Clinical trial NCT00482222: Combination Chemotherapy With or Without Cetuximab Before and After Surgery in Treating Patients With Resectable Liver Metastases Caused By Colorectal Cancer
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Colorectal Cancer
Metastatic Cancer
Keywords: adenocarcinoma of the colon
stage IV colon cancer
adenocarcinoma of the rectum
stage IV rectal cancer
liver metastases
recurrent colon cancer
recurrent rectal cancer
Lead sponsor: University of Southampton
Sponsor class: OTHER
Collaborators: name: University Hospital Southampton NHS Foundation Trust
First posted: 2007-06-05
Enrollment: 340
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free survival
timeFrame: end of study
Secondary outcomes:
measure: Response rate before surgery as assessed by RECIST criteria
timeFrame: end of study
measure: Pathological resection status
timeFrame: end of study
measure: Overall survival
timeFrame: end of study
measure: Toxicity
timeFrame: end of study
measure: Quality of life as assessed by the EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LMC21
timeFrame: end of study
measure: Cost effectiveness
timeFrame: end of study
measure: Safety
timeFrame: end of study
Other outcomes:
Locations:
city: Basildon
country: United Kingdom
facility: Basildon University Hospital
state: England
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire NHS Foundation Trust
state: England
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Guildford
country: United Kingdom
facility: St. Luke's Cancer Centre at Royal Surrey County Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: UCL Cancer Institute
state: England
city: London
country: United Kingdom
facility: Royal Marsden - London
state: England
city: London
country: United Kingdom
facility: Charing Cross Hospital
state: England
city: Merseyside
country: United Kingdom
facility: Clatterbridge Centre for Oncology
state: England
city: Newport
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Cancer Research Centre at Weston Park Hospital
state: England
city: Poole Dorset
country: United Kingdom
facility: Dorset Cancer Centre
state: England
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Westcliff-On-Sea
country: United Kingdom
facility: Southend University Hospital NHS Foundation Trust
state: England
city: Worthing
country: United Kingdom
facility: Worthing Hospital
state: England
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velindre Hospital
state: Wales
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
Study officials:
affiliation: University Hospital Southampton NHS Foundation Trust
name: John N. Primrose, MD
role: STUDY_CHAIR
References: