Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL)

This study has been completed.
Sponsor:
Information provided by:
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00154102
First received: September 8, 2005
Last updated: June 13, 2014
Last verified: June 2014
  Purpose

Drugs used against cancer 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. Giving combination chemotherapy together with cetuximab as first treatment after diagnosis of a metastatic colorectal cancer ('1st-line' treatment) may improve the treatment efficacy. However, it is not yet known whether giving combination chemotherapy together with cetuximab is more effective than combination chemotherapy alone. This open-label trial investigates the effectiveness of cetuximab in combination with a standard and effective chemotherapy (5-Fluorouracil (5FU)/Folinic acid (FA) plus irinotecan) for metastatic colorectal cancer in first-line setting, compared to the same chemotherapy alone on patient expressing the epidermal growth factor (EGF) receptor.

Patients expressing this EGF Receptor will be randomly assign in one of the 2 groups to either receive the combination chemotherapy alone or with cetuximab (open-label study) and will then be treated until progression of the disease or unacceptable toxicity occur. Regular efficacy assessments (every 8 weeks) based on imaging will be performed throughout the study together with regular safety assessments (e.g. safety labs). An independent Safety Board of experts will also monitor safety data.

After participant discontinuation from the trial, regular updates on further treatments and survival status will be requested from the investigator.

The entire study (from the first patient entering the study to the last collect of follow-up information) is 4-5 years long.


Condition Intervention Phase
Epidermal Growth Factor Receptor (EGFR) Expressing Metastatic Colorectal Cancer
Drug: Cetuximab
Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open, Randomized, Controlled, Multicenter Phase III Study Comparing 5FU/ FA Plus Irinotecan Plus Cetuximab Versus 5FU/FA Plus Irinotecan as First-line Treatment for Epidermal Growth Factor Receptor-expressing Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Progression-free Survival (PFS) Time - Independent Review Committee (IRC) Assessments [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]

    Duration from randomization until radiological progression (based on modified World Health Organisation (WHO) criteria) or death due to any cause.

    Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.


  • Progression-free Survival Time (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) - Independent Review Committee (IRC) Assessments [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]

    Duration from randomization until radiological progression (based on modified WHO criteria) or death due to any cause.

    Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.


  • Progression-free Survival Time (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]

    Duration from randomization until radiological progression (based on modified WHO criteria) or death due to any cause.

    Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.



Secondary Outcome Measures:
  • Overall Survival Time (OS) [ Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009 ] [ Designated as safety issue: No ]
    Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is later.

  • Overall Survival Time (KRAS Wild-Type Population) [ Time Frame: Time from randomisation to death or last day known to be alive reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009 ] [ Designated as safety issue: No ]
    Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is later.

  • Overall Survival Time (KRAS Mutant Population) [ Time Frame: Time from randomisation to death or last day known to be alive reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009 ] [ Designated as safety issue: No ]
    Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is later.

  • Best Overall Response Rate - Independent Review Committee (IRC) Assessments [ Time Frame: evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]
    The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).

  • Best Overall Response Rate (KRAS Wild-Type Population) - Independent Review Committee (IRC) Assessments [ Time Frame: evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]
    The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).

  • Best Overall Response Rate (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments [ Time Frame: evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]
    The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).

  • Disease Control Rate - Independent Review Committee (IRC) Assessments [ Time Frame: Evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]
    The disease control rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments (based on modified WHO criteria).

  • Duration of Response - Independent Review Committee (IRC) Assessments [ Time Frame: Time from first assessment of complete response or partial response to disease progression, death or last tumor assessment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]

    Time from first assessment of Complete Response or Partial Response to disease progression or death (within 60 days of last tumor assessment).

    Patients without event are censored on the date of last tumor assessment. Tumor assessments based on modified WHO criteria.


  • Participants With No Residual Tumor After Metastatic Surgery [ Time Frame: time from first dose up to 30 days after last dose of study treatment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 30 Nov 2007 ] [ Designated as safety issue: No ]
    Participants with no residual tumor after on-study surgery for metastases

  • Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status [ Time Frame: at baseline, at week 8, at week 16, at week 24, at week 32, and at week 40, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]
    Mean global health status scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL.

  • Quality of Life Assessment (EORTC QLQ-C30) Social Functioning [ Time Frame: at baseline, at week 8, at week 16, at week 24, at week 32, and at week 40, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006 ] [ Designated as safety issue: No ]
    Mean social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a higher level of functioning.

  • Safety - Number of Patients Experiencing Any Adverse Event [ Time Frame: time from first dose up to 30 days after last dose of study treatment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 30 Nov 2007 ] [ Designated as safety issue: Yes ]
    Please refer to Adverse Events section for further details


Enrollment: 1221
Study Start Date: May 2004
Study Completion Date: March 2011
Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cetuximab Plus FOLFIRI Drug: Cetuximab
Cetuximab intravenous infusion of 400mg/m^2 for the first infusion then weekly intravenous infusion of 250mg/m^2. Number of Cycles: until progression or unacceptable toxicity develops
Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)
Bi-weekly Irinotecan infusion of 180mg/m^2, Folinic Acid infusion of 400mg/m^2 (racemic) or 200mg/m^2 (L-form), 5-Fluorouracil bolus of 400mg/m^2 followed by a 46-hour continuous infusion of 2400mg/m^2 Number of Cycles: until progression or unacceptable toxicity develops
Active Comparator: FOLFIRI Alone Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)
Bi-weekly Irinotecan infusion of 180mg/m^2, Folinic Acid infusion of 400mg/m^2 (racemic) or 200mg/m^2 (L-form), 5-Fluorouracil bolus of 400mg/m^2 followed by a 46-hour continuous infusion of 2400mg/m^2 Number of Cycles: until progression or unacceptable toxicity develops

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum
  • Inoperable metastatic disease
  • Immunohistochemical evidence of epidermal growth factor receptor expression in tumor tissue
  • Presence of at least 1 bi-dimensionally measurable index lesion

Exclusion Criteria:

  • Previous irinotecan-based chemotherapy
  • Previous chemotherapy for colorectal cancer except adjuvant treatment if terminated more than 6 months before the start of study treatment
  • Radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30 days before the start of study treatment
  • Brain metastasis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00154102

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Sponsors and Collaborators
Merck KGaA
Investigators
Principal Investigator: Eric van Cutsem, Professor University Hospital Gasthuisberg, Department Internal Medicine, Leuven, Belgium
  More Information

Publications:
Lang I, Kohne CH, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Zubel A, Van Cutsem E Cetuximab plus FOLFIRI in 1st-line treatment of metastatic colorectal cancer: Quality of life (QoL) analysis of patients (pts) with KRAS wild-type (wt) tumours in the CRYSTAL trial. European Journal of Cancer Supplements. 2009 7(2):345

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Monika Foerster, Merck Serono
ClinicalTrials.gov Identifier: NCT00154102     History of Changes
Other Study ID Numbers: EMR 62202-013
Study First Received: September 8, 2005
Results First Received: November 30, 2010
Last Updated: June 13, 2014
Health Authority: Belgium: Federal Agency for Medicines and Health Products, FAMHP

Keywords provided by Merck KGaA:
Metastatic colorectal cancer
EGFR
Irinotecan
cetuximab
first-line treatment

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Irinotecan
Cetuximab
Leucovorin
Folic Acid
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances

ClinicalTrials.gov processed this record on August 28, 2014