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Sequential Versus Combination Chemotherapy in Advanced Colorectal Carcinoma

Primary Purpose

Advanced Colorectal Cancer

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
capecitabine-irinotecan
capecitabine+irinotecan (1st line)
Sponsored by
Dutch Colorectal Cancer Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Colorectal Cancer focused on measuring colorectal, cancer, capecitabine, irinotecan, oxaliplatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    1Capecitabine-irinotecan

    2capecitabine plus irinotecan

    Arm Description

    1st line- 2nd line (3rd line oxaliplatin plus capecitabine)

    1st line (2nd line oxaliplatin plus capecitabine)

    Outcomes

    Primary Outcome Measures

    Overall survival

    Secondary Outcome Measures

    Tumour response
    Progression free survival
    Quality of life
    Toxicity profile

    Full Information

    First Posted
    April 5, 2006
    Last Updated
    September 5, 2008
    Sponsor
    Dutch Colorectal Cancer Group
    Collaborators
    Koningin Wilhelmina Fonds, Sanofi, Hoffmann-La Roche
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00312000
    Brief Title
    Sequential Versus Combination Chemotherapy in Advanced Colorectal Carcinoma
    Official Title
    A Randomised Study of Sequential Versus Combination Chemotherapy in Patients With Previously Untreated Advanced Colorectal Carcinoma
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2008
    Overall Recruitment Status
    Completed
    Study Start Date
    January 2003 (undefined)
    Primary Completion Date
    February 2006 (Actual)
    Study Completion Date
    December 2006 (Actual)

    3. Sponsor/Collaborators

    Name of the Sponsor
    Dutch Colorectal Cancer Group
    Collaborators
    Koningin Wilhelmina Fonds, Sanofi, Hoffmann-La Roche

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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.
    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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Advanced Colorectal Cancer
    Keywords
    colorectal, cancer, capecitabine, irinotecan, oxaliplatin

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    820 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    1Capecitabine-irinotecan
    Arm Type
    Active Comparator
    Arm Description
    1st line- 2nd line (3rd line oxaliplatin plus capecitabine)
    Arm Title
    2capecitabine plus irinotecan
    Arm Type
    Experimental
    Arm Description
    1st line (2nd line oxaliplatin plus capecitabine)
    Intervention Type
    Drug
    Intervention Name(s)
    capecitabine-irinotecan
    Intervention Description
    st line capecitabine 1250 mg/m2 orally b.i.d. on day 1-14 nd line q 3 w irinotecan 350 mg/m2 IV infusion on day 1
    Intervention Type
    Drug
    Intervention Name(s)
    capecitabine+irinotecan (1st line)
    Intervention Description
    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
    Primary Outcome Measure Information:
    Title
    Overall survival
    Time Frame
    study duration
    Secondary Outcome Measure Information:
    Title
    Tumour response
    Time Frame
    study duration
    Title
    Progression free survival
    Time Frame
    study duration
    Title
    Quality of life
    Time Frame
    study duration
    Title
    Toxicity profile
    Time Frame
    study duration

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    C. J. A. Punt, Prof.Dr.
    Organizational Affiliation
    University Medical Center St. Radboud, Nijmegen, The Netherlands
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    16873425
    Citation
    Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Akkermans-Vogelaar JM, Punt CJ. Randomised study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer, an interim safety analysis. A Dutch Colorectal Cancer Group (DCCG) phase III study. Ann Oncol. 2006 Oct;17(10):1523-8. doi: 10.1093/annonc/mdl179. Epub 2006 Jul 27.
    Results Reference
    result
    PubMed Identifier
    17630036
    Citation
    Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. doi: 10.1016/S0140-6736(07)61086-1.
    Results Reference
    result
    PubMed Identifier
    23692811
    Citation
    van Kessel CS, Samim M, Koopman M, van den Bosch MA, Borel Rinkes IH, Punt CJ, van Hillegersberg R. Radiological heterogeneity in response to chemotherapy is associated with poor survival in patients with colorectal liver metastases. Eur J Cancer. 2013 Jul;49(11):2486-93. doi: 10.1016/j.ejca.2013.03.027. Epub 2013 May 18.
    Results Reference
    derived
    Links:
    URL
    http://www.dccg.nl
    Description
    site of the Dutch Colorectal Cancer Group

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    Sequential Versus Combination Chemotherapy in Advanced Colorectal Carcinoma

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