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Oxaliplatin and Cetuximab in First-line Treatment of Metastatic Colorectal Cancer (mCRC) (OPUS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00125034
First received: July 28, 2005
Last updated: August 23, 2011
Last verified: August 2011
History of Changes
Results First Received: August 23, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: Neoplasm Metastasis
Colorectal Cancer
Interventions: Biological: Cetuximab
Drug: Oxaliplatin

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First & last subject randomized: 27 Jul 2005 & 8 Mar 2006, respectively. Primary outcome and disease control rate cut-off dates 4 Aug 2006, others: 1 Mar 2007; except overall survival, KRAS overall survival and KRAS progression-free survival outcomes, metastatic surgery outcome and adverse events: 30 Nov 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
629 subjects were prescreened, of whom 344 subjects were randomised. 338 subjects (Safety Population) received treatment. One subject was erroneously randomized, and was excluded from the ITT population (337 subjects).

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Participant Flow:   Overall Study
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
STARTED     170 [1]   168 [2]
COMPLETED     170     168  
NOT COMPLETED     0     0  
[1] Randomized & treated. 1 subject was not randomized correctly and was excluded in the ITT population.
[2] Randomized & treated



  Baseline Characteristics
  Hide Baseline Characteristics

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
Total Total of all reporting groups

Baseline Measures
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone     Total  
Number of Participants  
[units: participants]
 		  169     168     337  
Age  
[units: participants]
 		     
<=18 years     0     0     0  
Between 18 and 65 years     96     109     205  
>=65 years     73     59     132  
Age  
[units: years]
Median ( Full Range ) 		  62.0  
  ( 24 to 82 )   		  60.0  
  ( 30 to 82 )   		  61.0  
  ( 24 to 82 )  
Gender  
[units: participants]
 		     
Female     80     76     156  
Male     89     92     181  
Region of Enrollment [1]
[units: participants]
 		     
Portugal     0     3     3  
Spain     19     16     35  
Ukraine     24     25     49  
Austria     16     9     25  
Russian Federation     25     24     49  
Israel     0     1     1  
Italy     8     6     14  
France     3     12     15  
Belgium     12     6     18  
Poland     30     31     61  
Romania     18     13     31  
Germany     14     22     36  
[1] Figures refer to randomized and treated participants



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Best Overall Response Rate - Independent Review Committee (IRC)   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006 ]

Measure Type Primary
Measure Title Best Overall Response Rate - Independent Review Committee (IRC)
Measure Description 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 World Health Organisation (WHO) criteria) as assessed by an IRC.
Time Frame Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary analysis on the Intent to Treat (ITT) population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  169     168  
Best Overall Response Rate - Independent Review Committee (IRC)  
[units: percentage of participants]
Number ( 95% Confidence Interval ) 		  45.6  
  ( 37.9 to 53.4 )   		  35.7  
  ( 28.5 to 43.5 )  


Statistical Analysis 1 for Best Overall Response Rate - Independent Review Committee (IRC)
Groups [1] All groups
Method [2] stratified Cochran-Mantel-Haenszel test
P Value [3] 0.064
Odds Ratio (OR) [4] 1.516
95% Confidence Interval ( 0.975 to 2.335 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Assuming a difference in rate of best confirmed response of at least 20% between the 2 treatments, ie an approximately 70% response rate under cetuximab plus FOLFOX-4 & 50% under FOLFOX-4 alone for the stratum with ECOG PS0–1 & 66% and 45% respectively for the ECOG PS2 stratum, the common OddsR over the strata was expected to be 2.33. A sample size of approximately 146/group was calculated as necessary to detect a significant overall response of at least 2.33 at level α=0.05 with a power of 90%
[2] Other relevant information, such as adjustments or degrees of freedom:
  Stratified odds ratio and Cochran-Mantel-Haenszel (CMH) statistics were calculated considering the randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population)   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007 ]

Measure Type Secondary
Measure Title Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population)
Measure Description 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) as assessed by an IRC.
Time Frame Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KRAS Wild-Type population

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  82     97  
Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population)  
[units: percentage of participants]
Number ( 95% Confidence Interval ) 		  57.3  
  ( 45.9 to 68.2 )   		  34.0  
  ( 24.7 to 44.3 )  


Statistical Analysis 1 for Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population)
Groups [1] All groups
Method [2] stratified Cochran-Mantel-Haenszel test
P Value [3] 0.0027
Odds Ratio (OR) [4] 2.551
95% Confidence Interval ( 1.380 to 4.717 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Stratified odds ratio and Cochran-Mantel-Haenszel (CMH) statistics were calculated considering the randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Best Overall Response Rate (KRAS Mutant Population)   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007 ]

Measure Type Secondary
Measure Title Best Overall Response Rate (KRAS Mutant Population)
Measure Description 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) as assessed by an IRC.
Time Frame Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KRAS Mutant population

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  77     59  
Best Overall Response Rate (KRAS Mutant Population)  
[units: percentage of participants]
Number ( 95% Confidence Interval ) 		  33.8  
  ( 23.4 to 45.5 )   		  52.5  
  ( 39.1 to 65.7 )  


Statistical Analysis 1 for Best Overall Response Rate (KRAS Mutant Population)
Groups [1] All groups
Method [2] stratified Cochran-Mantel-Haenszel test
P Value [3] 0.0290
Odds Ratio (OR) [4] 0.459
95% Confidence Interval ( 0.228 to 0.924 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Stratified odds ratio and Cochran-Mantel-Haenszel (CMH) statistics were calculated considering the randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Progression-free Survival Time   [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007 ]

Measure Type Secondary
Measure Title Progression-free Survival Time
Measure Description

Duration from randomization until radiological progression as assessed by an IRC (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 Frame Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  169     168  
Progression-free Survival Time  
[units: months]
Median ( 95% Confidence Interval ) 		  7.2  
  ( 5.6 to 7.7 )   		  7.2  
  ( 6.0 to 7.8 )  


Statistical Analysis 1 for Progression-free Survival Time
Groups [1] All groups
Method [2] Stratified Log Rank
P Value [3] 0.6170
Hazard Ratio (HR) [4] 0.931
95% Confidence Interval ( 0.705 to 1.230 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



5.  Secondary:   Progression-free Survival Time (KRAS Wild-Type Population)   [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

Measure Type Secondary
Measure Title Progression-free Survival Time (KRAS Wild-Type Population)
Measure Description

Duration from randomization until radiological progression as assessed by an IRC (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 Frame Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KRAS Wild-Type population

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  82     97  
Progression-free Survival Time (KRAS Wild-Type Population)  
[units: months]
Median ( 95% Confidence Interval ) 		  8.3  
  ( 7.2 to 12.0 )   		  7.2  
  ( 5.6 to 7.4 )  


Statistical Analysis 1 for Progression-free Survival Time (KRAS Wild-Type Population)
Groups [1] All groups
Method [2] Stratified Log Rank
P Value [3] 0.0064
Hazard Ratio (HR) [4] 0.567
95% Confidence Interval ( 0.375 to 0.856 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



6.  Secondary:   Progression-free Survival Time (KRAS Mutant Population)   [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

Measure Type Secondary
Measure Title Progression-free Survival Time (KRAS Mutant Population)
Measure Description

Duration from randomization until radiological progression as assessed by an IRC (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 Frame Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KRAS Mutant population

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  77     59  
Progression-free Survival Time (KRAS Mutant Population)  
[units: months]
Median ( 95% Confidence Interval ) 		  5.5  
  ( 4.0 to 7.3 )   		  8.6  
  ( 6.5 to 9.4 )  


Statistical Analysis 1 for Progression-free Survival Time (KRAS Mutant Population)
Groups [1] All groups
Method [2] Stratified Log Rank
P Value [3] 0.0153
Hazard Ratio (HR) [4] 1.720
95% Confidence Interval ( 1.104 to 2.679 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   Overall Survival Time   [ Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

Measure Type Secondary
Measure Title Overall Survival Time
Measure Description 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, whatever is earlier.
Time Frame Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  169     168  
Overall Survival Time  
[units: months]
Median ( 95% Confidence Interval ) 		  18.3  
  ( 14.8 to 20.4 )   		  18.0  
  ( 16.7 to 21.8 )  


Statistical Analysis 1 for Overall Survival Time
Groups [1] All groups
Method [2] Stratified log rank
P Value [3] 0.9050
Hazard Ratio (HR) [4] 1.015
95% Confidence Interval ( 0.791 to 1.303 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



8.  Secondary:   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, 27 Jul 2005, until cut-off date 30 November 2008 ]

Measure Type Secondary
Measure Title Overall Survival Time (KRAS Wild-Type Population)
Measure Description 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, whatever is earlier.
Time Frame Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KRAS Wild-Type population

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  82     97  
Overall Survival Time (KRAS Wild-Type Population)  
[units: months]
Median ( 95% Confidence Interval ) 		  22.8  
  ( 19.3 to 25.9 )   		  18.5  
  ( 16.4 to 22.6 )  


Statistical Analysis 1 for Overall Survival Time (KRAS Wild-Type Population)
Groups [1] All groups
Method [2] Stratified log rank
P Value [3] 0.3854
Hazard Ratio (HR) [4] 0.855
95% Confidence Interval ( 0.599 to 1.219 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



9.  Secondary:   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, 27 Jul 2005, until cut-off date 30 November 2008 ]

Measure Type Secondary
Measure Title Overall Survival Time (KRAS Mutant Population)
Measure Description 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, whatever is earlier.
Time Frame Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KRAS Mutant population

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  77     59  
Overall Survival Time (KRAS Mutant Population)  
[units: months]
Median ( 95% Confidence Interval ) 		  13.4  
  ( 10.5 to 17.7 )   		  17.5  
  ( 14.7 to 24.8 )  


Statistical Analysis 1 for Overall Survival Time (KRAS Mutant Population)
Groups [1] All groups
Method [2] Stratified log rank
P Value [3] 0.2004
Hazard Ratio (HR) [4] 1.290
95% Confidence Interval ( 0.873 to 1.906 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



10.  Secondary:   Participants With No Residual Tumor After Metastatic Surgery   [ Time Frame: Time from first dose up to 30 days after the last dose of study treatment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008 ]

Measure Type Secondary
Measure Title Participants With No Residual Tumor After Metastatic Surgery
Measure Description No residual tumor after on-study surgery for metastases.
Time Frame Time from first dose up to 30 days after the last dose of study treatment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  169     168  
Participants With No Residual Tumor After Metastatic Surgery  
[units: participants]
 		  8     4  

No statistical analysis provided for Participants With No Residual Tumor After Metastatic Surgery



11.  Secondary:   Disease Control Rate (Cut Off Date 4 August 2006)   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006 ]

Measure Type Secondary
Measure Title Disease Control Rate (Cut Off Date 4 August 2006)
Measure Description 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 as assessed by IRC (based on modified WHO criteria).
Time Frame Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  169     168  
Disease Control Rate (Cut Off Date 4 August 2006)  
[units: percentage of participants]
Number ( 95% Confidence Interval ) 		  85.2  
  ( 78.9 to 90.2 )   		  81.0  
  ( 74.2 to 86.6 )  

No statistical analysis provided for Disease Control Rate (Cut Off Date 4 August 2006)



12.  Secondary:   Duration of Response   [ 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, 27 Jul 2005, until cut-off date 01 Mar 2007 ]

Measure Type Secondary
Measure Title Duration of Response
Measure Description

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 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, 27 Jul 2005, until cut-off date 01 Mar 2007  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  169     168  
Duration of Response  
[units: months]
Median ( 95% Confidence Interval ) 		  9.0  
  ( 5.9 to 11.1 )   		  5.7  
  ( 5.4 to 7.7 )  

No statistical analysis provided for Duration of Response



13.  Secondary:   Safety - Number of Patients Experiencing Any Adverse Event   [ Time Frame: time from first dose up to 30 after last dose of study treatment, reported between day of first patient dose of study treatment, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

Measure Type Secondary
Measure Title Safety - Number of Patients Experiencing Any Adverse Event
Measure Description Please refer to Adverse Events section for further details
Time Frame time from first dose up to 30 after last dose of study treatment, reported between day of first patient dose of study treatment, 27 Jul 2005, until cut-off date 30 Nov 2008  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population

Reporting Groups
  Description
Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Measured Values
    Cetuximab Plus FOLFOX-4     FOLFOX-4 Alone  
Number of Participants Analyzed  
[units: participants]
 		  170     168  
Safety - Number of Patients Experiencing Any Adverse Event  
[units: participants]
 		  170     165  

No statistical analysis provided for Safety - Number of Patients Experiencing Any Adverse Event




  Serious Adverse Events
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  Other Adverse Events
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
A non-specific outcome measure 'Safety' was deleted from this entry in error. A replacement outcome has been created. The 'Safety' outcome refers to adverse events and these are shown in the 'Adverse Events' section.  


Results Point of Contact:  
Name/Title: Inmaculada Ollero/Clinical Trial Manager
Organization: Merck Serono
phone: +34935655433
e-mail: iollero@merck.es


Publications of Results:


Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT00125034     History of Changes
Other Study ID Numbers: EMR 62202-047
Study First Received: July 28, 2005
Results First Received: August 23, 2011
Last Updated: August 23, 2011
Health Authority: Germany: Federal Institute for Drugs and Medical Devices