Combination Chemotherapy and Cetuximab as First-Line Therapy in Treating Patients With Advanced and/or Metastatic Colorectal Cancer

September 15, 2021 updated by: Cheryl Pugh

A Two-arm Phase II Randomised Trial of Intermittent Chemotherapy Plus Continuous Cetuximab and of Intermittent Chemotherapy Plus Intermittent Cetuximab in First Line Treatment of Patients With K-ras-normal (Wild-type) Metastatic Colorectal Cancer

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. 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 giving combination chemotherapy together with intermittent cetuximab is more effective than combination chemotherapy given together with continuous cetuximab in treating colorectal cancer.

PURPOSE: This randomized phase II trial is studying giving combination chemotherapy together with intermittent cetuximab to see how well it works compared to combination chemotherapy given together with continuous cetuximab as first-line therapy in treating patients with advanced or metastatic colorectal cancer.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • To compare the activity, in terms of failure-free survival, of patients with K-ras-normal (wild type) advanced and/or metastatic colorectal cancer treated with intermittent combination chemotherapy comprising oxaliplatin, leucovorin calcium, and fluorouracil (OxMdG) or oxaliplatin and capecitabine (XELOX) and intermittent vs continuous cetuximab as first-line therapy.
  • To compare the safety and feasibility of these regimens in these patients.

Secondary

  • To compare the safety of cetuximab reintroduction, in terms of frequency of grade 3-4 allergic reactions in these patients.
  • To compare improvement in disease control (i.e., complete response plus partial response plus stable disease) at 24 weeks in patients treated with these regimens.
  • To compare overall and progression-free survival of patients treated with these regimens.
  • To compare response rates at 12, 24, and 36 weeks in patients treated with these regimens.
  • To compare toxicity of these regimens in these patients.

OUTLINE: This is a multicenter study. Patients are randomised to 1 of 2 treatment arms.

  • Arm I (intermittent chemotherapy and intermittent cetuximab): Patients receive 1 of the following combination chemotherapy and cetuximab regimens:

    • OxMdG: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Patients also receive cetuximab IV over 1-2 hours on days 1 and 8. Treatment repeats every 14 days for up to 6 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.
    • XELOX (for patients with line-related problems): Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-15 (28 doses). Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.

After completion of 12 weeks of study therapy, patients with disease progression are removed from study. Patients with stable or responding disease stop treatment with OxMdG or XELOX and cetuximab and undergo clinical evaluation at least every 6 weeks until disease progression or clinical deterioration. Upon evidence of disease progression or clinical deterioration, patients restart treatment with OxMdG or XELOX and cetuximab as before and continue to alternate 12 weeks of treatment with treatment breaks in the absence of disease progression or unacceptable toxicity. Patients with disease progression during study therapy stop treatment and proceed to second-line therapy or best supportive care.

  • Arm II (intermittent chemotherapy and continuous cetuximab): Patients receive OxMdG or XELOX and cetuximab for 12 weeks as in arm I. Patients with disease progression after 12 weeks of study therapy are removed from study. Patients with stable or responding disease* after 12 weeks of study therapy stop treatment with OxMdG or XELOX and continue treatment with cetuximab weekly as monotherapy in the absence of disease progression or unacceptable toxicity. Patients undergo clinical evaluation as in arm I. Upon progression, patients restart treatment with OxMdG or XELOX and continue cetuximab, as before, alternating 12 weeks of combined OxMdG or XELOX and cetuximab therapy with cetuximab monotherapy. Patients with disease progression during study therapy stop treatment and proceed to second-line therapy as in arm I.

Previously collected tumor tissue samples are obtained at baseline and analyzed by IHC for EGFR status of tumor.

After completion of study treatment, patients are followed every 12 weeks.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Study Type

Interventional

Enrollment (Actual)

169

Phase

  • Phase 2

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

  • Cyprus
      • Nicosia, Cyprus
        • Bank Of Cyprus Oncology Centre
  • United Kingdom
      • Bath, United Kingdom
        • Royal United Hospital
      • Bournemouth, United Kingdom
        • Royal Bournemouth Hospital
      • Cambridge, United Kingdom
        • Addenbrookes Hospital
      • Dartford, United Kingdom
        • Darent Valley Hospital
      • Hereford, United Kingdom
        • Hereford County Hospital
      • London, United Kingdom
        • Charing Cross Hospital
      • London, United Kingdom
        • Guys and St Thomas' Hospitals
      • Poole, United Kingdom
        • Dorset Cancer Centre, Poole Hospital
      • Sheffield, United Kingdom, S10 2SJ
        • Weston Park
      • Southport, United Kingdom
        • Southport and Ormskirk
      • St Helens, United Kingdom
        • St Helens and Whiston hospitals
      • Warrington, United Kingdom
        • Warrington and Halton Hospitals
      • Worcester, United Kingdom
        • Worcestershire Royal Hospital
    • England
      • Bradford, England, United Kingdom, BD9 6RJ
        • Bradford Royal Infirmary
      • Cheltenham, England, United Kingdom, GL53 7AN
        • Gloucestershire Oncology Centre at Cheltenham General Hospital
      • Colchester, England, United Kingdom, C03 3NB
        • Essex County Hospital
      • Dorchester, England, United Kingdom, DT1 2JY
        • Dorset County Hospital
      • Guildford, England, United Kingdom, GU2 7XX
        • St. Luke's Cancer Centre at Royal Surrey County Hospital
      • London, England, United Kingdom, W12 OHS
        • Hammersmith Hospital
      • London, England, United Kingdom, W2 1NY
        • St. Mary's Hospital
      • Oxford, England, United Kingdom, OX3 7LJ
        • Churchill Hospital
      • Peterborough, England, United Kingdom, PE3 6DA
        • Peterborough Hospitals Trust
      • Stoke-On-Trent, England, United Kingdom, ST4 7LN
        • University Hospital of North Staffordshire
    • Wales
      • Swansea, Wales, United Kingdom, SA2 8QA
        • Singleton Hospital

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 to 100 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Diagnosis of colorectal adenocarcinoma, defined by 1 of the following:

    • Prior or current histologically confirmed primary adenocarcinoma of colon or rectum with clinical or radiological evidence of advanced and/or metastatic disease
    • Histologically and cytologically confirmed metastatic adenocarcinoma with clinical and/or radiological evidence of colorectal primary tumor
  • Unidimensionally measurable disease by RECIST criteria

  • Inoperable metastatic or locoregional disease

    • Potentially resectable liver metastases allowed provided the following criteria are met:

      • Fewer than 4 unilobar liver metastases, each < 4 cm in size and without major vascular involvement
      • No combination chemotherapy allowed prior to the planned resection of operable liver metastases
  • No confirmed K-ras mutation of tumor after screening
  • No brain metastases

PATIENT CHARACTERISTICS:

  • WHO performance status 0-2
  • Must be considered fit to undergo combination chemotherapy
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Serum bilirubin ≤ 1.25 times upper limit of normal (ULN)
  • Alkaline phosphatase ≤ 5 times ULN
  • AST or ALT ≤ 2.5 times ULN
  • Creatinine clearance ≥ 50mL/min OR glomerular filtration rate ≥ 50 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No severe uncontrolled concurrent medical illness (including poorly controlled angina or myocardial infarction within the past 12 weeks) likely to interfere with protocol treatments
  • No psychiatric or neurological condition that would preclude study compliance with oral medication or giving informed consent
  • No partial or complete bowel obstruction
  • No preexisting neuropathy > grade 1
  • No prior or current malignant disease which, in the judgement of the treating investigator, is likely to interfere with COIN-B treatment or assessment of response
  • No patients with known hypersensitivity reactions to any of the components of the study treatments
  • No proven dihydropyrimidine dehydrogenase deficiency (DPD) or personal or family history of DPD

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No prior systemic palliative chemotherapy for metastatic disease
  • No prior oxaliplatin
  • More than 1 month since prior adjuvant chemotherapy comprising fluorouracil (with or without leucovorin calcium), capecitabine, or irinotecan hydrochloride
  • More than 1 month since prior chemoradiotherapy comprising fluorouracil (with or without leucovorin calcium) or capecitabine for rectal cancer
  • No ongoing requirement for contraindicated concurrent medication
  • No concurrent enrollment in any type of study other than observational studies

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: D
Intermittent chemotherapy plus intermittent cetuximab treatment comprising 12 weeks of chemotherapy plus cetuximab followed by a period off all therapy, with reintroduction of the same chemotherapy and cetuximab regimen for a further 12 weeks after initial progression off treatment
Drug: fluorouracil
Drug: leucovorin calcium
Other: laboratory biomarker analysis
Drug: oxaliplatin
Drug: capecitabine
Other: immunohistochemistry staining method
Biological: cetuximab
Experimental: E
Intermittent chemotherapy plus continuous cetuximab treatment comprising 12 weeks of chemotherapy plus cetuximab followed by a period of withdrawal of the chemotherapy, but continued weekly cetuximab monotherapy (maintenance cetuximab), with reintroduction of the same chemotherapy regimen to the cetuximab for a further 12 weeks after initial progression off chemotherapy treatment
Drug: fluorouracil
Drug: leucovorin calcium
Other: laboratory biomarker analysis
Drug: oxaliplatin
Drug: capecitabine
Other: immunohistochemistry staining method
Biological: cetuximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Failure-free survival at 10 months
Time Frame: 10 months
10 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Safety of cetuximab reintroduction, in terms of risk of grade 3-4 allergic reactions
Time Frame: 12, 24 and 36 weeks
12, 24 and 36 weeks
Proportion of patients achieving disease control (complete response plus partial response plus stable disease) at 24 weeks
Time Frame: 24 weeks
24 weeks
Overall survival
Time Frame: at 12, 24 and 36 weeks
at 12, 24 and 36 weeks
Progression-free survival
Time Frame: at 12, 24 and 36 weeks
at 12, 24 and 36 weeks
Response rates
Time Frame: at 12, 24 and 36 weeks
at 12, 24 and 36 weeks
Toxicity of each treatment regimen by NCI CTCAE v3.0
Time Frame: at 12, 24 and 36 weeks
at 12, 24 and 36 weeks

Collaborators and Investigators

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

Sponsor

Cheryl Pugh

Investigators

  • Principal Investigator: Harpreet S. Wasan, Hammersmith Hospitals NHS Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

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

July 1, 2007

Primary Completion (Actual)

June 1, 2010

Study Completion (Actual)

September 1, 2015

Study Registration Dates

First Submitted

March 19, 2008

First Submitted That Met QC Criteria

March 19, 2008

First Posted (Estimate)

March 20, 2008

Study Record Updates

Last Update Posted (Actual)

September 22, 2021

Last Update Submitted That Met QC Criteria

September 15, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000589635
  • MRC-CTU-COIN-B/CR11
  • EUDRACT:2006-003049-17
  • ISRCTN38375681
  • EU-20828
  • MERCK-MRC-CTU-COIN-B/CR11

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Publication

Study Data/Documents

  1. Clinical Study Report

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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