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

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00125034
• Collaborator: (none)
• Enrollment: 344
• Locations: 78
• Arms: 2
• Duration (Months): 64
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open label, randomized, controlled, multicenter phase II study comparing 5-FU/FA + oxaliplatin (FOLFOX-4) + cetuximab versus 5-FU/FA + oxaliplatin as first-line treatment for epidermal growth factor receptor (EGFR)-expressing mCRC.

Condition or Disease	Intervention/Treatment	Phase
Neoplasm Metastasis; Colorectal Cancer	Biological: Cetuximab; Drug: Oxaliplatin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 344 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open, Randomized, Controlled, Multicenter Phase II Study Comparing 5-FU/FA Plus Oxaliplatin (FOLFOX-4) Plus Cetuximab Versus 5-FU/FA Plus Oxaliplatin (FOLFOX-4) as First-line Treatment for Epidermal Growth Factor Receptor-expressing Metastatic Colorectal Cancer
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Mar 1, 2007
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cetuximab Plus FOLFOX-4	Biological: Cetuximab; Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin folinic acid (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-Fluorouracil (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
Active Comparator: FOLFOX-4 Alone	Drug: 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

Outcome Measures

Primary Outcome Measures

1. Best Overall Response Rate - Independent Review Committee (IRC) [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]

   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.

Secondary Outcome Measures

1. Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) [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]

   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.

2. Best Overall Response Rate (KRAS Mutant Population) [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]

   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.

3. Progression-free Survival Time [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]

   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.

4. Progression-free Survival Time (KRAS Wild-Type Population) [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]

   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.

5. Progression-free Survival Time (KRAS Mutant Population) [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]

   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.

6. Overall Survival Time [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]

   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.

7. Overall Survival Time (KRAS Wild-Type Population) [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]

   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.

8. Overall Survival Time (KRAS Mutant Population) [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]

   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.

9. Participants With No Residual Tumor After Metastatic Surgery [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]

   No residual tumor after on-study surgery for metastases.

10. Disease Control Rate (Cut Off Date 4 August 2006) [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]

    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).

11. Duration of Response [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]

    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.

12. Safety - Number of Patients Experiencing Any Adverse Event [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]

    Please refer to Adverse Events section for further details

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• First-line mCRC

• EGFR positive

• Bi-dimensional measurable index lesion

Exclusion Criteria:

• Previous exposure to EGFR-targeting therapy

• Previous oxaliplatin-based therapy

• Previous chemotherapy for colorectal cancer except adjuvant treatment with progression of disease documented > 6 months after end of adjuvant treatment

• Radiotherapy

• Surgery

• Any other investigational drug in the 30 days before randomization

• Brain metastasis and/or leptomeningeal disease

• Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Graz		Austria
2	Research Site	Linz		Austria
3	Research Site	Salzburg		Austria
4	Research Site	Wien		Austria
5	Research Site	Zams		Austria
6	Research Site	Antwerpen		Belgium
7	Research Site	Bonheiden		Belgium
8	Research Site	Brugge		Belgium
9	Research Site	Hasselt		Belgium
10	Research Site	Leuven		Belgium
11	Research Site	Roeselare		Belgium
12	Research Site	Turnhout		Belgium
13	Research Site	ZU Gent		Belgium
14	Research Site	Besancon		France
15	Research Site	Clermond Ferrand		France
16	Research Site	Clichy		France
17	Research Site	Montpellier		France
18	Research Site	Paris		France
19	Research Site	Rouen		France
20	Research Site	Strasbourg		France
21	Research Site	Aschaffenburg		Germany
22	Research Site	Dresden		Germany
23	Research Site	Essen		Germany
24	Research Site	Hamburg		Germany
25	Research Site	Kiel		Germany
26	Research Site	Magdeburg		Germany
27	Research Site	Mannheim		Germany
28	Research Site	Nürnberg		Germany
29	Research Site	Tübingen		Germany
30	Research Site	Athens		Greece
31	Research Site	Loannina		Greece
32	Research Site	Thessaloniki		Greece
33	Research Site	Haifa		Israel
34	Research Site	Kfar-Saba		Israel
35	Research Site	Petah Tiqva		Israel
36	Research Site	Rehovot		Israel
37	Research Site	Tel-Aviv		Israel
38	Research Site	Tel-Hashomer		Israel
39	Research Site	Brescia		Italy
40	Research Site	Milano		Italy
41	Research Site	Padova		Italy
42	Research Site	Pavia		Italy
43	Research Site	Rome		Italy
44	Research Site	Torino		Italy
45	Research Site	Bialystok		Poland
46	Research Site	Krakow		Poland
47	Research Site	Lublin		Poland
48	Research Site	Opole		Poland
49	Research Site	Poznan		Poland
50	Research Site	Szczecin		Poland
51	Research Site	Warszawa		Poland
52	Research Site	Lisbon		Portugal
53	Research Site	Santa Maira da Feira		Portugal
54	Research Site	Alba Iulia		Romania
55	Research Site	Bucurest		Romania
56	Research Site	Onesti		Romania
57	Research Site	Oradea		Romania
58	Research Site	Timisoara		Romania
59	Research Site	Kazan		Russian Federation
60	Research Site	Krasnodar		Russian Federation
61	Research Site	Moscow		Russian Federation
62	Research Site	Obninsk		Russian Federation
63	Research Site	Samara		Russian Federation
64	Research Site	St. Petersburg		Russian Federation
65	Research Site	Bilbao		Spain
66	Research Site	Burgos		Spain
67	Research Site	Girona		Spain
68	Research Site	Madrid		Spain
69	Research Site	Malaga		Spain
70	Research Site	Orense		Spain
71	Research Site	Reus		Spain
72	Research Site	Valencia		Spain
73	Research Site	Dnepropetrovsk		Ukraine
74	Research Site	Kharkov		Ukraine
75	Research Site	Kiev		Ukraine
76	Research Site	Lviv		Ukraine
77	Research Site	Simferopol		Ukraine
78	Research Site	Vinnitsa		Ukraine

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Principal Investigator: Bokemeyer, Prof. Dr., Klinik für Onkologie, Hämatologie und Knochenmarktransplantationen Universitätsklinikum Hamburg-Eppendorf, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT00125034
• Other Study ID Numbers: EMR 62202-047
• First Posted: Jul 29, 2005
• Last Update Posted: Aug 7, 2014
• Last Verified: Aug 1, 2011

• Keywords provided by Merck KGaA, Darmstadt, Germany: FOLFOX-4; Cetuximab; First-line mCRC; EGFR positive; metastatic CRC
• Additional relevant MeSH terms: Colorectal Neoplasms; Neoplasm Metastasis; Oxaliplatin; Cetuximab

Study Results

Participant Flow

Recruitment Details	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 Detail	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).

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	170	168
COMPLETED	170	168
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	169	168	337
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	96 56.8%	109 64.9%	205 60.8%
>=65 years	73 43.2%	59 35.1%	132 39.2%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62.0	60.0	61.0
Sex: Female, Male (Count of Participants)
Female	80 47.3%	76 45.2%	156 46.3%
Male	89 52.7%	92 54.8%	181 53.7%
Region of Enrollment (participants) [Number]
Portugal	0 0%	3 1.8%	3 0.9%
Spain	19 11.2%	16 9.5%	35 10.4%
Ukraine	24 14.2%	25 14.9%	49 14.5%
Austria	16 9.5%	9 5.4%	25 7.4%
Russian Federation	25 14.8%	24 14.3%	49 14.5%
Israel	0 0%	1 0.6%	1 0.3%
Italy	8 4.7%	6 3.6%	14 4.2%
France	3 1.8%	12 7.1%	15 4.5%
Belgium	12 7.1%	6 3.6%	18 5.3%
Poland	30 17.8%	31 18.5%	61 18.1%
Romania	18 10.7%	13 7.7%	31 9.2%
Germany	14 8.3%	22 13.1%	36 10.7%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response Rate - Independent Review Committee (IRC)
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	169	168
Number (95% Confidence Interval) [percentage of participants]	45.6 27%	35.7 21.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments	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%
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	stratified Cochran-Mantel-Haenszel test
	Comments	Stratified odds ratio and Cochran-Mantel-Haenszel (CMH) statistics were calculated considering the randomization strata.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.516
	Confidence Interval	(2-Sided) 95%; 0.975 to 2.335
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population)
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

Outcome Measure Data

Analysis Population Description

KRAS Wild-Type population

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	82	97
Number (95% Confidence Interval) [percentage of participants]	57.3 33.9%	34.0 20.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	stratified Cochran-Mantel-Haenszel test
	Comments	Stratified odds ratio and Cochran-Mantel-Haenszel (CMH) statistics were calculated considering the randomization strata.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.551
	Confidence Interval	(2-Sided) 95%; 1.380 to 4.717
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Best Overall Response Rate (KRAS Mutant Population)
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

Outcome Measure Data

Analysis Population Description

KRAS Mutant population

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	77	59
Number (95% Confidence Interval) [percentage of participants]	33.8 20%	52.5 31.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0290
	Comments
	Method	stratified Cochran-Mantel-Haenszel test
	Comments	Stratified odds ratio and Cochran-Mantel-Haenszel (CMH) statistics were calculated considering the randomization strata.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.459
	Confidence Interval	(2-Sided) 95%; 0.228 to 0.924
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Progression-free Survival Time
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	169	168
Median (95% Confidence Interval) [months]	7.2	7.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6170
	Comments
	Method	Stratified Log Rank
	Comments	Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.931
	Confidence Interval	(2-Sided) 95%; 0.705 to 1.230
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

KRAS Wild-Type population

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	82	97
Median (95% Confidence Interval) [months]	8.3	7.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0064
	Comments
	Method	Stratified Log Rank
	Comments	Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.567
	Confidence Interval	(2-Sided) 95%; 0.375 to 0.856
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Progression-free Survival Time (KRAS Mutant Population)
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

Outcome Measure Data

Analysis Population Description

KRAS Mutant population

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	77	59
Median (95% Confidence Interval) [months]	5.5	8.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0153
	Comments
	Method	Stratified Log Rank
	Comments	Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.720
	Confidence Interval	(2-Sided) 95%; 1.104 to 2.679
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Overall Survival Time
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	169	168
Median (95% Confidence Interval) [months]	18.3	18.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9050
	Comments
	Method	Stratified log rank
	Comments	Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.015
	Confidence Interval	(2-Sided) 95%; 0.791 to 1.303
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Overall Survival Time (KRAS Wild-Type Population)
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

Outcome Measure Data

Analysis Population Description

KRAS Wild-Type population

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	82	97
Median (95% Confidence Interval) [months]	22.8	18.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3854
	Comments
	Method	Stratified log rank
	Comments	Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.855
	Confidence Interval	(2-Sided) 95%; 0.599 to 1.219
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Overall Survival Time (KRAS Mutant Population)
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

Outcome Measure Data

Analysis Population Description

KRAS Mutant population

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	77	59
Median (95% Confidence Interval) [months]	13.4	17.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab Plus FOLFOX-4, FOLFOX-4 Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2004
	Comments
	Method	Stratified log rank
	Comments	Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.290
	Confidence Interval	(2-Sided) 95%; 0.873 to 1.906
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Participants With No Residual Tumor After Metastatic Surgery
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	169	168
Number [participants]	8 4.7%	4 2.4%

11. Secondary Outcome

Title	Disease Control Rate (Cut Off Date 4 August 2006)
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	169	168
Number (95% Confidence Interval) [percentage of participants]	85.2 50.4%	81.0 48.2%

12. Secondary Outcome

Title	Duration of Response
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	169	168
Median (95% Confidence Interval) [months]	9.0	5.7

13. Secondary Outcome

Title	Safety - Number of Patients Experiencing Any Adverse Event
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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Arm/Group Description	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.	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.
Measure Participants	170	168
Number [participants]	170 100.6%	165 98.2%

Adverse Events

Time Frame	Time from first dose up to 30 days after the last dose of study treatment.
Adverse Event Reporting Description	Treatment-emergent adverse events were defined as those with onset occurring at or after the first dosing day of study medication and up to 30 days after the last administration of any study drug or the clinical cut-off date.
Arm/Group Title	Cetuximab Plus FOLFOX-4		FOLFOX-4 Alone
Arm/Group Description	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.		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.
All Cause Mortality
	Cetuximab Plus FOLFOX-4		FOLFOX-4 Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cetuximab Plus FOLFOX-4		FOLFOX-4 Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/170 (35.9%)		43/168 (25.6%)
Blood and lymphatic system disorders
ANAEMIA	0/170 (0%)		1/168 (0.6%)
FEBRILE BONE MARROW APLASIA	0/170 (0%)		1/168 (0.6%)
FEBRILE NEUTROPENIA	4/170 (2.4%)		3/168 (1.8%)
LEUKOPENIA	3/170 (1.8%)		2/168 (1.2%)
NEUTROPENIA	4/170 (2.4%)		5/168 (3%)
THROMBOCYTOPENIA	0/170 (0%)		1/168 (0.6%)
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	1/170 (0.6%)		0/168 (0%)
ARRHYTHMIA SUPRAVENTRICULAR	2/170 (1.2%)		0/168 (0%)
ATRIAL FIBRILLATION	1/170 (0.6%)		0/168 (0%)
CARDIAC FAILURE	1/170 (0.6%)		0/168 (0%)
CARDIO-RESPIRATORY ARREST	2/170 (1.2%)		0/168 (0%)
LEFT VENTRICULAR DYSFUNCTION	1/170 (0.6%)		0/168 (0%)
Ear and labyrinth disorders
VERTIGO	1/170 (0.6%)		0/168 (0%)
Eye disorders
CONJUNCTIVITIS	1/170 (0.6%)		0/168 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	2/170 (1.2%)		1/168 (0.6%)
ASCITES	2/170 (1.2%)		0/168 (0%)
COLITIS	1/170 (0.6%)		0/168 (0%)
CONSTIPATION	2/170 (1.2%)		0/168 (0%)
DIARRHOEA	2/170 (1.2%)		2/168 (1.2%)
GASTROINTESTINAL PERFORATION	0/170 (0%)		1/168 (0.6%)
HAEMATEMESIS	0/170 (0%)		1/168 (0.6%)
ILEUS	4/170 (2.4%)		1/168 (0.6%)
INTESTINAL OBSTRUCTION	3/170 (1.8%)		0/168 (0%)
LARGE INTESTINAL OBSTRUCTION	1/170 (0.6%)		0/168 (0%)
NAUSEA	0/170 (0%)		1/168 (0.6%)
PANCREATITIS	1/170 (0.6%)		0/168 (0%)
PERITONITIS	0/170 (0%)		1/168 (0.6%)
RECTAL STENOSIS	0/170 (0%)		1/168 (0.6%)
SUBILEUS	0/170 (0%)		1/168 (0.6%)
VOMITING	2/170 (1.2%)		4/168 (2.4%)
General disorders
ASTHENIA	3/170 (1.8%)		1/168 (0.6%)
CHEST PAIN	1/170 (0.6%)		0/168 (0%)
FATIGUE	1/170 (0.6%)		1/168 (0.6%)
GENERAL PHYSICAL HEALTH DETERIORATION	0/170 (0%)		1/168 (0.6%)
INJECTION SITE REACTION	1/170 (0.6%)		0/168 (0%)
MASS	1/170 (0.6%)		0/168 (0%)
MUCOSAL INFLAMMATION	1/170 (0.6%)		0/168 (0%)
OBSTRUCTION	0/170 (0%)		1/168 (0.6%)
PYREXIA	4/170 (2.4%)		4/168 (2.4%)
Hepatobiliary disorders
BILE DUCT STONE	0/170 (0%)		1/168 (0.6%)
CHOLANGITIS	1/170 (0.6%)		0/168 (0%)
HEPATIC FAILURE	1/170 (0.6%)		0/168 (0%)
HEPATORENAL SYNDROME	1/170 (0.6%)		0/168 (0%)
HYPERBILIRUBINAEMIA	2/170 (1.2%)		0/168 (0%)
JAUNDICE	1/170 (0.6%)		0/168 (0%)
Immune system disorders
HYPERSENSITIVITY	5/170 (2.9%)		2/168 (1.2%)
Infections and infestations
ABSCESS NECK	0/170 (0%)		1/168 (0.6%)
BRONCHITIS	0/170 (0%)		1/168 (0.6%)
CATHETER RELATED INFECTION	0/170 (0%)		1/168 (0.6%)
CENTRAL LINE INFECTION	0/170 (0%)		1/168 (0.6%)
ERYSIPELAS	2/170 (1.2%)		0/168 (0%)
FEBRILE INFECTION	1/170 (0.6%)		0/168 (0%)
INFECTION	2/170 (1.2%)		1/168 (0.6%)
KIDNEY INFECTION	0/170 (0%)		1/168 (0.6%)
LUNG ABSCESS	1/170 (0.6%)		0/168 (0%)
PERITONITIS BACTERIAL	1/170 (0.6%)		0/168 (0%)
PNEUMONIA	3/170 (1.8%)		3/168 (1.8%)
PULMONARY TUBERCULOSIS	1/170 (0.6%)		0/168 (0%)
PYELONEPHRITIS ACUTE	0/170 (0%)		1/168 (0.6%)
SEPSIS	1/170 (0.6%)		0/168 (0%)
STAPHYLOCOCCAL SEPSIS	1/170 (0.6%)		0/168 (0%)
TUBERCULOSIS	1/170 (0.6%)		0/168 (0%)
URINARY TRACT INFECTION	0/170 (0%)		1/168 (0.6%)
Injury, poisoning and procedural complications
FALL	1/170 (0.6%)		0/168 (0%)
HUMERUS FRACTURE	1/170 (0.6%)		0/168 (0%)
INCISIONAL HERNIA	1/170 (0.6%)		0/168 (0%)
WOUND DEHISCENCE	1/170 (0.6%)		0/168 (0%)
Metabolism and nutrition disorders
ANOREXIA	3/170 (1.8%)		0/168 (0%)
DEHYDRATION	2/170 (1.2%)		1/168 (0.6%)
DIABETES MELLITUS INADEQUATE CONTROL	1/170 (0.6%)		0/168 (0%)
HYPERGLYCAEMIA	1/170 (0.6%)		0/168 (0%)
HYPOKALAEMIA	1/170 (0.6%)		0/168 (0%)
Nervous system disorders
DEPRESSED LEVEL OF CONSCIOUSNESS	2/170 (1.2%)		0/168 (0%)
DIZZINESS	0/170 (0%)		1/168 (0.6%)
EPILEPSY	0/170 (0%)		1/168 (0.6%)
PERIPHERAL SENSORY NEUROPATHY	1/170 (0.6%)		0/168 (0%)
SYNCOPE	1/170 (0.6%)		0/168 (0%)
Psychiatric disorders
ALCOHOLIC PSYCHOSIS	0/170 (0%)		1/168 (0.6%)
Renal and urinary disorders
RENAL FAILURE	1/170 (0.6%)		0/168 (0%)
URINARY RETENTION	0/170 (0%)		1/168 (0.6%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	1/170 (0.6%)		0/168 (0%)
MEDIASTINAL HAEMATOMA	1/170 (0.6%)		0/168 (0%)
PULMONARY EMBOLISM	5/170 (2.9%)		2/168 (1.2%)
TACHYPNOEA	1/170 (0.6%)		0/168 (0%)
Surgical and medical procedures
ILEOCOLOSTOMY	0/170 (0%)		1/168 (0.6%)
Vascular disorders
AXILLARY VEIN THROMBOSIS	1/170 (0.6%)		0/168 (0%)
CIRCULATORY COLLAPSE	0/170 (0%)		1/168 (0.6%)
EMBOLISM	0/170 (0%)		1/168 (0.6%)
HYPERTENSION	2/170 (1.2%)		0/168 (0%)
HYPOTENSION	1/170 (0.6%)		0/168 (0%)
INTERMITTENT CLAUDICATION	1/170 (0.6%)		0/168 (0%)
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	1/170 (0.6%)		0/168 (0%)
THROMBOPHLEBITIS	0/170 (0%)		1/168 (0.6%)
VENOUS THROMBOSIS	1/170 (0.6%)		0/168 (0%)
Other (Not Including Serious) Adverse Events
	Cetuximab Plus FOLFOX-4		FOLFOX-4 Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	170/170 (100%)		165/168 (98.2%)
Blood and lymphatic system disorders
ANAEMIA	44/170 (25.9%)		41/168 (24.4%)
LEUKOPENIA	49/170 (28.8%)		43/168 (25.6%)
NEUTROPENIA	77/170 (45.3%)		84/168 (50%)
THROMBOCYTOPENIA	45/170 (26.5%)		69/168 (41.1%)
Ear and labyrinth disorders
VERTIGO	9/170 (5.3%)		7/168 (4.2%)
Eye disorders
CONJUNCTIVITIS	23/170 (13.5%)		8/168 (4.8%)
Gastrointestinal disorders
ABDOMINAL PAIN	30/170 (17.6%)		29/168 (17.3%)
CONSTIPATION	32/170 (18.8%)		16/168 (9.5%)
DIARRHOEA	81/170 (47.6%)		68/168 (40.5%)
DYSPEPSIA	9/170 (5.3%)		9/168 (5.4%)
NAUSEA	69/170 (40.6%)		65/168 (38.7%)
STOMATITIS	33/170 (19.4%)		19/168 (11.3%)
VOMITING	48/170 (28.2%)		37/168 (22%)
General disorders
ASTHENIA	32/170 (18.8%)		31/168 (18.5%)
FATIGUE	54/170 (31.8%)		43/168 (25.6%)
MUCOSAL INFLAMMATION	22/170 (12.9%)		8/168 (4.8%)
PYREXIA	39/170 (22.9%)		30/168 (17.9%)
Immune system disorders
HYPERSENSITIVITY	13/170 (7.6%)		1/168 (0.6%)
Infections and infestations
PARONYCHIA	20/170 (11.8%)		0/168 (0%)
Investigations
WEIGHT DECREASED	26/170 (15.3%)		19/168 (11.3%)
Metabolism and nutrition disorders
ANOREXIA	34/170 (20%)		23/168 (13.7%)
HYPOCALCAEMIA	10/170 (5.9%)		0/168 (0%)
HYPOKALAEMIA	11/170 (6.5%)		5/168 (3%)
HYPOMAGNESAEMIA	16/170 (9.4%)		2/168 (1.2%)
Musculoskeletal and connective tissue disorders
BACK PAIN	10/170 (5.9%)		8/168 (4.8%)
Nervous system disorders
DIZZINESS	11/170 (6.5%)		3/168 (1.8%)
HEADACHE	11/170 (6.5%)		8/168 (4.8%)
NEUROPATHY	10/170 (5.9%)		16/168 (9.5%)
NEUROTOXICITY	12/170 (7.1%)		7/168 (4.2%)
PARAESTHESIA	19/170 (11.2%)		38/168 (22.6%)
PERIPHERAL SENSORY NEUROPATHY	46/170 (27.1%)		51/168 (30.4%)
POLYNEUROPATHY	9/170 (5.3%)		5/168 (3%)
Psychiatric disorders
INSOMNIA	9/170 (5.3%)		6/168 (3.6%)
Respiratory, thoracic and mediastinal disorders
COUGH	10/170 (5.9%)		7/168 (4.2%)
EPISTAXIS	15/170 (8.8%)		11/168 (6.5%)
Skin and subcutaneous tissue disorders
ACNE	10/170 (5.9%)		0/168 (0%)
ALOPECIA	21/170 (12.4%)		17/168 (10.1%)
DERMATITIS ACNEIFORM	38/170 (22.4%)		1/168 (0.6%)
DRY SKIN	28/170 (16.5%)		3/168 (1.8%)
EXFOLIATIVE RASH	12/170 (7.1%)		0/168 (0%)
NAIL DISORDER	11/170 (6.5%)		2/168 (1.2%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	19/170 (11.2%)		7/168 (4.2%)
PRURITUS	15/170 (8.8%)		6/168 (3.6%)
RASH	90/170 (52.9%)		4/168 (2.4%)
SKIN FISSURES	17/170 (10%)		0/168 (0%)
SKIN TOXICITY	13/170 (7.6%)		0/168 (0%)
Vascular disorders
HYPERTENSION	11/170 (6.5%)		8/168 (4.8%)

Limitations/Caveats

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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.