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

January 22, 2013 updated by: University of Southampton

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

340

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • England
      • Basildon, England, United Kingdom, SS16 5NL
        • Recruiting
        • Basildon University Hospital
        • Contact:
          • Pauline Leonard, MD
          • Phone Number: 44-1702-435-555
      • Basingstoke, England, United Kingdom, RG24 9NA
        • Recruiting
        • Basingstoke and North Hampshire NHS Foundation Trust
        • Contact:
          • Charlotte Rees, MD
          • Phone Number: 44-125-631-4793
      • Bournemouth, England, United Kingdom, BH7 7DW
        • Recruiting
        • Royal Bournemouth Hospital
        • Contact:
      • Cambridge, England, United Kingdom, CB2 0QQ
      • Guildford, England, United Kingdom, GU2 7XX
        • Recruiting
        • St. Luke's Cancer Centre at Royal Surrey County Hospital
        • Contact:
          • Sharadah Essapen, MD
          • Phone Number: 44-1483-571-122
      • Liverpool, England, United Kingdom, L9 7AL
      • Liverpool, England, United Kingdom, L9 7AL
        • Recruiting
        • Royal Liverpool University Hospital
        • Contact:
          • Paula Ghaneh, MD
      • London, England, United Kingdom, SW3 6JJ
        • Recruiting
        • Royal Marsden - London
        • Contact:
          • David Cunningham, MD
          • Phone Number: 44-20-8661-3156
      • London, England, United Kingdom, EC1A 7BE
        • Recruiting
        • Saint Bartholomew's Hospital
      • London, England, United Kingdom, W6 8RF
        • Recruiting
        • Charing Cross Hospital
        • Contact:
      • London, England, United Kingdom, NW3 2PF
        • Recruiting
        • UCL Cancer Institute
        • Contact:
      • Merseyside, England, United Kingdom, CH63 4JY
        • Recruiting
        • Clatterbridge Centre for Oncology
      • Newport, England, United Kingdom, PO30 5TG
        • Recruiting
        • St. Mary's Hospital
        • Contact:
          • Christopher Baughan, MD
          • Phone Number: 44-1983-524-081
      • Nottingham, England, United Kingdom, NG5 1PB
        • Recruiting
        • Cancer Research Centre at Weston Park Hospital
        • Contact:
          • J. Hornbuckle, MD
          • Phone Number: 44-115-969-1169 ext. 47599
      • Poole Dorset, England, United Kingdom, BH15 2JB
        • Recruiting
        • Dorset Cancer Centre
        • Contact:
          • Tamas Hickish, MD
          • Phone Number: 44-1202-442-532
      • Salisbury, England, United Kingdom, SP2 8BJ
        • Recruiting
        • Salisbury District Hospital
      • Southampton, England, United Kingdom, SO16 6YD
        • Recruiting
        • Southampton General Hospital
        • Contact:
      • Sutton, England, United Kingdom, SM2 5PT
        • Recruiting
        • Royal Marsden - Surrey
      • Westcliff-On-Sea, England, United Kingdom, SS0 0RY
        • Recruiting
        • Southend University Hospital NHS Foundation Trust
        • Contact:
          • Pauline Leonard, MD
          • Phone Number: 44-1702-435-555
      • Worthing, England, United Kingdom, BN11 2DH
        • Recruiting
        • Worthing Hospital
        • Contact:
          • Andrew Webb, MD
          • Phone Number: 44-1903-205-111
    • Wales
      • Cardiff, Wales, United Kingdom, CF14 2TL
        • Recruiting
        • Velindre Cancer Center at Velindre Hospital
        • Contact:
          • Timothy Maughan, MD
          • Phone Number: 44-2920-316-904
      • Cardiff, Wales, United Kingdom, CF14 4XW
        • Recruiting
        • University Hospital of Wales
        • Contact:
          • Timothy Maughan, MD
          • Phone Number: 44-2920-316-904

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Progression-free survival
Time Frame: end of study
end of study

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Southampton

Collaborators

University Hospital Southampton NHS Foundation Trust

Investigators

  • Study Chair: John N. Primrose, MD, University Hospital Southampton NHS Foundation Trust

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2007

Primary Completion (Anticipated)

December 1, 2014

Study Registration Dates

First Submitted

June 4, 2007

First Submitted That Met QC Criteria

June 4, 2007

First Posted (Estimate)

June 5, 2007

Study Record Updates

Last Update Posted (Estimate)

January 23, 2013

Last Update Submitted That Met QC Criteria

January 22, 2013

Last Verified

April 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000549541
  • USCTU-4351
  • USCTU-EPOC
  • EUDRACT-2006-003121-82
  • ISRCTN22944367
  • EU-20732

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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