	Failure-free survival at 2 years			No
Secondary	Response by RECIST criteria at 12 and 24 weeks			No
Secondary	Toxicity by NCI Common Toxicity Criteria version 3 throughout treatment and at follow-up			Yes
Secondary	Time of disease control at 2 years			No