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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Epidermal Growth Factor Receptor (EGFR) Expressing Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Cetuximab
* Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab Plus FOLFIRI<br> | Drug: Cetuximab<br>* 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<br>Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)<br>* 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<br>|
| Active Comparator: FOLFIRI Alone<br> | Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Time - Independent Review Committee (IRC) Assessments | 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. | 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 | 
| Progression-free Survival Time (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) - Independent Review Committee (IRC) Assessments | 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. | 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 | 
| Progression-free Survival Time (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time (OS) | 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. | 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 | 
| Overall Survival Time (KRAS Wild-Type Population) | 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. | 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 | 
| Overall Survival Time (KRAS Mutant Population) | 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. | 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 | 
| Best Overall Response Rate - Independent Review Committee (IRC) Assessments | 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). | 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 | 
| Best Overall Response Rate (KRAS Wild-Type Population) - Independent Review Committee (IRC) Assessments | 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). | 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 | 
| Best Overall Response Rate (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments | 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). | 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 | 
| Disease Control Rate - Independent Review Committee (IRC) Assessments | 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). | 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 | 
| Duration of Response - Independent Review Committee (IRC) Assessments | 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. | 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 | 
| Participants With No Residual Tumor After Metastatic Surgery | Participants with no residual tumor after on-study surgery for metastases | 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 | 
| Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | 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. | 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 | 
| Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | 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. | 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 | 
| Safety - Number of Patients Experiencing Any Adverse Event | Please refer to Adverse Events section for further details | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic colorectal cancer, EGFR, Irinotecan, cetuximab, first-line treatment