Clinical trial NCT00182715: Combination Chemotherapy With or Without Cetuximab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer
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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
stage IV colon cancer
adenocarcinoma of the rectum
stage IV rectal cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2005-09-16
Enrollment: 2421
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Overall survival at 2 years
Secondary outcomes:
measure: Progression-free survival at 2 years
measure: Failure-free survival at 2 years
measure: Response by RECIST criteria at 12 and 24 weeks
measure: Toxicity by NCI Common Toxicity Criteria version 3 throughout treatment and at follow-up
measure: Time of disease control at 2 years
Other outcomes:
Locations:
city: Cork
country: Ireland
facility: Mercy University Hospital
city: Dublin
country: Ireland
facility: Adelaide and Meath Hospital, Dublin Incorporating the National Children's Hospital
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
city: Limerick
country: Ireland
facility: Mid-Western Cancer Centre at Mid-Western Regional Hospital
city: Waterford
country: Ireland
facility: Waterford Regional Hospital
city: Basingstoke
country: United Kingdom
facility: North Hampshire Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
state: England
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
state: England
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital NHS Trust
state: England
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: England
city: Brighton
country: United Kingdom
facility: Sussex Cancer Centre at Royal Sussex County Hospital
state: England
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Burton-upon-Trent
country: United Kingdom
facility: Queen's Hospital
state: England
city: Bury St. Edmunds
country: United Kingdom
facility: West Suffolk Hospital
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Carlisle
country: United Kingdom
facility: Cumberland Infirmary
state: England
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital
state: England
city: Colchester
country: United Kingdom
facility: Essex County Hospital
state: England
city: Derby
country: United Kingdom
facility: Derbyshire Royal Infirmary
state: England
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: England
city: Eastbourne
country: United Kingdom
facility: Eastbourne District General Hospital
state: England
city: Essex
country: United Kingdom
facility: Princess Alexandra Hospital
state: England
city: Guildford
country: United Kingdom
facility: St. Luke's Cancer Centre at Royal Surrey County Hospital
state: England
city: Huddersfield, West Yorks
country: United Kingdom
facility: Huddersfield Royal Infirmary
state: England
city: Hull
country: United Kingdom
facility: Princess Royal Hospital at Hull and East Yorkshire NHS Trust
state: England
city: Huntingdon
country: United Kingdom
facility: Hinchingbrooke Hospital
state: England
city: Leeds
country: United Kingdom
facility: Cookridge Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: Helen Rollason Cancer Care Centre at North Middlesex Hospital
state: England
city: London
country: United Kingdom
facility: University College of London Hospitals
state: England
city: London
country: United Kingdom
facility: Royal Free and University College Medical School
state: England
city: London
country: United Kingdom
facility: Queen Elizabeth Hospital - Woolwich
state: England
city: London
country: United Kingdom
facility: Cancer Research UK Clinical Groups at Guy's King's & St. Thomas' Hospitals
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: Royal Marsden - London
state: England
city: London
country: United Kingdom
facility: Hammersmith Hospital
state: England
city: London
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: London
country: United Kingdom
facility: Charing Cross Hospital
state: England
city: Merseyside
country: United Kingdom
facility: Southport and Formby District General Hospital
state: England
city: Newport
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: North Shields
country: United Kingdom
facility: North Tyneside Hospital
state: England
city: Northampton
country: United Kingdom
facility: Northampton General Hospital NHS Trust
state: England
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre at Mount Vernon Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital NHS Trust
state: England
city: Peterborough
country: United Kingdom
facility: Peterborough Hospitals Trust
state: England
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: England
city: Poole Dorset
country: United Kingdom
facility: Poole Hospital NHS Trust
state: England
city: Portsmouth Hants
country: United Kingdom
facility: Portsmouth Oncology Centre at Saint Mary's Hospital
state: England
city: Prescot Merseyside
country: United Kingdom
facility: Whiston Hospital
state: England
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
state: England
city: Saint Leonards-on-Sea
country: United Kingdom
facility: Conquest Hospital
state: England
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: England
city: Scarborough
country: United Kingdom
facility: Scarborough General Hospital
state: England
city: South Shields
country: United Kingdom
facility: South Tyneside District Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Stoke-On-Trent
country: United Kingdom
facility: University Hospital of North Staffordshire
state: England
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Swindon
country: United Kingdom
facility: Great Western Hospital
state: England
city: Torquay
country: United Kingdom
facility: Torbay Hospital
state: England
city: Truro, Cornwall
country: United Kingdom
facility: Royal Cornwall Hospital
state: England
city: Walsall
country: United Kingdom
facility: Walsall Manor Hospital
state: England
city: West Midlands
country: United Kingdom
facility: Good Hope Hospital Trust
state: England
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital
state: England
city: Worcester
country: United Kingdom
facility: Worcester Royal Hospital
state: England
city: Worthing
country: United Kingdom
facility: Worthing Hospital
state: England
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
state: England
city: Belfast
country: United Kingdom
facility: Belfast City Hospital Trust Incorporating Belvoir Park Hospital
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: East Kilbride
country: United Kingdom
facility: Hairmyres Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Edinburgh Cancer Centre at Western General Hospital
state: Scotland
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
state: Scotland
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velindre Hospital
state: Wales
city: Rhyl, Denbighshire
country: United Kingdom
facility: Glan Clwyd Hospital
state: Wales
city: Swansea
country: United Kingdom
facility: South West Wales Cancer Institute
state: Wales
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor Hospital
state: Wales
Study officials:
affiliation: Velindre NHS Trust
name: Timothy Maughan, MD
role: STUDY_CHAIR
References:
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 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.
citation: 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.
citation: 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.
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.