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

Sponsor

Velindre NHS Trust (Other)

Overall Status

Unknown status

CT.gov ID

NCT00182715

Collaborator

(none)

2,421

Enrollment

Locations

29.5

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: cetuximab Drug: capecitabine Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

2421 participants

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Mar 1, 2005

Anticipated Primary Completion Date :

May 1, 2009

Outcome Measures

Primary Outcome Measures

Overall survival at 2 years []

Secondary Outcome Measures

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

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