TAILOR: A Trial to Compare Oxaliplatin, Folinic Acid (FA) and 5-Fluorouracil (5FU) Combination Chemotherapy (FOLFOX-4) With or Without Cetuximab in the 1st Line Treatment of Metastatic Colorectal Cancer (mCRC) in Chinese Rat Sarcoma Viral Oncogene Homolog (RAS) Wild-type Patients

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01228734
• Collaborator: (none)
• Enrollment: 553
• Locations: 25
• Arms: 2
• Actual Duration (Months): 88.7
• Patients Per Site: 22.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study was to assess whether the progression free survival (PFS) time with FOLFOX-4 plus cetuximab is longer than that with FOLFOX-4 alone as first-line treatment for mCRC in Chinese subjects with RAS wild-type tumors.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: Cetuximab; Drug: Oxaliplatin; Drug: Folinic Acid; Drug: 5Fluorouracil	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 553 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Randomized, Controlled, Multicenter Phase III Trial to Compare Cetuximab in Combination With FOLFOX-4 Versus FOLFOX-4 Alone in the First Line Treatment of Metastatic Colorectal Cancer in Chinese Subjects With RAS Wild-type Status
• Actual Study Start Date: Sep 9, 2010
• Actual Primary Completion Date: Jan 25, 2016
• Actual Study Completion Date: Jan 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cetuximab + FOLFOX-4 Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-fluorouracil (5-FU)/folinic acid (FA). Cetuximab was always administered every 7 days with an initial dose of 400 milligram per square meter (mg/m^2) at 5 milligram per minute (mg/min) and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Drug: Cetuximab; Cetuximab was administered every 7 days at an initial dose of 400 milligram per square meter (mg/m^2) at 5 milligram per minute (mg/min) and 250 mg/m^2 at 10 mg/min for subsequent infusions until progression of disease, withdrawal of consent, or unacceptable toxicity to cetuximab.; Other Names: Erbitux C225 ; Drug: Oxaliplatin; Oxaliplatin 85 mg/m^2 infusion over 120 minutes on Day 1, Day 2, and then every 2 weeks until progression of disease, withdrawal of consent, or unacceptable toxicity.; Drug: Folinic Acid; FA 200 mg/m^2 infusion over 120 minutes on Day 1, Day 2, and then every 2 weeks until progression of disease, withdrawal of consent, or unacceptable toxicity.; Drug: 5Fluorouracil; 5-FU as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infusion over 22 hours on Day 1, Day 2, and then every 2 weeks until progression of disease, withdrawal of consent, or unacceptable toxicity.
Active Comparator: FOLFOX-4 Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Drug: Oxaliplatin; Oxaliplatin 85 mg/m^2 infusion over 120 minutes on Day 1, Day 2, and then every 2 weeks until progression of disease, withdrawal of consent, or unacceptable toxicity.; Drug: Folinic Acid; FA 200 mg/m^2 infusion over 120 minutes on Day 1, Day 2, and then every 2 weeks until progression of disease, withdrawal of consent, or unacceptable toxicity.; Drug: 5Fluorouracil; 5-FU as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infusion over 22 hours on Day 1, Day 2, and then every 2 weeks until progression of disease, withdrawal of consent, or unacceptable toxicity.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) Time [Baseline up to 333 weeks]

   PFS was defined as the duration (in months) from randomization until the first progressive disease (PD) observation as assessed by the Independent Review Committee (IRC) according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.0, or death due to any cause when death occurred within 90 days of randomization or the last tumor assessment, whichever was later. PD was defined as at least a 20% increase in the sum of longest diameter (LD) of the target lesions, taking as references the smallest sum LD since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.

Secondary Outcome Measures

1. Overall Survival (OS) Time [Baseline up to 333 weeks]

   OS was defined as the time (in months) from randomization to death. For subjects who were still alive at the analysis data cut-off date or who lost to follow-up, survival was censored at the last recorded date that the subject was known to be alive.

2. Best Overall Response Rate (ORR) [Baseline up to 333 weeks]

   The Best ORR was defined as the percentage of subjects having achieved complete response (CR) or partial response (PR) according to RECIST version 1.0 as determined by the IRC. CR: defined as disappearance of all target and all non-target lesions and no new lesions. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters, no progression of non-target lesions and no new lesions.

3. Time to Treatment Failure (TTF) [Baseline up to 333 weeks]

   TTF was defined as time from randomization to date of the first occurrence of radiologically confirmed PD as determined by IRC, Clinical PD according to the Investigator's assessment (if radiological confirmation of PD by IRC was unavailable), discontinuation of treatment due to progression or adverse event, start of new anticancer therapy, withdrawal of consent, or death within 90 days of last tumor assessment or randomization. Subjects without event were censored on the date of last tumor assessment.

4. Number of Subjects With Curative Surgery of Liver Metastases [Baseline up to 333 weeks]

   The number of subjects who underwent liver metastatic surgery after start of treatment and the outcome of surgery with respect to residual tumor after surgery (R0, R1, R2, not evaluable) were summarized. In case of resection of more than one metastasis, the worst outcome of surgery defined the overall status of a subject. R0 = No residual tumor after resection (all lesions resected completely); R1 = Metastases not resected completely with microscopic residual lesions; and R2 = Metastases not resected completely with macroscopic residual lesions.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed written informed consent (first and second)

• Chinese with Chinese citizenship

• Male or female subjects greater than or equal to (>=) 18 years of age

• Medically accepted effective contraception if procreative potential exists (applicable for both male and female subjects until at least 90 days after the last dose of trial treatment)

• Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum

• First occurrence of metastatic disease (not curatively resectable) RAS wild-type status in tumor tissue

• At least one measurable lesion by computer tomography (CT) or magnetic resonance imaging (MRI) according to RECIST (not in an irradiated area)

• Life expectancy of at least 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry

• White blood cell count >= 3 × 10x9/L with neutrophils >= 1.5 × 10x9/L, platelet count

= 100 × 10x9/L and hemoglobin >= 6.21 mmol/L (10 g/dL)

• Total bilirubin <= 1.5 × upper limit of reference range

• Aspartate transaminase (AST) and alanine transaminase (ALT) <= 2.5 × upper limit of reference range or <= 5 × upper reference range in subjects with liver metastasis

• Serum creatinine <= 1.5 × upper limit of reference range

• Recovery from relevant toxicity due to previous treatment before trial entry

Exclusion Criteria:

• Previous chemotherapy for CRC except adjuvant treatment if terminated > 9 months (oxaliplatin-based chemotherapy) or > 6 months (non-oxaliplatin-based chemotherapy) before the start of treatment in this trial

• Radiotherapy or surgery (excluding prior diagnostic biopsy) in the 30 days before trial treatment

• Previous treatment with monoclonal antibody therapy, vascular endothelial growth factor (VEGF) pathway-targeting therapy, epidermal growth factor receptor (EGFR) pathway-targeting therapy, or other signal transduction inhibitors

• History of organ allograft, autologous stem cell transplantation, or allogeneic stem cell transplantation

• Renal replacement therapy

• Intake of any investigational medication within 30 days before trial entry

• Concurrent chronic systemic immune therapy or hormone therapy except physiologic replacement

• Granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) within 3 weeks of trial entry (these growth factors may be used during the trial thereafter)

• Other non-permitted concomitant anticancer therapies

• Known brain metastasis and/or leptomeningeal disease. Subjects with neurological symptoms should undergo a CT scan/MRI of the brain to exclude brain metastasis

• Previous malignancy other than CRC in the last 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix

• Clinically significant cardiovascular disease, e.g. cardiac failure of New York Heart Association classes III-IV, uncontrolled coronary artery disease, cardiomyopathy, uncontrolled arrhythmia, uncontrolled hypertension, or history of myocardial infarction in the last 5 years, or left ventricular ejection fraction below the institutional range of normal on a baseline multiple gated acquisition scan or echocardiogram

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

• Active clinically serious infections (> grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0), including active tuberculosis

• Known and declared history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C

• Peripheral neuropathy > grade 1

• Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such

• Uncontrolled diabetes mellitus, pulmonary fibrosis, acute pulmonary disorder, interstitial pneumonia, or liver failure

• Known hypersensitivity or allergic reactions against any of the components of the trial treatments

• Pregnancy (absence to be confirmed by serum β-human chorionic gonadotropin test) or breastfeeding

• Ongoing alcohol or drug abuse

• Presence of a medical or psychological condition that would not permit the subject to complete the trial or sign informed consent

• Participation in another clinical trial within the past 30 days

• Other significant disease that in the investigator's opinion should exclude the subject from the trial

• Legal incapacity or limited legal capacity

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fujian Province Cancer Hospital	Fuzhou	Fujian	China	350014
2	Fuzhou General Hospital	Fuzhou	Fujian	China	350025
3	First Hospital Affiliated to Guangzhou University of Chinese Medicine	Guangzhou	Guangdong	China	510405
4	Nanfang Hospital	Guangzhou	Guangdong	China	510515
5	The Tumor Hospital of Harbin Medical University	Harbin	Heilongjiang	China	150040
6	Union Hospital of Tongji Medical College of Huazhong University of Science and Technology	Wuhan	Hubei	China	430023
7	Jilin Cancer Hospital	Changchun	Jilin	China	130012
8	First Affiliated Hospital of Jilin University	Changchun	Jilin	China	130021
9	The Affiliated Hospital of Medical College Qingdao University	Qingdao	Shandong	China	266003
10	The First Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China	310009
11	Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University	Hangzhou	Zhejiang	China	310016
12	307 Hospital of PLA	Beijing		China	100071
13	The General Hospital of the People's Liberation Army	Beijing		China	100853
14	Affiliated Hospital of Bengbu Medical College	Bengbu		China	233004
15	The Xiangya 2nd Hospital of Central South University	Changsha, Hunan		China	410011
16	Southwest Hospital	Chongqing		China	400038
17	Yunnan Provincial Tumor Hospital	KunMing, Yunnan		China	650118
18	The First Affiliated Hospital of Nanchang University	Nanchang, Jiangxi		China	330006
19	Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai		China	200025
20	Fudan University Shanghai Cancer Center	Shanghai		China	200032
21	Shanghai First People's Hospital	Shanghai		China	200080
22	Fudan University Zhongshan Hospital	Shanghai		China
23	The First Affiliated Hospital of Soochow University	Shuzhou, Jiangsu		China	215006
24	Tianjin People's Hospital	Tianjin		China	30000
25	Xijing Hospital the 4th Military Medical University of PLA	Xi'an		China	710032

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck Serono Co., Ltd., Beijing, an affiliate of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01228734
• Other Study ID Numbers: EMR62202-057
• First Posted: Oct 26, 2010
• Last Update Posted: Jan 28, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by Merck KGaA, Darmstadt, Germany: Metastatic colorectal cancer; RAS wild type; Cetuximab; First line treatment; First occurrence of metastatic colorectal cancer in Chinese subjects with RAS wildtype; status
• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Folic Acid; Fluorouracil; Oxaliplatin; Cetuximab; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	The study was planned to enroll subjects with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type (wt) tumors.Following modification of approved EU indication of cetuximab,a decision made to amend study population from subjects with KRAS wt tumors to those with RAS wt tumors. All efficacy/safety analysis based on subjects with RAS wt tumor.
Pre-assignment Detail	First subject first visit/last subject last visit: 30 September 2010/31 Jan 2018. A total of 553 subjects were enrolled in the trial. 504 subjects were randomized in the study, of which 397 were with RAS wt tumors. Participant Flow is presented for the subjects with RAS wt tumors.

Arm/Group Title	Cetuximab + FOLFOX4	FOLFOX4
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-fluorouracil (5-FU)/folinic acid (FA). Cetuximab was always administered every 7 days with an initial dose of 400 milligram per square meter (mg/m^2) at 5 milligram per minute (mg/min) and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.
Period Title: Overall Study
STARTED	193	204
Modified Intent-to-treat Population	193	200
Modified Safety Population	194	199
COMPLETED	193	200
NOT COMPLETED	0	4

Baseline Characteristics

Arm/Group Title	Cetuximab + FOLFOX-4	FOLFOX-4	Total
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-FU/FA. Cetuximab was always administered every 7 days with an initial dose of 400 mg/m^2 at 5 mg/min and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Total of all reporting groups
Overall Participants	193	200	393
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.8 (11.8)	55.1 (11.2)	54.9 (11.5)
Sex: Female, Male (Count of Participants)
Female	66 34.2%	61 30.5%	127 32.3%
Male	127 65.8%	139 69.5%	266 67.7%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) Time
Description	PFS was defined as the duration (in months) from randomization until the first progressive disease (PD) observation as assessed by the Independent Review Committee (IRC) according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.0, or death due to any cause when death occurred within 90 days of randomization or the last tumor assessment, whichever was later. PD was defined as at least a 20% increase in the sum of longest diameter (LD) of the target lesions, taking as references the smallest sum LD since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.
Time Frame	Baseline up to 333 weeks

Outcome Measure Data

Analysis Population Description

MITT population included all subjects with RAS wild-type tumor status who were randomized to study treatment and who received at least 1 dose of study treatment. Subjects were analyzed as randomized.

Arm/Group Title	Cetuximab + FOLFOX-4	FOLFOX-4
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-FU/FA. Cetuximab was always administered every 7 days with an initial dose of 400 mg/m^2 at 5 mg/min and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.
Measure Participants	193	200
Median (95% Confidence Interval) [months]	9.2	7.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab + FOLFOX-4, FOLFOX-4
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.629
	Confidence Interval	(2-Sided) 95%; 0.498 to 0.794
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival (OS) Time
Description	OS was defined as the time (in months) from randomization to death. For subjects who were still alive at the analysis data cut-off date or who lost to follow-up, survival was censored at the last recorded date that the subject was known to be alive.
Time Frame	Baseline up to 333 weeks

Outcome Measure Data

Analysis Population Description

MITT population included all subjects with RAS wild-type tumor status who were randomized to study treatment and who received at least 1 dose of study treatment. Subjects were analyzed as randomized.

Arm/Group Title	Cetuximab + FOLFOX-4	FOLFOX-4
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-FU/FA. Cetuximab was always administered every 7 days with an initial dose of 400 mg/m^2 at 5 mg/min and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.
Measure Participants	193	200
Median (95% Confidence Interval) [months]	20.8	16.5

3. Secondary Outcome

Title	Best Overall Response Rate (ORR)
Description	The Best ORR was defined as the percentage of subjects having achieved complete response (CR) or partial response (PR) according to RECIST version 1.0 as determined by the IRC. CR: defined as disappearance of all target and all non-target lesions and no new lesions. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters, no progression of non-target lesions and no new lesions.
Time Frame	Baseline up to 333 weeks

Outcome Measure Data

Analysis Population Description

MITT population included all subjects with RAS wild-type tumor status who were randomized to study treatment and who received at least 1 dose of study treatment. Subjects were analyzed as randomized.

Arm/Group Title	Cetuximab + FOLFOX-4	FOLFOX-4
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-FU/FA. Cetuximab was always administered every 7 days with an initial dose of 400 mg/m^2 at 5 mg/min and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.
Measure Participants	193	200
Number (95% Confidence Interval) [percentage of subjects]	66.3	40.5

4. Secondary Outcome

Title	Time to Treatment Failure (TTF)
Description	TTF was defined as time from randomization to date of the first occurrence of radiologically confirmed PD as determined by IRC, Clinical PD according to the Investigator's assessment (if radiological confirmation of PD by IRC was unavailable), discontinuation of treatment due to progression or adverse event, start of new anticancer therapy, withdrawal of consent, or death within 90 days of last tumor assessment or randomization. Subjects without event were censored on the date of last tumor assessment.
Time Frame	Baseline up to 333 weeks

Outcome Measure Data

Analysis Population Description

MITT population included all subjects with RAS wild-type tumor status who were randomized to study treatment and who received at least 1 dose of study treatment. Subjects were analyzed as randomized.

Arm/Group Title	Cetuximab + FOLFOX-4	FOLFOX-4
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-FU/FA. Cetuximab was always administered every 7 days with an initial dose of 400 mg/m^2 at 5 mg/min and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.
Measure Participants	193	200
Median (95% Confidence Interval) [months]	9.2	5.6

5. Secondary Outcome

Title	Number of Subjects With Curative Surgery of Liver Metastases
Description	The number of subjects who underwent liver metastatic surgery after start of treatment and the outcome of surgery with respect to residual tumor after surgery (R0, R1, R2, not evaluable) were summarized. In case of resection of more than one metastasis, the worst outcome of surgery defined the overall status of a subject. R0 = No residual tumor after resection (all lesions resected completely); R1 = Metastases not resected completely with microscopic residual lesions; and R2 = Metastases not resected completely with macroscopic residual lesions.
Time Frame	Baseline up to 333 weeks

Outcome Measure Data

Analysis Population Description

MITT population included all subjects with RAS wild-type tumor status who were randomized to study treatment and who received at least 1 dose of study treatment. Subjects were analyzed as randomized. Here "Number Analyzed" signifies those subjects who were evaluable for the specified categories.

Arm/Group Title	Cetuximab + FOLFOX-4	FOLFOX-4
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-FU/FA. Cetuximab was always administered every 7 days with an initial dose of 400 mg/m^2 at 5 mg/min and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.	Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.
Measure Participants	193	200
Subjects with liver surgery	9	6
Subjects with liver surgery outcome: R0	7	2
Subjects with liver surgery outcome: R1	1	2
Subjects with liver surgery outcome: R2	0	0
Subjects not evaluable	0	0

Adverse Events

Time Frame	Baseline up to Safety Follow up (assessed up to 333 weeks)
Adverse Event Reporting Description	Modified safety population included all subjects with RAS wild type tumor status who received any study treatment (cetuximab, oxaliplatin or 5-FU/FA). Subjects were analyzed as treated.
Arm/Group Title	Cetuximab + FOLFOX-4		FOLFOX-4
Arm/Group Description	Subjects received cetuximab in combination with FOLFOX-4 chemotherapy regimen. FOLFOX-4 chemotherapy regimen consists of a combination of oxaliplatin with 5-FU/FA. Cetuximab was always administered every 7 days with an initial dose of 400 mg/m^2 at 5 mg/min and 250 mg/m^2 at 10 mg/min for subsequent infusions, followed by oxaliplatin 85 mg/m^2 infused over 120 minutes at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin, FA was administered at a dose of 200 mg/m^2 infused over 120 minutes, on Day 1, Day 2, and every 2 weeks and then 5- FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours, on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.		Subjects received FOLFOX-4 chemotherapy regimen that consists of a combination of oxaliplatin with 5-FU/FA. Oxaliplatin 85 mg/m^2 infused over 120 minutes was administered first or simultaneously with FA at a dose of 200 mg/m^2 infused over 120 minutes on Day 1, Day 2, and every 2 weeks and then 5-FU was administered as a bolus of 400 mg/m^2/day intravenously over 2-4 minutes followed by 600 mg/m^2/day infused over 22 hours on Day 1, Day 2, and every 2 weeks. All subjects received treatment until progression of disease, withdrawal of consent, or unacceptable toxicity.
All Cause Mortality
	Cetuximab + FOLFOX-4		FOLFOX-4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	157/194 (80.9%)		173/199 (86.9%)
Serious Adverse Events
	Cetuximab + FOLFOX-4		FOLFOX-4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/194 (21.6%)		27/199 (13.6%)
Blood and lymphatic system disorders
BONE MARROW FAILURE	1/194 (0.5%)		1/199 (0.5%)
FEBRILE NEUTROPENIA	1/194 (0.5%)		0/199 (0%)
LEUKOPENIA	1/194 (0.5%)		0/199 (0%)
NEUTROPENIA	1/194 (0.5%)		1/199 (0.5%)
THROMBOCYTOPENIA	0/194 (0%)		2/199 (1%)
THROMBOCYTOPENIC PURPURA	0/194 (0%)		2/199 (1%)
THROMBOCYTOPENIC PURPURA	0/194 (0%)		1/199 (0.5%)
Cardiac disorders
ATRIAL FLUTTER	0/194 (0%)		1/199 (0.5%)
VENTRICULAR TACHYCARDIA	1/194 (0.5%)		0/199 (0%)
Eye disorders
RETINAL DETACHMENT	1/194 (0.5%)		0/199 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	1/194 (0.5%)		0/199 (0%)
ANAL FISTULA	1/194 (0.5%)		0/199 (0%)
DIARRHOEA	1/194 (0.5%)		0/199 (0%)
ENTERITIS	1/194 (0.5%)		0/199 (0%)
INCARCERATED INGUINAL HERNIA	1/194 (0.5%)		0/199 (0%)
INTESTINAL OBSTRUCTION	7/194 (3.6%)		4/199 (2%)
INTESTINAL PERFORATION	1/194 (0.5%)		0/199 (0%)
LARGE INTESTINAL OBSTRUCTION	1/194 (0.5%)		0/199 (0%)
SMALL INTESTINAL OBSTRUCTION	0/194 (0%)		1/199 (0.5%)
LARGE INTESTINE POLYP	1/194 (0.5%)		0/199 (0%)
General disorders
MULTI-ORGAN FAILURE	3/194 (1.5%)		3/199 (1.5%)
PYREXIA	0/194 (0%)		1/199 (0.5%)
SUDDEN DEATH	1/194 (0.5%)		0/199 (0%)
Hepatobiliary disorders
CHOLECYSTITIS	0/194 (0%)		1/199 (0.5%)
HEPATIC FAILURE	2/194 (1%)		0/199 (0%)
HYPERBILIRUBINAEMIA	1/194 (0.5%)		1/199 (0.5%)
JAUNDICE CHOLESTATIC	0/194 (0%)		1/199 (0.5%)
Immune system disorders
DRUG HYPERSENSITIVITY	2/194 (1%)		1/199 (0.5%)
Infections and infestations
ANAL ABSCESS	0/194 (0%)		1/199 (0.5%)
EPIDIDYMITIS	1/194 (0.5%)		0/199 (0%)
INFECTION	0/194 (0%)		1/199 (0.5%)
LOWER RESPIRATORY TRACT INFECTION	1/194 (0.5%)		0/199 (0%)
PNEUMONIA	1/194 (0.5%)		1/199 (0.5%)
SEPTIC SHOCK	1/194 (0.5%)		0/199 (0%)
SKIN INFECTION	1/194 (0.5%)		1/199 (0.5%)
STAPHYLOCOCCAL BACTERAEMIA	0/194 (0%)		1/199 (0.5%)
STAPHYLOCOCCAL INFECTION	1/194 (0.5%)		0/199 (0%)
INFUSION SITE INFECTION	1/194 (0.5%)		0/199 (0%)
RESPIRATORY TRACT INFECTION	1/194 (0.5%)		1/199 (0.5%)
Investigations
HAEMOGLOBIN DECREASED	1/194 (0.5%)		0/199 (0%)
ALANINE AMINOTRANSFERASE INCREASED	1/194 (0.5%)		0/199 (0%)
ASPARTATE AMINOTRANSFERASE INCREASED	1/194 (0.5%)		0/199 (0%)
Metabolism and nutrition disorders
TYPE 2 DIABETES MELLITUS	1/194 (0.5%)		0/199 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
COLON CANCER METASTATIC	1/194 (0.5%)		0/199 (0%)
Nervous system disorders
CEREBRAL INFARCTION	0/194 (0%)		2/199 (1%)
HEADACHE	0/194 (0%)		1/199 (0.5%)
HEPATIC ENCEPHALOPATHY	1/194 (0.5%)		0/199 (0%)
SYNCOPE	1/194 (0.5%)		0/199 (0%)
Psychiatric disorders
SUICIDE ATTEMPT	1/194 (0.5%)		0/199 (0%)
Renal and urinary disorders
RENAL FAILURE	1/194 (0.5%)		0/199 (0%)
URETERIC OBSTRUCTION	2/194 (1%)		0/199 (0%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA AT REST	2/194 (1%)		0/199 (0%)
Vascular disorders
AXILLARY VEIN THROMBOSIS	1/194 (0.5%)		0/199 (0%)
DEEP VEIN THROMBOSIS	1/194 (0.5%)		0/199 (0%)
JUGULAR VEIN THROMBOSIS	1/194 (0.5%)		0/199 (0%)
PHLEBITIS	0/194 (0%)		2/199 (1%)
SUBCLAVIAN VEIN THROMBOSIS	1/194 (0.5%)		0/199 (0%)
VENOUS THROMBOSIS LIMB	2/194 (1%)		1/199 (0.5%)
Other (Not Including Serious) Adverse Events
	Cetuximab + FOLFOX-4		FOLFOX-4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	194/194 (100%)		194/199 (97.5%)
Blood and lymphatic system disorders
ANAEMIA	28/194 (14.4%)		24/199 (12.1%)
BONE MARROW FAILURE	18/194 (9.3%)		14/199 (7%)
LEUKOPENIA	151/194 (77.8%)		146/199 (73.4%)
NEUTROPENIA	156/194 (80.4%)		149/199 (74.9%)
THROMBOCYTOPENIA	92/194 (47.4%)		102/199 (51.3%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	21/194 (10.8%)		13/199 (6.5%)
ABDOMINAL PAIN	37/194 (19.1%)		19/199 (9.5%)
CONSTIPATION	43/194 (22.2%)		29/199 (14.6%)
DIARRHOEA	69/194 (35.6%)		35/199 (17.6%)
GASTROOESOPHAGEAL REFLUX DISEASE	12/194 (6.2%)		5/199 (2.5%)
HAEMATOCHEZIA	10/194 (5.2%)		5/199 (2.5%)
MOUTH ULCERATION	22/194 (11.3%)		9/199 (4.5%)
NAUSEA	70/194 (36.1%)		92/199 (46.2%)
STOMATITIS	32/194 (16.5%)		14/199 (7%)
VOMITING	43/194 (22.2%)		52/199 (26.1%)
General disorders
FATIGUE	77/194 (39.7%)		56/199 (28.1%)
PYREXIA	59/194 (30.4%)		48/199 (24.1%)
ASTHENIA	11/194 (5.7%)		13/199 (6.5%)
Hepatobiliary disorders
HYPERBILIRUBINAEMIA	19/194 (9.8%)		21/199 (10.6%)
LIVER INJURY	12/194 (6.2%)		6/199 (3%)
Immune system disorders
DRUG HYPERSENSITIVITY	18/194 (9.3%)		15/199 (7.5%)
Infections and infestations
NASOPHARYNGITIS	10/194 (5.2%)		4/199 (2%)
PARONYCHIA	28/194 (14.4%)		0/199 (0%)
UPPER RESPIRATORY TRACT INFECTION	18/194 (9.3%)		14/199 (7%)
Injury, poisoning and procedural complications
INFUSION RELATED REACTION	20/194 (10.3%)		12/199 (6%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	65/194 (33.5%)		54/199 (27.1%)
ASPARTATE AMINOTRANSFERASE INCREASED	58/194 (29.9%)		58/199 (29.1%)
BLOOD ALBUMIN DECREASED	12/194 (6.2%)		4/199 (2%)
BLOOD ALKALINE PHOSPHATASE INCREASED	16/194 (8.2%)		8/199 (4%)
BLOOD BILIRUBIN INCREASED	15/194 (7.7%)		7/199 (3.5%)
BLOOD LACTATE DEHYDROGENASE INCREASED	11/194 (5.7%)		11/199 (5.5%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	12/194 (6.2%)		11/199 (5.5%)
HAEMOGLOBIN DECREASED	28/194 (14.4%)		42/199 (21.1%)
NEUTROPHIL COUNT DECREASED	11/194 (5.7%)		13/199 (6.5%)
PLATELET COUNT DECREASED	19/194 (9.8%)		18/199 (9%)
WEIGHT DECREASED	51/194 (26.3%)		26/199 (13.1%)
WEIGHT INCREASED	23/194 (11.9%)		14/199 (7%)
WHITE BLOOD CELL COUNT DECREASED	14/194 (7.2%)		9/199 (4.5%)
Metabolism and nutrition disorders
DECREASED APPETITE	75/194 (38.7%)		60/199 (30.2%)
HYPERGLYCAEMIA	10/194 (5.2%)		5/199 (2.5%)
HYPOALBUMINAEMIA	13/194 (6.7%)		13/199 (6.5%)
HYPOCALCAEMIA	23/194 (11.9%)		14/199 (7%)
HYPONATRAEMIA	16/194 (8.2%)		18/199 (9%)
HYPOPHOSPHATAEMIA	12/194 (6.2%)		4/199 (2%)
HYPOKALAEMIA	65/194 (33.5%)		38/199 (19.1%)
HYPOMAGNESAEMIA	39/194 (20.1%)		6/199 (3%)
HYPOPROTEINAEMIA	7/194 (3.6%)		11/199 (5.5%)
Musculoskeletal and connective tissue disorders
BACK PAIN	11/194 (5.7%)		11/199 (5.5%)
Nervous system disorders
HYPOAESTHESIA	25/194 (12.9%)		27/199 (13.6%)
NEUROTOXICITY	15/194 (7.7%)		18/199 (9%)
Psychiatric disorders
INSOMNIA	11/194 (5.7%)		10/199 (5%)
INSOMNIA	10/194 (5.2%)		10/199 (5%)
Respiratory, thoracic and mediastinal disorders
COUGH	18/194 (9.3%)		16/199 (8%)
Skin and subcutaneous tissue disorders
DERMATITIS ACNEIFORM	31/194 (16%)		1/199 (0.5%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	17/194 (8.8%)		7/199 (3.5%)
PRURITUS	10/194 (5.2%)		3/199 (1.5%)
RASH	120/194 (61.9%)		7/199 (3.5%)
SKIN FISSURES	17/194 (8.8%)		0/199 (0%)
DRY SKIN	11/194 (5.7%)		0/199 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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