Sequential Versus Combination Chemotherapy in Advanced Colorectal Carcinoma

September 5, 2008 updated by: Dutch Colorectal Cancer Group

A Randomised Study of Sequential Versus Combination Chemotherapy in Patients With Previously Untreated Advanced Colorectal Carcinoma

Primary objective:To assess the efficacy, defined as overall survival, of sequential versus combination chemotherapy for advanced colorectal cancer (CRC).

Methodology Open, randomised multicenter phase III study. Randomisation by centre will be centralized. 820 patiënts with histologically proven advanced CRC; not amenable to curative surgery. Measurable or evaluable disease. Age 18 years and above. WHO performance status 0-2.

Test products:

Arm A: First line: capecitabine capecitabine 1250 mg/m2 orally b.i.d. on day 1-14 (q3),until progression or unacceptable toxicity. Second line: irinotecan 350 mg/m2 IV infusion on day 1 (q3),until progression or unacceptable toxicity. Third line: oxaliplatin 130 mg/m2 IV infusion on day 1 and capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (q3). Arm B: First line: irinotecan 250 mg/m2 IV infusion in 30 minutes on day 1 and capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (q3), until progression or unacceptable toxicity. Second line: oxaliplatin 130 mg/m2 IV on day 1 and capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (q3), until progression or unacceptable toxicity.

Patients will be followed by CT-scan every 9 weeks for response while on treatment, or at any other moment when progression is suspected. After cessation of chemotherapy, patients will be followed every 3 months until death. Clinical and laboratory toxicity/symptomatology will be graded according to NCI common criteria.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Objectives: Primary objective:

To assess the efficacy, defined as overall survival, of sequential versus combination chemotherapy for advanced CRC.

Secondary objectives are to assess:

To assess Tumour response (CR, PR or SD) Progression free survival Quality of life Toxicity profile Methodology Open, randomised multicenter phase III study. Randomisation by centre will be centralized by IKC. Number of patients 820 Main criteria for inclusion Histology and staging disease

  • Histologically proven advanced CRC; not amenable to curative surgery;
  • Of Note: In case of a single metastasis, histological or cytological proof of colorectal carcinoma should be obtained prior to randomisation.
  • Measurable or evaluable disease. Serum CEA as the only parameter for disease activity is not allowed.

General conditions

  • Written informed consent;
  • Age 18 years and above;
  • WHO performance status 0-2;
  • Adequate bone marrow function (WBC > 3.0 x 109/L, platelets > 100 x 109/L, Hb > 6 mmol/L);
  • Adequate hepatic function: total bilirubin < 1. 5 x upper normal limit, ASAT and ALAT < 3 x upper normal limits (in case of liver metastases < 5 x upper normal limits);
  • Adequate renal function: creatinin < 1. 5 x upper normal limits. Other
  • Expected adequacy of follow-up.

Main criteria for exclusion General conditions

  • Pregnancy or lactation;
  • Patients (M/F) with reproductive potential not implementing adequate contraceptives measures.

Prior or current history

  • Prior chemotherapy for advanced disease; prior adjuvant chemotherapy is allowed, provided that the last drug administration took place more than 6 months prior to randomisation.
  • Serious concomitant diseases preventing the safe administration of chemotherapy or likely to interfere with the study assessments;
  • Serious active infections;
  • Inflammatory bowel disease or other diseases associated with chronic diarrhoea;
  • Previous extensive irradiation of pelvis or abdomen;
  • Other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin.

Concomitant treatments

  • Concomitant (or within 4 weeks before randomisation) administration of any other experimental drug under investigation;
  • Concurrent treatment with any other anti-cancer therapy. Test product, dose and mode of administration Arm A First line: capecitabine

Every 3 weeks (q 3):

capecitabine 1250 mg/m2 orally b.i.d. on day 1-14. This schedule will be continued until progression or unacceptable toxicity. Continuation after 6 months without disease progression and/or severe toxicity at the investigator's discretion.

Second line: irinotecan

Every 3 weeks (q 3):

irinotecan 350 mg/m2 IV infusion on day 1. This schedule will be continued until progression or unacceptable toxicity. Continuation after 6 months without disease progression and/or severe toxicity at the investigator's discretion.

Third line: oxaliplatin plus capecitabine oxaliplatin 130 mg/m2 IV infusion on day 1 and capecitabine 1000 mg/m2 orally b.i.d. on day 1-14. This schedule will be continued until progression or unacceptable toxicity. Continuation after 6 months without disease progression and/or severe toxicity at the investigator's discretion.

Arm B First line: irinotecan plus capecitabine

Every 3 weeks (q 3):

irinotecan 250 mg/m2 IV infusion in 30 minutes on day 1 2 hours after discontinuation of the infusion followed by capecitabine 1000 mg/m2 orally b.i.d. on day 1-14. This schedule will be continued until progression or unacceptable toxicity. Continuation after 6 months without disease progression and/or severe toxicity at the investigator's discretion.

Second line: oxaliplatin plus capecitabine

Every 3 weeks (q 3):

oxaliplatin 130 mg/m2 IV infusion in 2 hours on day 1 and capecitabine 1000 mg/m2 orally b.i.d. on day 1-14. This schedule will be continued until progression or unacceptable toxicity. Continuation after 6 months without disease progression and/or severe toxicity at the investigator's discretion.

Duration of treatment and follow-up Treatment is continued until disease progression, or unacceptable toxicity. Patients will be followed by CT-scan every 9 weeks for response while on treatment, or at any other moment when progression is suspected. After cessation of chemotherapy, patients will be followed every 3 months until death. Death or progression should be reported whenever it occurs.

Criteria for evaluation Efficacy All patients will be included in the survival analysis (intent-to-treat). All patients receiving > 9 weeks of treatment (i.e. 3 cycles) will be considered evaluable for response, unless documented progression occurred earlier.

Safety profile Safety will be analysed in each treatment group. Patients having received > treatment doses are evaluable for toxicity. Evaluation will be performed by patient and by cycle on the intent-to-treat population. Clinical and laboratory toxicity/symptomatology will be graded according to NCI common criteria. The adverse events which are not reported in NCI common criteria will be graded as: mild, moderate, severe, life threatening.

Statistical methodology The expected median survival in Arm A (standard arm) is 14 months. It is anticipated that the median survival in Arm B (experimental arm) will be 19 months. 620 patients (310 in each arm) are needed to show this increase in median survival (>=0,05 and >=0,80).

Stratification parameters Patients will be stratified for the following parameters:

  • WHO performance status 0-1 vs 2
  • Serum LDH normal versus above normal
  • Prior adjuvant therapy versus no prior adjuvant therapy
  • Predominant localisation of metastases in the liver vs extrahepatic site(s)
  • Per participating institution

Study Type

Interventional

Enrollment (Actual)

820

Phase

  • Phase 3

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

Inclusion Criteria:

  • Histology and staging disease

    • Histologically proven CRC; advanced disease, not amenable to curative surgery;
    • Of Note: In case of a single metastasis, histological or cytological proof of colorectal carcinoma should be obtained prior to randomisation.
    • Measurable or evaluable disease; Serum CEA as the only parameter for disease activity is not allowed.

  • General conditions

    • Written informed consent;
    • Age 18 years and above;
    • WHO performance status 0-2;
    • Adequate bone marrow function(WBC > 3.0 x 109/L, platelets > 100 x 109/L, Hb > 6 mmol/L);
    • Adequate hepatic function: total bilirubin < 1. 5 x upper normal limit, ASAT and ALAT < 3 x upper normal limits; in case of liver metastases < 5 x upper normal limits
    • Adequate renal function: creatinin < 1. 5 x upper normal limits.
  • Other - Expected adequacy of follow-up.

Exclusion Criteria:

  • General conditions

    • Pregnancy or lactation;
    • Patients (M/F) with reproductive potential not implementing adequate contraceptives measures.

  • Prior or current history

    • Prior chemotherapy for advanced disease; prior adjuvant chemotherapy is allowed provided that the last administration was given > 6 months prior to randomisation.
    • Serious concomitant diseases preventing the safe administration of chemotherapy or likely to interfere with the study assessments;
    • Serious active infections;
    • Inflammatory bowel disease or other diseases associated with chronic diarrhoea;
    • Previous extensive irradiation of the pelvis or abdomen;
    • Other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin.

  • Concomitant treatments

    • Concomitant (or within 4 weeks before randomisation) administration of any other experimental drug under investigation;
    • Concurrent treatment with any other anti-cancer therapy.

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: 1Capecitabine-irinotecan
1st line- 2nd line (3rd line oxaliplatin plus capecitabine)
Drug: capecitabine-irinotecan
  1. st line capecitabine 1250 mg/m2 orally b.i.d. on day 1-14
  2. nd line q 3 w irinotecan 350 mg/m2 IV infusion on day 1
Experimental: 2capecitabine plus irinotecan
1st line (2nd line oxaliplatin plus capecitabine)
Drug: capecitabine+irinotecan (1st line)
q 3 w irinotecan 250 mg/m2 IV infusion in 30 minutes on day 1 2 hours after discontinuation of the infusion followed by capecitabine 1000 mg/m2 orally b.i.d. on day 1-14

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Overall survival
Time Frame: study duration
study duration

Secondary Outcome Measures

Outcome Measure
Time Frame
Quality of life
Time Frame: study duration
study duration
Tumour response
Time Frame: study duration
study duration
Progression free survival
Time Frame: study duration
study duration
Toxicity profile
Time Frame: study duration
study duration

Collaborators and Investigators

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

Sponsor

Dutch Colorectal Cancer Group

Collaborators

Sanofi
Hoffmann-La Roche
Koningin Wilhelmina Fonds

Investigators

  • Principal Investigator: C. J. A. Punt, Prof.Dr., University Medical Center St. Radboud, Nijmegen, The Netherlands

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.

General Publications

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

January 1, 2003

Primary Completion (Actual)

February 1, 2006

Study Completion (Actual)

December 1, 2006

Study Registration Dates

First Submitted

April 5, 2006

First Submitted That Met QC Criteria

April 5, 2006

First Posted (Estimate)

April 7, 2006

Study Record Updates

Last Update Posted (Estimate)

September 8, 2008

Last Update Submitted That Met QC Criteria

September 5, 2008

Last Verified

September 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CAIRO1

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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