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Clinical Trial Results:
A prospective randomised open label trial of oxaliplatin / irinotecan plus fluorouracil versus oxaliplatin / irinotecan plus fluorouracil and cetuximab pre and post operatively in patients with resectable colorectal liver metastases requiring chemotherapy.

Summary
EudraCT number	2006-003121-82
Trial protocol	GB
Global end of trial date	18 Dec 2016

Results information
Results version number	v1(current)
This version publication date	13 Dec 2021
First version publication date	13 Dec 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

4351

ISRCTN number

ISRCTN22944367

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University Hospital Southampton NHS Foundation Trust

Sponsor organisation address

MP138, Tremona Road, Southampton, United Kingdom, SO16 6YD

Public contact

Professor John Primrose, University Surgical Unit MP816, Southampton General Hospital Tremona Road Southampton SO16 6YD, 02380 796144, j.n.primrose@southampton.ac.uk

Scientific contact

Professor John Primrose, University Surgical Unit MP816, Southampton General Hospital Tremona Road Southampton SO16 6YD, 02380 796144, j.n.primrose@southampton.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

22 May 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Dec 2016

Global end of trial reached?

Yes

Global end of trial date

18 Dec 2016

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary aim of the New EPOC trial is to determine whether the addition of cetuximab to oxaliplatin plus modified de Gramont or irinotecan plus modified de Gramont combination chemotherapy results in improved progression free survival when compared with combination chemotherapy alone in patients who do not possess a KRAS mutant genotype confirmed by laboratory analysis.

Protection of trial subjects

Treatment duration and breaks o Arm A (Control, OxMdG / IrMdG): These patients will receive 12 weeks of pre-operative and 12 weeks of post-operative chemotherapy dependent on cumulative toxicity, post-surgical performance status or because of patient choice to stop chemotherapy. Patients in this arm should continue on treatment with no more than a three week interval off treatment for any reason although the post surgical interval can be 6 weeks. The cumulative toxicity that is most likely to occur is the neuropathy associated with Oxaliplatin, which increases in incidence from about 12 weeks duration of therapy. If this occurs, patients may continue on the fluorouraracil component of the regimen with dose increment. If the neuropathy resolves to < grade 1 the Oxaliplatin may be reintroduced cautiously at the investigator’s discretion. o Arm B: OxMdG / IrMdG plus Cetuximab: These patients will receive chemotherapy as Arm A above plus Cetuximab. Patients in this arm should continue on treatment with no more than a three week interval off treatment for any reason although the post surgical interval can be 6 weeks. Cetuximab will be continued if chemotherapy is stopped because of toxicity or patient choice, but should be discontinued on recurrence or unacceptable Cetuximab toxicity.

Background therapy

OxMdG: l-folinic acid (175 mg flat dose IV over 2 h) or d,l-folinic acid (350 mg flat dose IV over 2 h), concurrent administration of Oxaliplatin (85 mg/m2 IV over 2 h) plus 5 minute bolus of 5FU (400 mg/m2) followed by a 46 h IV infusion of 5FU 2400 mg/m2 repeated every 2 weeks as used in the FOCUS trial or IrMdG: Irinotecan 180 mg/m2 IV over 30 minutes, l-folinic acid (175 mg flat dose IV over 2 h) or d,lfolinic acid (350 mg flat dose IV over 2 h) plus 5 minute bolus of 5FU (400 mg/m2) followed by a 46 h IV infusion of 5FU 2400 mg/m2 repeated every 2 weeks as used in the FOCUS trial in patients intolerant of Oxaliplatin. NOTE: Prior to the introduction of IrMdG, patients could receive CAPOX: Oxaliplatin 130 mg/m2 IV over 2 hours plus capecitabine 1000 mg/m2 bid po days 1-15 (28 doses) repeated 3 weekly Background of these drugs (from latest version of protocol 11Oct17): Over 16,000 people die of colorectal cancer per annum in the UK (CR-UK Cancer Statistics, http://info.cancerresearchuk.org/cancerstats/reports/), most of whom die with metastatic disease. However the treatment of metastatic colorectal cancer is improving. The median survival has improved from about 6 months with best supportive care alone, through 10-12 months with 5FU regimens, up to 16-20 months in recent randomised trials including Irinotecan and/or Oxaliplatin and up to 27 months in other recent studies using targeted monoclonal antibodies. Recent data demonstrate increased response rates (31-56%), median progression-free survival (PFS, 6.5-9.0 months) and median overall survival (OS, 14.5-21.4 months) achieved with combination chemotherapy in first line therapy. The CR08 [FOCUS] trial compared 5 different schedules of administration of 5FU (using the modified de Gramont regimen) in combination with Irinotecan or Oxaliplatin in either first or second line therapy and has demonstrated the efficacy of first line combination chemotherapy.

Evidence for comparator

Cetuximab (Merck KGaA, Darmstadt, Germany) is a monoclonal antibody to EGFR with activity in KRAS exon 2 wild-type colorectal cancer as a single agent. After promising phase 2 data, several studies assessed the benefit of cetuximab and panitumumab, a similar antibody, in combination with chemotherapy. In 2005, the COIN trial was initiated to investigate the addition of cetuximab to oxaliplatin and fluoropyrimidine chemotherapy in first-line treatment of advanced colorectal cancer. The New EPOC trial was begun as a rational extension to the COIN study, the EPOC study, and supportive phase 2 data, using much the same investigational strategies to assess whether the addition of cetuximab to oxaliplatin–fluoropyrimidine chemotherapy improved outcomes for patients with operable liver metastasis.

Actual start date of recruitment

26 Feb 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Scientific research

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 271

Worldwide total number of subjects

271

EEA total number of subjects

271

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

138

From 65 to 84 years

133

85 years and over

Subject disposition

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Recruitment details

271/288 required pts were randomised between 26Feb07-12Oct12. 14 pts were non-kRAS exon 2 wild-type (before amendment requiring kRAS testing), leaving 257 pts for the primary analyses. The study was closed to recruitment by the Trial Steering Committee on advice from the IDMC on 01Nov12 when the predefined futility criteria were met.

Screening details

All patients were recruited from UK National Health Service hospitals. The study was approved by the South West Research Ethics Committee, and data were reviewed by the Independent data monitoring committee (IDMC). Written informed consent was obtained from all patients before random assignment.

Number of subjects started

823 ^[1]

Number of subjects completed

257

Reason: Number of subjects

Not meeting inclusion criteria: 402

Reason: Number of subjects

Patient/clinician choice: 104

Reason: Number of subjects

Other: 60

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Number in pre-assignment period reflects the number of patients screened for the study as per the published CONSORT diagram. The worldwide number is the number registered to the trial.

Period 1 title

Primary Analysis Population (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemotherapy alone

Arm description

Patients in this arm will receive either OxMdG or IrMdG: OxMdG: l-folinic acid (175 mg flat dose IV over 2 h) or d,l-folinic acid (350 mg flat dose IV over 2 h), concurrent administration of Oxaliplatin (85 mg/m2 IV over 2 h) plus 5 minute bolus 5FU (400 mg/m2) followed by a 46 h IV infusion of 5FU 2400 mg/m2 repeated every 2 weeks as used in the FOCUS trial or IrMdG: Irinotecan 180 mg/m2 IV over 30 minutes, l-folinic acid (175 mg flat dose IV over 2 h) or d,l-folinic acid (350 mg flat dose IV over 2 h) plus 5 minute bolus of 5FU (400 mg/m2) followed by a 46 h IV infusion of 5FU 2400 mg/m2 repeated every 2 weeks as used in the FOCUS trial in patients intolerant of Oxaliplatin. NOTE: Prior to the introduction of IrMdG, patients could receive CAPOX: Oxaliplatin 130 mg/m2 IV over 2 hours plus capecitabine 1000 mg/m2 bid po days 1-15 (28 doses) repeated 3 weekly

Arm type

Active comparator

Investigational medicinal product name

l-folinic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

175 mg flat dose IV over 2 h

Investigational medicinal product name

d,l-folinic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

350 mg flat dose IV over 2 h

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

concurrent administration of Oxaliplatin (85 mg/m2 IV over 2 h)

Investigational medicinal product name

5FU

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

5 minute bolus of 5FU (400 mg/m2; may also be given as a short 5 minute infusion or 15-30 minute infusion where this reflects local practice)

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan 180 mg/m2 IV over 30 minutes

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

capecitabine 1000 mg/m2 bid po days 1-15 (28 doses) repeated 3 weekly

Chemotherapy and Cetuximab

Arm description

Patients in this arm will receive either OxMdG or IrMdG, and Cetuximab (see Cetuximab dosage and administration details section): OxMdG: l-folinic acid (175 mg flat dose IV over 2 h) or d,l-folinic acid (350 mg flat dose IV over 2 h), concurrent administration of Oxaliplatin (85 mg/m2 IV over 2 h) plus 5 minute bolus of 5FU (400 mg/m2) followed by a 46 h IV infusion of 5FU 2400 mg/m2 repeated every 2 weeks as used in the FOCUS trial or IrMdG: Irinotecan 180 mg/m2 IV over 30 minutes, l-folinic acid (175 mg flat dose IV over 2 h) or d,l-folinic acid (350 mg flat dose IV over 2 h) plus 5 minute bolus of 5FU (400 mg/m2) followed by a 46 h IV infusion of 5FU 2400 mg/m2 repeated every 2 weeks as used in the FOCUS trial in patients intolerant of Oxaliplatin. NOTE: Prior to the introduction of IrMdG, patients could receive CAPOX: Oxaliplatin 130 mg/m2 IV over 2 hours plus capecitabine 1000 mg/m2 bid po days 1-15 (28 doses) repeated 3 weekly

Arm type

Experimental

Investigational medicinal product name

l-folinic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

175 mg flat dose IV over 2 h

Investigational medicinal product name

d,l-folinic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

350 mg flat dose IV over 2 h

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

concurrent administration of Oxaliplatin (85 mg/m2 IV over 2 h)

Investigational medicinal product name

5FU

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

5 minute bolus of 5FU (400 mg/m2; may also be given as a short 5 minute infusion or 15-30 minute infusion where this reflects local practice)

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients will receive Cetuximab intravenous infusions at a dose of 500 mg/m2 to be administered over 2 hours and thereafter fortnightly infusions, or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 for patients on the CAPOX regimen. Cetuximab is provided in ready use vials containing 5 mg/ml. Once removed from the vial, Cetuximab must be used within 8 hours if stored at room temperature.

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan 180 mg/m2 IV over 30 minutes

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

capecitabine 1000 mg/m2 bid po days 1-15 (28 doses) repeated 3 weekly

Number of subjects in period 1 ^[2]	Chemotherapy alone	Chemotherapy and Cetuximab
Started	128	129
Completed pre-operative chemotherapy	99 ^[3]	103 ^[4]
Operated	113 ^[5]	108 ^[6]
Resected	108 ^[7]	100 ^[8]
Completed post-operative chemotherapy	59 ^[9]	62 ^[10]
Completed	128	129

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Numbers in baseline period reflect the number of randomised patients. The worldwide number includes those registered but not randomised to a treatment arm.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.
[10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all patients were included in each milestone as the milestones were set up to show how many patients received each intervention. Number completed includes all randomised patients followed-up.

Baseline characteristics

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Reporting group title

Chemotherapy alone

Reporting group description

Reporting group title

Chemotherapy and Cetuximab

Reporting group description

Reporting group values	Chemotherapy alone	Chemotherapy and Cetuximab	Total
Number of subjects	128	129	257
Age categorical
Units: Subjects
Adults (18-64 years)	61	69	130
From 65-84 years	67	60	127
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	65 (59 to 70)	64 (59 to 69)	-
Gender categorical
Units: Subjects
Female	47	37	84
Male	81	92	173
WHO performance status
Units: Subjects
WHO of 0	86	87	173
WHO of 1	42	39	81
WHO of 2	0	3	3
CEA level if raised (ng/ml)
Units: Subjects
CEA <= 5	45	42	87
5 > CEA <= 30	48	50	98
CEA > 30	31	34	65
Missing	4	3	7
Minimisation factor 1 (See description)
Does patient have one or more of the following >=4 metastases, poor differentiation at biopsy, N2 disease?
Units: Subjects
Yes	68	71	139
No	60	57	117
Missing	0	1	1
Minimisation factor 2 (See description)
Prior treatment with Oxaliplatin
Units: Subjects
Yes	11	15	26
No	117	114	231
Minimisation factor 3 (See description)
Surgical Site.
Units: Subjects
Aintree	8	9	17
Barts	6	5	11
Basingstoke	12	10	22
Belfast	1	0	1
Bristol	20	22	42
Cambridge (Addenbrookes)	3	1	4
Cardiff	1	1	2
Edinburgh	1	0	1
Hammersmith	4	4	8
Hampstead	10	10	20
King's College	7	8	15
London	9	9	18
Manchester	0	3	3
Royal Marsden (London)	6	9	15
Nottingham	1	2	3
Pennine	9	10	19
Sheffield	11	10	21
Southampton	15	13	28
Surrey	4	2	6
Missing	0	1	1
Extension of the primary cancer
Units: Subjects
Absent (T1 or T2)	18	11	29
Present (T3 or T4)	107	109	216
Not Available	3	9	12
Lymphatic spread of the primary cancer
Units: Subjects
Absent (N0)	42	41	83
Present (N1 or N2)	83	78	161
Not Available	3	10	13
Presentation of Disease
Units: Subjects
Synchronous metastases	73	88	161
Non-synchronous metastases	55	41	96
Prior Treatment (see description)
Prior treatment with Oxaliplatin/ Prior adjuvant chemotherapy for primary cancer
Units: Subjects
Yes (both)	10	12	22
Yes (adjuvant chemotherapy only)	15	9	24
Yes (oxaliplatin chemotherapy only)	1	3	4
No	102	105	207
Site of Primary Tumour
Units: Subjects
Right colon	22	20	42
Left Colon	23	30	53
Rectum	39	31	70
Rectosigmoid junction	19	20	39
Other	25	28	53
Number of lesions measured
Units: Subjects
1 Lesion	63	59	122
2 Lesions	34	30	64
3 Lesions	15	26	41
4 Lesions	8	9	17
5 Lesions	8	4	12
Not measured	0	1	1
Poor differentiation at biopsy
Units: Subjects
Yes	10	15	25
No	109	109	218
Missing	9	5	14
Planned backbone treatment
Planned backbone treatment (using regimen received at cycle 1)
Units: Subjects
CAPOX	27	24	51
OxMdG	87	89	176
IrMdG	11	15	26
Missing	3	1	4
>3cm tumour diameter in at least one lesion at screening assessment
Units: Subjects
Yes	63	75	138
No	65	54	119
Extrahepatic involvement
Units: Subjects
Yes	3	6	9
No	125	122	247
Missing	0	1	1
Lymph node positive primary
Lymph node positive primary (yes/no)
Units: Subjects
Yes	83	78	161
No	42	41	83
Missing	3	10	13
Status of primary tumour
Units: Subjects
Resected	119	110	229
Unresected	9	18	27
Missing	0	1	1
Number of metastases
Units: Subjects
1 to 3	103	97	200
4 or more	25	32	57
Time from primary tumour diagnosis to metastatic disease diagnosis (years), categorical
Time from primary tumour diagnosis to metastatic disease diagnosis (years), categorical
Units: Subjects
<2 years	116	115	231
2 or more years	12	14	26
Plasma CEA level at the time of diagnosis of liver metastases
Plasma CEA level (ng/ml) at the time of diagnosis of liver metastases
Units: Subjects
<=5	45	42	87
>5 to <=30	48	50	98
>30	31	34	65
Missing	4	3	7
Plasma CEA level at the time of diagnosis of liver metastases, binary
Plasma CEA level (ng/ml) at the time of diagnosis of liver metastases, binary
Units: Subjects
>30	31	34	65
<=30	93	92	185
Missing	4	3	7
Time from primary tumour diagnosis to randomisation
Units: Months
median (inter-quartile range (Q1-Q3))	4.3 (2.6 to 17.5)	3.5 (2.4 to 11.4)	-
Sum of the largest diameters of lesions on imaging
Sum of the largest diameters of lesions on imaging (in mm), using the 5 largest lesions.
Units: mm
median (inter-quartile range (Q1-Q3))	44.5 (27 to 73)	53 (30 to 83)	-
Time from metastatic disease diagnosis to randomisation
Units: Months
median (inter-quartile range (Q1-Q3))	2.02 (1.22 to 3.12)	2.14 (1.31 to 3.06)	-

End points

Top of page

Reporting group title

Chemotherapy alone

Reporting group description

Reporting group title

Chemotherapy and Cetuximab

Reporting group description

Primary: Progression-Free Survival (primary endpoint, at interim analysis)

Top of page

End point title

Progression-Free Survival (primary endpoint, at interim analysis)

End point description

End point type

Primary

End point timeframe

Median Progression-Free Survival, associated unadjusted Hazard Ratio (pre-specified primary endpoint) and adjusted HR (secondary) assessed when on 01Nov12 median follow-up was 21.1 months in the chemo alone arm and 19.8 months in the chemo+cetuximab arm

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	117 ^[1]	119 ^[2]
Units: Months
number (confidence interval 95%)	20.5 (16.8 to 26.7)	14.1 (11.8 to 15.9)

Attachments

KM PFS by Arm (at Interim)

Notes
[1] - 11 not reached/withdrew consent before/not assessed for RECIST assessment at time of analysis
[2] - 10 not reached/withdrew consent before/not assessed for RECIST assessment at time of analysis

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for hazard ratio: Arm A (Chemotherapy Alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.03

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.48

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

2.12

Adjusted Hazard Ratio

Statistical analysis description

Hazard Ratio adjusted for minimisation factors. Reference category for hazard ratio: Arm A (Chemotherapy Alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.059

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.42

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

2.04

Primary: Progression Free Survival (at final analysis)

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End point title

Progression Free Survival (at final analysis)

End point description

End point type

Primary

End point timeframe

Median PFS, unadjusted Hazard Ratio (primary), and Hazard Ratio adjusted for minimisation factors (secondary) assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	128	129
Units: Months
number (confidence interval 95%)	22.0 (18.3 to 26.8)	16.0 (13.8 to 19.0)

Attachments

KM PFS by Arm (at Final)

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy and Cetuximab v Chemotherapy alone

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.304

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.56

Adjusted Hazard Ratio

Statistical analysis description

Hazard Ratio adjusted for minimisation factors. Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.401

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.52

Secondary: Overall Survival (at interim analysis)

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End point title

Overall Survival (at interim analysis)

End point description

End point type

Secondary

End point timeframe

Median Overall Survival and associated unadjusted Hazard Ratio assessed on 1 Nov 2012 when median follow-up was 21.1 months in the chemotherapy alone arm and 19.8 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	117 ^[3]	119 ^[4]
Units: Months
number (confidence interval 95%)	0 (0 to 0)	39.1 (23.6 to 100)

Attachments

KM OS by Arm (at Interim)

Notes
[3] - 11 not reached/withdrew/not assessed at time of analysis. Median Overall Survival not reached.
[4] - 10 not reached/withdrew/not assessed at time of analysis. Median OS upper CI not reached.

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.16

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

2.6

Secondary: Overall Survival (at final analysis)

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End point title

Overall Survival (at final analysis)

End point description

End point type

Secondary

End point timeframe

Median Overall Survival, unadjusted Hazard Ratio, and Hazard Ratio adjusted for minimisation factors assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	128 ^[5]	129
Units: Months
number (confidence interval 95%)	81.0 (59.6 to 100)	55.0 (43.5 to 71.5)

Attachments

KM OS by Arm (at Final)

Notes
[5] - (Median Overall Survival Upper CI not reached)

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.036

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.45

Confidence interval

level

95%

sides

2-sided

lower limit

1.02

upper limit

2.05

Adjusted Hazard Ratio

Statistical analysis description

Hazard Ratio adjusted for minimisation factors. Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.44

Confidence interval

level

95%

sides

2-sided

lower limit

1.02

upper limit

2.05

Secondary: Progression Free Survival (pts not on CAPOX, at final analysis)

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End point title

Progression Free Survival (pts not on CAPOX, at final analysis)

End point description

End point type

Secondary

End point timeframe

Median PFS and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	101 ^[6]	105 ^[7]
Units: Months
number (confidence interval 95%)	22.2 (18.3 to 26.8)	15.2 (13.0 to 19.0)

Attachments

KM PFS by Arm (pts not on CAPOX at Final)

Notes
[6] - Excluding patients on CAPOX.
[7] - Excluding patients on CAPOX.

No statistical analyses for this end point

Secondary: Pathological Resection status (at final analysis)

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End point title

Pathological Resection status (at final analysis)

End point description

End point type

Secondary

End point timeframe

at final analysis

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	108 ^[8]	100 ^[9]
Units: subjects
R0	89	79
R1	13	17
R2	6	4

Notes
[8] - Only patients who had surgery and resection performed
[9] - Only patients who had surgery and resection performed

No statistical analyses for this end point

Secondary: Response to Pre-Operative Chemotherapy (after pre-op, at final analysis)

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End point title

Response to Pre-Operative Chemotherapy (after pre-op, at final analysis)

End point description

End point type

Secondary

End point timeframe

at final analysis

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	120 ^[10]	126 ^[11]
Units: number
Complete Response	6	8
Partial Response	72	85
Stable Disease	33	23
Progressive Disease	9	10

Notes
[10] - Excludes pts where not assessable or that died/withdrew before pre-operation visit at week 13
[11] - Excludes pts where not assessable or that died/withdrew before pre-operation visit at week 13

No statistical analyses for this end point

Secondary: Relative reduction in sum of the largest diameters of lesions on imaging (at final analysis)

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End point title

Relative reduction in sum of the largest diameters of lesions on imaging (at final analysis)

End point description

Relative reduction in the sum of the largest diameters of lesions on imaging from baseline to pre-op visit (i.e. visit closest to, but before, surgery).

End point type

Secondary

End point timeframe

at final analysis

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	128	129
Units: percent
median (inter-quartile range (Q1-Q3))	33.7 (23.4 to 50.4)	52.2 (16.7 to 72.3)

No statistical analyses for this end point

Secondary: Surgical Complications (at final analysis)

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End point title

Surgical Complications (at final analysis)

End point description

End point type

Secondary

End point timeframe

Surgical complications within 30 days of surgery. Assessed at final analysis.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	113 ^[12]	108 ^[13]
Units: Number of patients
At least one surgical complication	28	26
Deaths during surgery	0	0
Post-op death (30 days after liver resection)	0	1

Notes
[12] - Includes only analysis population who were operated on (prior to disease progression)
[13] - Includes only analysis population who were operated on (prior to disease progression)

No statistical analyses for this end point

Other pre-specified: Overall Survival (pts on OxMdG, at final analysis)

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End point title

Overall Survival (pts on OxMdG, at final analysis)

End point description

End point type

Other pre-specified

End point timeframe

Median Overall Survival and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	87 ^[14]	89 ^[15]
Units: Months
number (confidence interval 95%)	59.2 (59.2 to 100)	56.5 (43.5 to 100)

Attachments

KM OS by Arm (pts on OxMdG at Final)

Notes
[14] - Excludes patients not on OxMdG. Median and Upper CI not reached.
[15] - Excludes patients not on OxMdG. Upper CI not reached.

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.06

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

2.36

Other pre-specified: Progression Free Survival (pts on OxMdG, at final analysis)

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End point title

Progression Free Survival (pts on OxMdG, at final analysis)

End point description

End point type

Other pre-specified

End point timeframe

Median PFS and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	87 ^[16]	89 ^[17]
Units: Months
number (confidence interval 95%)	22.2 (18.7 to 26.8)	15.2 (12.6 to 26.6)

Attachments

KM PFS by Arm (pts on OxMdG at Final)

Notes
[16] - Excludes patients not on OxMdG.
[17] - Excludes patients not on OxMdG.

No statistical analyses for this end point

Other pre-specified: Overall Survival (pts who responded to systemic treatment, at final analysis)

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End point title

Overall Survival (pts who responded to systemic treatment, at final analysis)

End point description

End point type

Other pre-specified

End point timeframe

Median Overall Survival and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	78 ^[18]	93 ^[19]
Units: Months
number (confidence interval 95%)	81.1 (65.7 to 100)	60.7 (48.0 to 100)

Attachments

KM OS by Arm (pts responded to sys trt at Final)

Notes
[18] - Excluding those who did not respond to systemic treatment. Upper CI not reached so set to 100
[19] - Excluding those who did not respond to systemic treatment. Upper CI not reached so set to 100

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.133

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

2.21

Other pre-specified: Progression Free Survival (pts who responded to systemic treatment, at final analysis)

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End point title

Progression Free Survival (pts who responded to systemic treatment, at final analysis)

End point description

End point type

Other pre-specified

End point timeframe

Median PFS and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	78 ^[20]	93 ^[21]
Units: Months
number (confidence interval 95%)	23.2 (19.1 to 35.5)	17.6 (14.8 to 27.4)

Attachments

KM PFS by Arm (pts responded to sys trt at Final)

Notes
[20] - Excluding those who did not respond to systemic treatment.
[21] - Excluding those who did not respond to systemic treatment.

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy and Cetuximab v Chemotherapy alone

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.802

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

1.51

Other pre-specified: Overall Survival (pts not on CAPOX, at final analysis)

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End point title

Overall Survival (pts not on CAPOX, at final analysis)

End point description

End point type

Other pre-specified

End point timeframe

Median Overall Survival and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	101 ^[22]	105 ^[23]
Units: Months
number (confidence interval 95%)	24.0 (24.0 to 100)	16.1 (13.9 to 100)

Attachments

KM OS by Arm (pts not on CAPOX at Final)

Notes
[22] - Excluding patients on CAPOX. Median and upper CI not reached.
[23] - Excluding patients on CAPOX. Upper CI not reached.

No statistical analyses for this end point

Post-hoc: Overall Survival (pts with left sided tumour, at final analysis)

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End point title

Overall Survival (pts with left sided tumour, at final analysis)

End point description

End point type

Post-hoc

End point timeframe

Median Overall Survival and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	103 ^[24]	100 ^[25]
Units: Months
number (confidence interval 95%)	81.0 (59.6 to 100)	60.7 (45.8 to 100)

Attachments

KM OS by Arm (pts with left tumour at Final)

Notes
[24] - Excluding patients without left sided tumour. Upper CI not reached
[25] - Excluding patients without left sided tumour. Upper CI not reached

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.148

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.99

Post-hoc: Progression free Survival (pts with left sided tumour, at final analysis)

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End point title

Progression free Survival (pts with left sided tumour, at final analysis)

End point description

End point type

Post-hoc

End point timeframe

Median PFS and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	103 ^[26]	100 ^[27]
Units: Months
number (confidence interval 95%)	21.9 (16.9 to 26.7)	15.7 (13.8 to 24.3)

Attachments

KM PFS by Arm (pts with left tumour at Final)

Notes
[26] - Excluding patients without left sided tumour.
[27] - Excluding patients without left sided tumour.

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.741

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.48

Post-hoc: Overall Survival (pts with right sided tumour, at final analysis)

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End point title

Overall Survival (pts with right sided tumour, at final analysis)

End point description

End point type

Post-hoc

End point timeframe

Median Overall Survival and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	25 ^[28]	29 ^[29]
Units: Months
number (confidence interval 95%)	36.2 (36.2 to 100)	42.6 (25.9 to 58.6)

Attachments

KM OS by Arm (pts with right tumour at Final)

Notes
[28] - Excluding patients without right sided primary tumour. Median and Upper CI not reached
[29] - Excluding patients without right sided primary tumour.

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.114

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

3.67

Post-hoc: Progression Free Survival (pts with right sided tumour, at final analysis)

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End point title

Progression Free Survival (pts with right sided tumour, at final analysis)

End point description

End point type

Post-hoc

End point timeframe

Median PFS and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	25 ^[30]	29 ^[31]
Units: Months
number (confidence interval 95%)	24.1 (11.2 to 100)	14.8 (11.4 to 17.6)

Attachments

KM PFS by Arm (pts with right tumour at Final)

Notes
[30] - Excluding patients without right sided primary tumour. Upper CI not reached
[31] - Excluding patients without right sided primary tumour.

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for Hazard Ratio: Arm A (Chemotherapy alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

3.06

Post-hoc: Post Progression Survival (pts who progressed, at final analysis)

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End point title

Post Progression Survival (pts who progressed, at final analysis)

End point description

Defined as time from progression to death from any cause.

End point type

Post-hoc

End point timeframe

Median PPS and unadjusted Hazard Ratio assessed on 22 May 2018, when median follow-up was 67 in the chemotherapy alone arm and 65 months in the chemotherapy plus cetuximab arm.

End point values	Chemotherapy alone	Chemotherapy and Cetuximab
Number of subjects analysed	82 ^[32]	85 ^[33]
Units: Months
number (confidence interval 95%)	33.5 (25.3 to 41.2)	23.5 (16.0 to 31.3)

Attachments

KM PPS by Arm (pts who progressed at Final)

Notes
[32] - Only patients who progressed.
[33] - Only patients who progressed.

Unadjusted Hazard Ratio

Statistical analysis description

Reference category for hazard ratio: Arm A (Chemotherapy Alone)

Comparison groups

Chemotherapy alone v Chemotherapy and Cetuximab

Number of subjects included in analysis

167

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.02

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.55

Confidence interval

level

95%

sides

2-sided

lower limit

1.07

upper limit

2.24

Adverse events

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Timeframe for reporting adverse events

Investigators to notify SCTU of all SAEs occurring from the time of randomisation until 30 days after the last protocol treatment administration.

Adverse event reporting additional description

Due to the way adverse event data was collected in the NEW EPOC trial relatedness was not collected for the majority of adverse events recorded. Therefore, the true number of related AEs could be higher than reported in these figures.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Chemotherapy alone

Reporting group description

Reporting group title

Chemotherapy and Cetuximab

Reporting group description

Serious adverse events	Chemotherapy alone	Chemotherapy and Cetuximab
Total subjects affected by serious adverse events
subjects affected / exposed	52 / 134 (38.81%)	57 / 137 (41.61%)
number of deaths (all causes)	60	77
number of deaths resulting from adverse events	1	4
Vascular disorders
thromboembolicevent
Additional description: thromboembolicevent
subjects affected / exposed	8 / 134 (5.97%)	7 / 137 (5.11%)
occurrences causally related to treatment / all	5 / 10	4 / 7
deaths causally related to treatment / all	0 / 0	1 / 1
hypotension
Additional description: hypotension
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
phlebitis
Additional description: phlebitis
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
peripheralischemia
Additional description: peripheralischemia
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
fatigue
Additional description: fatigue
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
hypothermia
Additional description: hypothermia
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
non-cardiacchestpain
Additional description: non-cardiacchestpain
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
fever
Additional description: fever
subjects affected / exposed	7 / 134 (5.22%)	3 / 137 (2.19%)
occurrences causally related to treatment / all	0 / 8	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
chestpain-cardiac
Additional description: chestpain-cardiac
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
edemalimbs
Additional description: edemalimbs
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
infusionsiteextravasation
Additional description: infusionsiteextravasation
subjects affected / exposed	2 / 134 (1.49%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
allergicreaction
Additional description: allergicreaction
subjects affected / exposed	1 / 134 (0.75%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
dyspnea
Additional description: dyspnea
subjects affected / exposed	2 / 134 (1.49%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
respiratoryfailure
Additional description: respiratoryfailure
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
thromboembolicevent
Additional description: thromboembolicevent
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
laryngospasm
Additional description: laryngospasm
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
confusion
Additional description: confusion
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Deranged liver function tests
Additional description: Deranged liver function tests
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
neutrophilcountdecreased
Additional description: neutrophilcountdecreased
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
intestinalstomasitebleeding
Additional description: intestinalstomasitebleeding
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
biliaryanastomoticleak
Additional description: biliaryanastomoticleak
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
injury,poisoningandproceduralcomplications-other,infectedpostopcollection
Additional description: injury,poisoningandproceduralcomplications-other,infectedpostopcollection
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
acutecoronarysyndrome
Additional description: acutecoronarysyndrome
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	1 / 2
heartfailure
Additional description: heartfailure
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
myocardialinfarction
Additional description: myocardialinfarction
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
chestpain-cardiac
Additional description: chestpain-cardiac
subjects affected / exposed	2 / 134 (1.49%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
atrialfibrillation
Additional description: atrialfibrillation
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
supraventriculartachycardia
Additional description: supraventriculartachycardia
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
cardiacarrest
Additional description: cardiacarrest
subjects affected / exposed	0 / 134 (0.00%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Nervous system disorders
headache
Additional description: headache
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
stroke
Additional description: stroke
subjects affected / exposed	0 / 134 (0.00%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
peripheralneuropathy
Additional description: peripheralneuropathy
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
syncope
Additional description: syncope
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ischemiacerebrovascular
Additional description: ischemiacerebrovascular
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
encephalopathy
Additional description: encephalopathy
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
febrileneutropenia
Additional description: febrileneutropenia
subjects affected / exposed	2 / 134 (1.49%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
anemia
Additional description: anemia
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
constipation
Additional description: constipation
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
diarrhea
Additional description: diarrhea
subjects affected / exposed	9 / 134 (6.72%)	7 / 137 (5.11%)
occurrences causally related to treatment / all	4 / 10	5 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
vomiting
Additional description: vomiting
subjects affected / exposed	7 / 134 (5.22%)	5 / 137 (3.65%)
occurrences causally related to treatment / all	8 / 13	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
obstructiongastric
Additional description: obstructiongastric
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
abdominalpain
Additional description: abdominalpain
subjects affected / exposed	5 / 134 (3.73%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	1 / 5	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
bowelobstruction
Additional description: bowelobstruction
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
mucositisoral
Additional description: mucositisoral
subjects affected / exposed	0 / 134 (0.00%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
nausea
Additional description: nausea
subjects affected / exposed	2 / 134 (1.49%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
uppergastrointestinalhemorrhage
Additional description: uppergastrointestinalhemorrhage
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
hepatichemorrhage
Additional description: hepatichemorrhage
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
portalveinthrombosis
Additional description: portalveinthrombosis
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
acutekidneyinjury
Additional description: acutekidneyinjury
subjects affected / exposed	1 / 134 (0.75%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
backpain
Additional description: backpain
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
devicerelatedinfection
Additional description: devicerelatedinfection
subjects affected / exposed	3 / 134 (2.24%)	5 / 137 (3.65%)
occurrences causally related to treatment / all	0 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
infection
Additional description: infection
subjects affected / exposed	2 / 134 (1.49%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
anorectalinfection
Additional description: anorectalinfection
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
infectionsandinfestations-other,infectionunknownactiology
Additional description: infectionsandinfestations-other,infectionunknownactiology
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
abdominalinfection
Additional description: abdominalinfection
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
sepsis
Additional description: sepsis
subjects affected / exposed	2 / 134 (1.49%)	5 / 137 (3.65%)
occurrences causally related to treatment / all	0 / 2	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
lunginfection
Additional description: lunginfection
subjects affected / exposed	2 / 134 (1.49%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
biliarytractinfection
Additional description: biliarytractinfection
subjects affected / exposed	0 / 134 (0.00%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
hypomagnesemia
Additional description: hypomagnesemia
subjects affected / exposed	0 / 134 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
dehydration
Additional description: dehydration
subjects affected / exposed	5 / 134 (3.73%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	2 / 5	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
hyperglycemia
Additional description: hyperglycemia
subjects affected / exposed	1 / 134 (0.75%)	0 / 137 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Chemotherapy alone	Chemotherapy and Cetuximab
Total subjects affected by non serious adverse events
subjects affected / exposed	132 / 134 (98.51%)	136 / 137 (99.27%)
Vascular disorders
phlebitis
Additional description: phlebitis
subjects affected / exposed	20 / 134 (14.93%)	18 / 137 (13.14%)
occurrences all number	45	23
thromboembolicevent
Additional description: thromboembolicevent
subjects affected / exposed	9 / 134 (6.72%)	10 / 137 (7.30%)
occurrences all number	11	14
General disorders and administration site conditions
flulikesymptoms
Additional description: flulikesymptoms
subjects affected / exposed	3 / 134 (2.24%)	8 / 137 (5.84%)
occurrences all number	4	8
fever
Additional description: fever
subjects affected / exposed	7 / 134 (5.22%)	6 / 137 (4.38%)
occurrences all number	7	7
fatigue
Additional description: fatigue
subjects affected / exposed	10 / 134 (7.46%)	3 / 137 (2.19%)
occurrences all number	27	5
Respiratory, thoracic and mediastinal disorders
sorethroat
Additional description: sorethroat
subjects affected / exposed	3 / 134 (2.24%)	7 / 137 (5.11%)
occurrences all number	3	10
hiccups
Additional description: hiccups
subjects affected / exposed	6 / 134 (4.48%)	8 / 137 (5.84%)
occurrences all number	11	9
epistaxis
Additional description: epistaxis
subjects affected / exposed	16 / 134 (11.94%)	12 / 137 (8.76%)
occurrences all number	24	20
cough
Additional description: cough
subjects affected / exposed	8 / 134 (5.97%)	10 / 137 (7.30%)
occurrences all number	10	12
dyspnea
Additional description: dyspnea
subjects affected / exposed	9 / 134 (6.72%)	12 / 137 (8.76%)
occurrences all number	14	17
Psychiatric disorders
anxiety
Additional description: anxiety
subjects affected / exposed	8 / 134 (5.97%)	4 / 137 (2.92%)
occurrences all number	13	5
insomnia
Additional description: insomnia
subjects affected / exposed	17 / 134 (12.69%)	13 / 137 (9.49%)
occurrences all number	47	41
depression
Additional description: depression
subjects affected / exposed	12 / 134 (8.96%)	14 / 137 (10.22%)
occurrences all number	24	23
Investigations
neutrophilcountdecreased
Additional description: neutrophilcountdecreased
subjects affected / exposed	72 / 134 (53.73%)	64 / 137 (46.72%)
occurrences all number	194	152
Deranged liver function tests
Additional description: Deranged liver function tests
subjects affected / exposed	18 / 134 (13.43%)	14 / 137 (10.22%)
occurrences all number	91	110
Nervous system disorders
dysgeusia
Additional description: dysgeusia
subjects affected / exposed	30 / 134 (22.39%)	23 / 137 (16.79%)
occurrences all number	62	57
headache
Additional description: headache
subjects affected / exposed	8 / 134 (5.97%)	10 / 137 (7.30%)
occurrences all number	12	15
dizziness
Additional description: dizziness
subjects affected / exposed	16 / 134 (11.94%)	8 / 137 (5.84%)
occurrences all number	23	15
lethargy
Additional description: lethargy
subjects affected / exposed	111 / 134 (82.84%)	124 / 137 (90.51%)
occurrences all number	718	718
peripheralneuropathy
Additional description: peripheralneuropathy
subjects affected / exposed	120 / 134 (89.55%)	112 / 137 (81.75%)
occurrences all number	806	707
Blood and lymphatic system disorders
other-platelets
Additional description: other-platelets
subjects affected / exposed	75 / 134 (55.97%)	55 / 137 (40.15%)
occurrences all number	293	192
other-whitecellcountlow
Additional description: other-whitecellcountlow
subjects affected / exposed	48 / 134 (35.82%)	55 / 137 (40.15%)
occurrences all number	145	137
anemia
Additional description: anemia
subjects affected / exposed	78 / 134 (58.21%)	83 / 137 (60.58%)
occurrences all number	468	417
Eye disorders
wateringeyes
Additional description: wateringeyes
subjects affected / exposed	8 / 134 (5.97%)	4 / 137 (2.92%)
occurrences all number	10	9
Gastrointestinal disorders
flatulence
Additional description: flatulence
subjects affected / exposed	8 / 134 (5.97%)	7 / 137 (5.11%)
occurrences all number	11	13
vomiting
Additional description: vomiting
subjects affected / exposed	46 / 134 (34.33%)	38 / 137 (27.74%)
occurrences all number	75	64
abdominalpain
Additional description: abdominalpain
subjects affected / exposed	12 / 134 (8.96%)	9 / 137 (6.57%)
occurrences all number	20	11
gastroesophagealrefluxdisease/dyspepsia
Additional description: gastroesophagealrefluxdisease/dyspepsia
subjects affected / exposed	25 / 134 (18.66%)	32 / 137 (23.36%)
occurrences all number	45	63
diarrhea
Additional description: diarrhea
subjects affected / exposed	95 / 134 (70.90%)	98 / 137 (71.53%)
occurrences all number	368	385
mucositisoral
Additional description: mucositisoral
subjects affected / exposed	69 / 134 (51.49%)	101 / 137 (73.72%)
occurrences all number	203	448
nausea
Additional description: nausea
subjects affected / exposed	92 / 134 (68.66%)	81 / 137 (59.12%)
occurrences all number	343	256
drymouth
Additional description: drymouth
subjects affected / exposed	11 / 134 (8.21%)	11 / 137 (8.03%)
occurrences all number	21	25
constipation
Additional description: constipation
subjects affected / exposed	47 / 134 (35.07%)	55 / 137 (40.15%)
occurrences all number	131	170
Skin and subcutaneous tissue disorders
nailchanges
Additional description: nailchanges
subjects affected / exposed	24 / 134 (17.91%)	47 / 137 (34.31%)
occurrences all number	45	121
alopecia
Additional description: alopecia
subjects affected / exposed	38 / 134 (28.36%)	37 / 137 (27.01%)
occurrences all number	119	92
palmar-plantarerythrodysesthesiasyndrome
Additional description: palmar-plantarerythrodysesthesiasyndrome
subjects affected / exposed	41 / 134 (30.60%)	86 / 137 (62.77%)
occurrences all number	86	270
dryskin
Additional description: dryskin
subjects affected / exposed	9 / 134 (6.72%)	16 / 137 (11.68%)
occurrences all number	22	29
skinrash
Additional description: skinrash
subjects affected / exposed	43 / 134 (32.09%)	125 / 137 (91.24%)
occurrences all number	76	811
pruritus
Additional description: pruritus
subjects affected / exposed	4 / 134 (2.99%)	7 / 137 (5.11%)
occurrences all number	12	10
Musculoskeletal and connective tissue disorders
pain
Additional description: pain
subjects affected / exposed	84 / 134 (62.69%)	84 / 137 (61.31%)
occurrences all number	298	250
myalgia
Additional description: myalgia
subjects affected / exposed	2 / 134 (1.49%)	7 / 137 (5.11%)
occurrences all number	2	11
Infections and infestations
upperrespiratorytractinfection
Additional description: upperrespiratorytractinfection
subjects affected / exposed	13 / 134 (9.70%)	9 / 137 (6.57%)
occurrences all number	17	12
devicerelatedinfection
Additional description: devicerelatedinfection
subjects affected / exposed	9 / 134 (6.72%)	9 / 137 (6.57%)
occurrences all number	10	12
lunginfection
Additional description: lunginfection
subjects affected / exposed	5 / 134 (3.73%)	10 / 137 (7.30%)
occurrences all number	7	11
thrush
Additional description: thrush
subjects affected / exposed	10 / 134 (7.46%)	9 / 137 (6.57%)
occurrences all number	30	15
skininfection
Additional description: skininfection
subjects affected / exposed	1 / 134 (0.75%)	7 / 137 (5.11%)
occurrences all number	1	9
Metabolism and nutrition disorders
hypokalaemia
Additional description: hypokalaemia
subjects affected / exposed	8 / 134 (5.97%)	8 / 137 (5.84%)
occurrences all number	16	11
anorexia
Additional description: anorexia
subjects affected / exposed	56 / 134 (41.79%)	61 / 137 (44.53%)
occurrences all number	159	123
hypomagnesemia
Additional description: hypomagnesemia
subjects affected / exposed	19 / 134 (14.18%)	29 / 137 (21.17%)
occurrences all number	59	74

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

24 Jul 2007

- Urgent safety measure reduce dose of capecitabine - Approving GPv3 18th Oct 07

16 Jan 2008

Clarification of treatment regimens, Tissue collection details. Stratification details.

14 Mar 2008

Changing formulation of cetuximab from 2mg/ml to 5mg/ml + other minor amendments

04 Jul 2008

Urgent safety measure to introduce KRAS genotyping

11 Jul 2008

Wrong date for PIS on consent form for KRAS

16 Sep 2008

- Addition of irinotecan docs updated - Updated investigator brochure

22 Apr 2009

- Clarification of randomisation stratification criteria - QoL Questionnaire v4 minor amendement - Update of kRAS PIS & ICF

28 Jul 2010

Removal of CAPOX chemotherapy regimen

08 Dec 2010

Update to cetuximab infusion rate, update to radiation risk assess. Addition 5 sites. Update to delivery of chemo following cetuximab. Change to kRAS ICF.

16 Jan 2012

Update to sample size. Study size now 288 patients. Change to PIS to reflect this. Removal of Mount Vernon, and Basildon

23 Nov 2012

Patient Information Letter – subsequent to cessation of cetuximab and recruitment to study

02 Jan 2013

Kras – seeking consent from 22 patients who entered study prior to implementing Kras consent

08 Feb 2013

Informing MHRA of cessation of cetuximab and recruitment

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
01 Nov 2012	The study was closed to recruitment by the trial steering committee on advice from the data monitoring and ethics committee on Nov 1, 2012, when the predefined futility criteria were met, using a method proposed by Freidlin and colleagues (the lower limit of the 95% CI for the progression-free survival hazard ratio [HR] was >1, where the reference category for the hazard ratio was Arm A [Chemotherapy alone]).	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/24717919
http://www.ncbi.nlm.nih.gov/pubmed/27434036

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Clinical trials

Clinical Trial Results: A prospective randomised open label trial of oxaliplatin / irinotecan plus fluorouracil versus oxaliplatin / irinotecan plus fluorouracil and cetuximab pre and post operatively in patients with resectable colorectal liver metastases requiring chemotherapy.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (primary endpoint, at interim analysis)

Primary: Progression-Free Survival (primary endpoint, at interim analysis)

Primary: Progression Free Survival (at final analysis)

Primary: Progression Free Survival (at final analysis)

Secondary: Overall Survival (at interim analysis)

Secondary: Overall Survival (at interim analysis)

Secondary: Overall Survival (at final analysis)

Secondary: Overall Survival (at final analysis)

Secondary: Progression Free Survival (pts not on CAPOX, at final analysis)

Secondary: Progression Free Survival (pts not on CAPOX, at final analysis)

Secondary: Pathological Resection status (at final analysis)

Secondary: Pathological Resection status (at final analysis)

Secondary: Response to Pre-Operative Chemotherapy (after pre-op, at final analysis)

Secondary: Response to Pre-Operative Chemotherapy (after pre-op, at final analysis)

Secondary: Relative reduction in sum of the largest diameters of lesions on imaging (at final analysis)

Secondary: Relative reduction in sum of the largest diameters of lesions on imaging (at final analysis)

Secondary: Surgical Complications (at final analysis)

Secondary: Surgical Complications (at final analysis)

Other pre-specified: Overall Survival (pts on OxMdG, at final analysis)

Other pre-specified: Overall Survival (pts on OxMdG, at final analysis)

Other pre-specified: Progression Free Survival (pts on OxMdG, at final analysis)

Other pre-specified: Progression Free Survival (pts on OxMdG, at final analysis)

Other pre-specified: Overall Survival (pts who responded to systemic treatment, at final analysis)

Other pre-specified: Overall Survival (pts who responded to systemic treatment, at final analysis)

Other pre-specified: Progression Free Survival (pts who responded to systemic treatment, at final analysis)

Other pre-specified: Progression Free Survival (pts who responded to systemic treatment, at final analysis)

Other pre-specified: Overall Survival (pts not on CAPOX, at final analysis)

Other pre-specified: Overall Survival (pts not on CAPOX, at final analysis)

Post-hoc: Overall Survival (pts with left sided tumour, at final analysis)

Post-hoc: Overall Survival (pts with left sided tumour, at final analysis)

Post-hoc: Progression free Survival (pts with left sided tumour, at final analysis)

Post-hoc: Progression free Survival (pts with left sided tumour, at final analysis)

Post-hoc: Overall Survival (pts with right sided tumour, at final analysis)

Post-hoc: Overall Survival (pts with right sided tumour, at final analysis)

Post-hoc: Progression Free Survival (pts with right sided tumour, at final analysis)

Post-hoc: Progression Free Survival (pts with right sided tumour, at final analysis)

Post-hoc: Post Progression Survival (pts who progressed, at final analysis)

Post-hoc: Post Progression Survival (pts who progressed, at final analysis)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A prospective randomised open label trial of oxaliplatin / irinotecan plus fluorouracil versus oxaliplatin / irinotecan plus fluorouracil and cetuximab pre and post operatively in patients with resectable colorectal liver metastases requiring chemotherapy.