Combination Chemotherapy With or Without Cetuximab Before and After Surgery in Treating Patients With Resectable Liver Metastases Caused By Colorectal Cancer

Sponsor

University of Southampton (Other)

Overall Status

Unknown status

CT.gov ID

NCT00482222

Collaborator

University Hospital Southampton NHS Foundation Trust (Other)

340

Enrollment

Locations

Arms

15.5

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, fluorouracil, leucovorin, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Giving combination chemotherapy together with monoclonal antibodies before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. It is not yet known whether combination chemotherapy is more effective with or without cetuximab in treating liver metastases caused by colorectal cancer.

PURPOSE: This randomized phase III trial is studying combination chemotherapy to compare how well it works when given with or without cetuximab before and after surgery in treating patients with resectable liver metastases caused by colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic Cancer	Biological: cetuximab Drug: capecitabine Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Other: study of socioeconomic and demographic variables Procedure: adjuvant therapy Procedure: neoadjuvant therapy Procedure: quality-of-life assessment	Phase 3

Detailed Description

OBJECTIVES:

Primary

Compare progression-free survival of patients with resectable colorectal liver metastases treated with neoadjuvant and adjuvant combination chemotherapy with vs without cetuximab.

Secondary

Compare the overall survival of patients treated with these regimens.
Compare the quality of life of patients treated with these regimens.
Compare the cost effectiveness of these regimens in these patients.

OUTLINE: This is a prospective, randomized, multicenter, open-label study. Patients are stratified according to participating center and assigned chemotherapy regimen. Patients are randomized to 1 of 2 treatment arms.

Neoadjuvant therapy:
Arm I: Patients receive 1 of the following chemotherapy regimens:
OxMdG: Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
CAPOX: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Arm II: Patients receive 1 of the following regimens:
OxMdG + cetuximab: Patients receive cetuximab IV over 1-2 hours on day 1 and OxMdG chemotherapy as in arm I. Treatment repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
CAPOX + cetuximab: Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15 and CAPOX chemotherapy as in arm I. Treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Surgery: Beginning 2-6 weeks after completion of chemotherapy, patients in both arms undergo liver resection.
Adjuvant therapy: Beginning 4-8 weeks after completion of surgery, patients receive treatment (OxMdG or CAPOX with or without cetuximab) as in arm I or II of neoadjuvant therapy.
Arm I: Treatment with OxMdG repeats every 2 weeks for up to 6 courses and treatment with CAPOX repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Arm II: Treatment with OxMdG + cetuximab repeats every 2 weeks for up to 6 courses and treatment with CAPOX + cetuximab repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 12 weeks during chemotherapy, at completion of study treatment, every 3 months for 1 year, and then every 6 months thereafter.

Cost per life year and per quality-adjusted life year is assessed at baseline, every 12 weeks during treatment, and then at 3, 5, and 10 years.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

Study Design

Study Type:

Interventional

Anticipated Enrollment :

340 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Prospective Randomised Open Label Trial of Oxaliplatin/Fluoropyrimidine Versus Oxaliplatin/Fluoropyrimidine Plus Cetuximab Pre and Post Operatively in Patients With Resectable Colorectal Liver Metastasis Requiring Chemotherapy

Study Start Date :

Feb 1, 2007

Anticipated Primary Completion Date :

Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: OxMdG / IrMdG chemotherapy OxMdG / IrMdG chemotherapy for 12 weeks Followed by surgery OxMdG / IrMdG chemotherapy for 12 weeks	Drug: capecitabine Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Other: study of socioeconomic and demographic variables Procedure: adjuvant therapy Procedure: neoadjuvant therapy Procedure: quality-of-life assessment
Experimental: OxMdG / IrMdG chemotherapy with cetuximab OxMdG / IrMdG chemotherapy with cetuximab for 12 weeks Followed by Surgery OxMdG / IrMdG chemotherapy with cetuximab for 12 weeks	Biological: cetuximab Drug: capecitabine Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Other: study of socioeconomic and demographic variables Procedure: adjuvant therapy Procedure: neoadjuvant therapy Procedure: quality-of-life assessment

Arm

Intervention/Treatment

Active Comparator: OxMdG / IrMdG chemotherapy

OxMdG / IrMdG chemotherapy for 12 weeks Followed by surgery OxMdG / IrMdG chemotherapy for 12 weeks

Drug: capecitabine

Drug: fluorouracil

Drug: leucovorin calcium

Drug: oxaliplatin

Other: study of socioeconomic and demographic variables

Procedure: adjuvant therapy

Procedure: neoadjuvant therapy

Procedure: quality-of-life assessment

Experimental: OxMdG / IrMdG chemotherapy with cetuximab

OxMdG / IrMdG chemotherapy with cetuximab for 12 weeks Followed by Surgery OxMdG / IrMdG chemotherapy with cetuximab for 12 weeks

Biological: cetuximab

Drug: capecitabine

Drug: fluorouracil

Drug: leucovorin calcium

Drug: oxaliplatin

Other: study of socioeconomic and demographic variables

Procedure: adjuvant therapy

Procedure: neoadjuvant therapy

Procedure: quality-of-life assessment

Outcome Measures

Primary Outcome Measures

Progression-free survival [end of study]

Secondary Outcome Measures

Response rate before surgery as assessed by RECIST criteria [end of study]
Pathological resection status [end of study]
Overall survival [end of study]
Toxicity [end of study]
Quality of life as assessed by the EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LMC21 [end of study]
Cost effectiveness [end of study]
Safety [end of study]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically* or radiologically confirmed primary adenocarcinoma of the colon or rectum
Advanced and/or metastatic disease NOTE: *Liver metastases should not be biopsied
Must have potentially resectable liver metastases present, as defined by any of the following:
Metachronous metastases AND complete resection of the primary tumor without gross or microscopic evidence of residual disease (R0)
Synchronous metastases AND R0 resection of the primary tumor > 1 month before study entry
Synchronous metastases with sufficient evidence (e.g., by CT scan or diagnostic laparoscopy) that both the primary tumor and the liver metastases can be completely resected during the same procedure and resection of primary tumor can be delayed for 3-4 months
Suboptimally resectable disease (i.e., potentially resectable disease with compromise of the resection margins)
No detectable extrahepatic tumor that cannot be completely resected
Unidimensionally measurable disease
No brain metastases

PATIENT CHARACTERISTICS:

WHO performance status 0-2
WBC ≥ 4,000/mm³
ANC ≥ 1,500/mm³
Platelet count > 150,000/mm³
Bilirubin ≤ 1.25 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 5 times ULN
AST or ALT ≤ 3 times ULN
Creatinine clearance > 50 mL/min OR glomerular filtration rate > 50 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment
No psychiatric or neurological condition that would preclude study compliance
No partial or complete bowel obstruction
No preexisting neuropathy > grade 1
No other prior or concurrent malignant disease that, in the opinion of the investigator, would preclude study treatment
No concurrent severe uncontrolled medical illness (including poorly-controlled angina or myocardial infarction within the past 3 months) that would preclude study treatment
No known hypersensitivity reaction to any of the components of the study drugs

PRIOR CONCURRENT THERAPY:

No prior systemic chemotherapy for metastatic disease
More than 6 months since prior adjuvant chemotherapy comprising fluorouracil, leucovorin calcium, capecitabine, or irinotecan hydrochloride
More than 1 month since prior rectal chemoradiotherapy comprising fluorouracil and leucovorin calcium
No concurrent contraindicated medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Basildon University Hospital	Basildon	England	United Kingdom	SS16 5NL
2	Basingstoke and North Hampshire NHS Foundation Trust	Basingstoke	England	United Kingdom	RG24 9NA
3	Royal Bournemouth Hospital	Bournemouth	England	United Kingdom	BH7 7DW
4	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 0QQ
5	St. Luke's Cancer Centre at Royal Surrey County Hospital	Guildford	England	United Kingdom	GU2 7XX
6	Aintree University Hospital	Liverpool	England	United Kingdom	L9 7AL
7	Royal Liverpool University Hospital	Liverpool	England	United Kingdom	L9 7AL
8	Saint Bartholomew's Hospital	London	England	United Kingdom	EC1A 7BE
9	UCL Cancer Institute	London	England	United Kingdom	NW3 2PF
10	Royal Marsden - London	London	England	United Kingdom	SW3 6JJ
11	Charing Cross Hospital	London	England	United Kingdom	W6 8RF
12	Clatterbridge Centre for Oncology	Merseyside	England	United Kingdom	CH63 4JY
13	St. Mary's Hospital	Newport	England	United Kingdom	PO30 5TG
14	Cancer Research Centre at Weston Park Hospital	Nottingham	England	United Kingdom	NG5 1PB
15	Dorset Cancer Centre	Poole Dorset	England	United Kingdom	BH15 2JB
16	Salisbury District Hospital	Salisbury	England	United Kingdom	SP2 8BJ
17	Southampton General Hospital	Southampton	England	United Kingdom	SO16 6YD
18	Royal Marsden - Surrey	Sutton	England	United Kingdom	SM2 5PT
19	Southend University Hospital NHS Foundation Trust	Westcliff-On-Sea	England	United Kingdom	SS0 0RY
20	Worthing Hospital	Worthing	England	United Kingdom	BN11 2DH
21	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales	United Kingdom	CF14 2TL
22	University Hospital of Wales	Cardiff	Wales	United Kingdom	CF14 4XW