A Study in Second Line Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT01183780

Recruitment Status : Completed

First Posted : August 18, 2010

Results First Posted : July 15, 2015

Last Update Posted : September 25, 2019

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Sponsor:

Information provided by (Responsible Party):

Eli Lilly and Company

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Colorectal Cancer
Interventions	Biological: Ramucirumab Biological: Placebo Drug: Irinotecan Drug: Folinic Acid Drug: 5-Fluorouracil
Enrollment	1072

Participant Flow

Recruitment Details
Pre-assignment Details	Completers included participants who died from any cause and participants who were alive and on study at conclusion however were off treatment.


Arm/Group Title	Ramucirumab + FOLFIRI	Placebo + FOLFIRI
Arm/Group Description	On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...
Arm/Group Description	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil (FOLFIRI). Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 milligrams/kilogram (mg/kg) administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Period Title: Overall Study
Started	536	536
Received at Least 1 Dose of Study Drug	528	529
Completed	505	511
Not Completed	31	25
Reason Not Completed
Withdrawal by Subject	25	14
Lost to Follow-up	6	11

Baseline Characteristics

Arm/Group Title		Ramucirumab + FOLFIRI	Placebo + FOLFIRI	Total
Arm/Group Description		On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...	Total of all reporting groups
Arm/Group Description		On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	Total of all reporting groups
Overall Number of Baseline Participants		536	536	1072
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized participants.
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	536 participants	536 participants	1072 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	324 60.4%	321 59.9%	645 60.2%
	>=65 years	212 39.6%	215 40.1%	427 39.8%
Age, Continuous Median (Full Range) Unit of measure: Years
	Number Analyzed	536 participants	536 participants	1072 participants
		62.0 (21.0 to 83.0)	62.0 (33.0 to 87.0)	62.0 (21.0 to 87.0)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	536 participants	536 participants	1072 participants
	Female	247 46.1%	210 39.2%	457 42.6%
	Male	289 53.9%	326 60.8%	615 57.4%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	536 participants	536 participants	1072 participants
	Hispanic or Latino	38 7.1%	39 7.3%	77 7.2%
	Not Hispanic or Latino	248 46.3%	221 41.2%	469 43.8%
	Unknown or Not Reported	250 46.6%	276 51.5%	526 49.1%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	536 participants	536 participants	1072 participants
	American Indian or Alaska Native	0 0.0%	1 0.2%	1 0.1%
	Asian	111 20.7%	103 19.2%	214 20.0%
	Native Hawaiian or Other Pacific Islander	1 0.2%	1 0.2%	2 0.2%
	Black or African American	14 2.6%	16 3.0%	30 2.8%
	White	405 75.6%	410 76.5%	815 76.0%
	More than one race	3 0.6%	0 0.0%	3 0.3%
	Unknown or Not Reported	2 0.4%	5 0.9%	7 0.7%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	536 participants	536 participants	1072 participants
United States		141	142	283
Portugal		2	2	4
Taiwan		5	6	11
Greece		8	8	16
Spain		51	60	111
Israel		7	7	14
Italy		17	20	37
India		1	2	3
France		12	15	27
Puerto Rico		2	1	3
Australia		16	19	35
Denmark		3	8	11
Netherlands		9	5	14
Korea, Republic of		22	25	47
Finland		9	3	12
Austria		6	12	18
Czech Republic		40	37	77
Hungary		24	23	47
Argentina		7	11	18
Belgium		30	22	52
Brazil		2	3	5
Romania		19	14	33
Germany		19	25	44
Japan		74	62	136
Sweden		10	4	14

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	OS was defined as the time in months from the date of randomization to...
Description	OS was defined as the time in months from the date of randomization to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last known date alive.
Time Frame	Randomization to Date of Death from Any Cause Up to 39.36 Months

Outcome Measure Data

Analysis Population Description

All randomized participants. Participants censored: Ramucirumab + FOLFIRI group = 164; Placebo + FOLFIRI= 139.


Arm/Group Title	Ramucirumab + FOLFIRI	Placebo + FOLFIRI
Arm/Group Description:	On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...
Arm/Group Description:	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Overall Number of Participants Analyzed	536	536
Median (95% Confidence Interval) Unit of Measure: months
	13.3 (12.4 to 14.5)	11.7 (10.8 to 12.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + FOLFIRI, Placebo + FOLFIRI
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0219
	Comments	[Not Specified]
	Method	Log Rank
	Comments	The analysis was performed on stratified data.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.844
	Confidence Interval	(2-Sided) 95% 0.730 to 0.976
	Estimation Comments	The estimation was performed on stratified data.

2.Secondary Outcome


Title	Progression-free Survival (PFS) Time
Description	PFS was defined as the time from the date of randomization until the d...
Description	PFS was defined as the time from the date of randomization until the date of objectively determined progressive disease (PD) [according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1] or death due to any cause, whichever was first. PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). Participants who died without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment.
Time Frame	Randomization to Measured PD or Date of Death from Any Cause Up to 38.01 Months

Outcome Measure Data

Analysis Population Description

All randomized participants. Participants censored: Ramucirumab + FOLFIRI = 60; Placebo + FOLFIRI = 42.


Arm/Group Title	Ramucirumab + FOLFIRI	Placebo + FOLFIRI
Arm/Group Description:	On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...
Arm/Group Description:	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Overall Number of Participants Analyzed	536	536
Median (95% Confidence Interval) Unit of Measure: months
	5.7 (5.5 to 6.2)	4.5 (4.2 to 5.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + FOLFIRI, Placebo + FOLFIRI
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Analysis was performed on stratified data.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.793
	Confidence Interval	(2-Sided) 95% 0.697 to 0.903
	Estimation Comments	Analysis was performed on stratified data.

3.Secondary Outcome


Title	Percentage of Participants Achieving an Objective Response (Objective Response Rate)
Description	The objective response rate is equal to the proportion of participants...
Description	The objective response rate is equal to the proportion of participants achieving a best overall response of partial response or complete response (PR + CR). Response was defined using RECIST, v. 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and normalization of tumor marker level of non-target lesions; PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameter.
Time Frame	Randomization until Disease Progression Up to 38.01 Months

Outcome Measure Data

Analysis Population Description

All randomized participants.


Arm/Group Title	Ramucirumab + FOLFIRI	Placebo + FOLFIRI
Arm/Group Description:	On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...
Arm/Group Description:	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Overall Number of Participants Analyzed	536	536
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	13.4 (10.7 to 16.6)	12.5 (9.8 to 15.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + FOLFIRI, Placebo + FOLFIRI
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6336
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

4.Secondary Outcome


Title	Change From Baseline in European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 Global Health Status
Description	The EORTC QLQ-C30 (v. 3.0) is a self-administered, cancer-specific que...
Description	The EORTC QLQ-C30 (v. 3.0) is a self-administered, cancer-specific questionnaire with multidimensional scales assessing 15 domains (5 functional domains, 9 symptoms, and global health status). A linear transformation was applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For the functional domains and global health status scale, higher scores represent a better level of functioning. For symptom scales, higher scores represent a greater degree of symptoms. Maximum improvement is the best post-baseline change.
Time Frame	Baseline Up to 171 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who had EORTC QLQ-C30 assessed at baseline and post-baseline .


Arm/Group Title	Ramucirumab + FOLFIRI	Placebo + FOLFIRI
Arm/Group Description:	On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...
Arm/Group Description:	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Overall Number of Participants Analyzed	491	486
Mean (Standard Deviation) Unit of Measure: units on a scale
	4.0 (20.61)	6.6 (18.84)

5.Secondary Outcome


Title	Change From Baseline in EuroQol- 5D (EQ-5D)
Description	The EQ-5D is a generic, multidimensional, health status instrument. Th...
Description	The EQ-5D is a generic, multidimensional, health status instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). A negative change indicated a worsening of the participant's health status.
Time Frame	Baseline and 30-Day Follow-Up (FU) up to 171 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who had EQ-5D assessed at baseline and 30-day FU.


Arm/Group Title	Ramucirumab + FOLFIRI	Placebo + FOLFIRI
Arm/Group Description:	On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...
Arm/Group Description:	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Overall Number of Participants Analyzed	308	310
Mean (Standard Deviation) Unit of Measure: units on a scale
	-0.097 (0.279)	-0.103 (0.264)

6.Secondary Outcome


Title	Percentage of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies
Description	Blood samples were tested to determine if a participant reacted to ram...
Description	Blood samples were tested to determine if a participant reacted to ramucirumab by producing anti-ramucirumab antibodies. Samples were identified as treatment emergent anti-drug antibody (TE ADA) if the post-treatment sample had an increase of at least 4 fold in titer from pre-treatment values. If the pre-treatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence. The percentage of participants with TE ADA was calculated as: (the number of participants with TE ADA / total number of participants with at least 1 post-treatment immunogenicity sample analyzed)*100.
Time Frame	Cycles 1, 3, 5, and 30-Day FU

Outcome Measure Data

Analysis Population Description

All participants who received study treatment and who had immunogenicity samples analyzed at the specified time points.


Arm/Group Title	Ramucirumab + FOLFIRI	Placebo + FOLFIRI
Arm/Group Description:	On Day 1 of each 14-day cycle, part...	On Day 1 of each 14-day cycle, part...
Arm/Group Description:	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.	On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Overall Number of Participants Analyzed	516	512
Measure Type: Number Unit of Measure: percentage of participants
Immunogenicity Any Time During Study (n=516, 512)	5.6	5.5
Immunogenicity Post-Treatment (n=477, 473)	3.1	3.8

7.Secondary Outcome


Title	Observed Maximum Concentration (Cmax) and Observed Minimum Concentration (Cmin) of Ramucirumab
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Preinfusion and 1 hour postinfusion in Cycles 3, 5, 9, 13, and 17

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had evaluable data for Cmin and Cmax.


Arm/Group Title	Ramucirumab + FOLFIRI
Arm/Group Description:	On Day 1 of each 14-day cycle, part...
Arm/Group Description:	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
Overall Number of Participants Analyzed	248
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: micrograms/milliliter (ug/mL)
Cmin Dose 3 (n=248)	46.3 (45.0%)
Cmin Dose 5 (n=154)	65.1 (43.0%)
Cmin Dose 9 (n=27)	77.9 (51.0%)
Cmin Dose 13 (n=11)	75.9 (43.0%)
Cmin Dose 17 (n=5)	72.0 (49.0%)
Cmax Dose 3 (n=88)	221.0 (37.0%)
Cmax Dose 5 (n=51)	243.0 (39.0%)
Cmax Dose 9 (n=18)	262.0 (36.0%)
Cmax Dose 13 (n=12)	307.0 (33.0%)
Cmax Dose 17 (n=7)	253.0 (19.0%)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	One participant who was randomized into FOLFIRI + Placebo arm received Ramucirumab dose by mistake. For safety analysis of adverse events, this participant was categorized into FOLFIRI + Ramucirumab arm.

Arm/Group Title	FOLFIRI + Ramucirumab		FOLFIRI + Placebo
Arm/Group Description	On Day 1 of each 14-day cycle, part...		On Day 1 of each 14-day cycle, part...
Arm/Group Description	On Day 1 of each 14-day cycle, participants received ramucirumab followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Ramucirumab: 8 mg/kg administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.		On Day 1 of each 14-day cycle, participants received placebo followed by other study treatment in the following sequence: Irinotecan, Folinic Acid and 5-Fluorouracil. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met. Placebo: Administered intravenously. Irinotecan: 180 mg/m^2 administered intravenously. Folinic Acid: 400 mg/m^2 administered intravenously. 5-Fluorouracil: 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion.
All-Cause Mortality
	FOLFIRI + Ramucirumab		FOLFIRI + Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events Serious Adverse Events
	FOLFIRI + Ramucirumab		FOLFIRI + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	198/529 (37.43%)		175/528 (33.14%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Febrile neutropenia ^† 1	15/529 (2.84%)	16	8/528 (1.52%)	8
Leukopenia ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Neutropenia ^† 1	6/529 (1.13%)	7	1/528 (0.19%)	1
Thrombocytopenia ^† 1	0/529 (0.00%)	0	2/528 (0.38%)	4
Thrombotic microangiopathy ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Cardiac disorders
Acute myocardial infarction ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Angina pectoris ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Atrial fibrillation ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Atrial flutter ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Cardiac failure ^† 1	2/529 (0.38%)	2	2/528 (0.38%)	2
Cardio-respiratory arrest ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Congestive cardiomyopathy ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Myocardial infarction ^† 1	0/529 (0.00%)	0	3/528 (0.57%)	3
Pericarditis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Right ventricular failure ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Congenital, familial and genetic disorders
Pyloric stenosis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Eye disorders
Cataract ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	10/529 (1.89%)	12	14/528 (2.65%)	15
Abdominal pain lower ^† 1	0/529 (0.00%)	0	2/528 (0.38%)	2
Abdominal pain upper ^† 1	2/529 (0.38%)	3	0/528 (0.00%)	0
Anal fistula ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Anal haemorrhage ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Anal ulcer ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Ascites ^† 1	1/529 (0.19%)	2	3/528 (0.57%)	3
Colitis ^† 1	2/529 (0.38%)	2	2/528 (0.38%)	4
Constipation ^† 1	2/529 (0.38%)	3	3/528 (0.57%)	4
Diarrhoea ^† 1	19/529 (3.59%)	20	18/528 (3.41%)	21
Dyspepsia ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Enteritis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Enterocolitis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Gastric haemorrhage ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Gastritis ^† 1	3/529 (0.57%)	3	1/528 (0.19%)	1
Gastrointestinal inflammation ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	2
Gastrointestinal perforation ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Haematemesis ^† 1	3/529 (0.57%)	3	0/528 (0.00%)	0
Haemorrhoidal haemorrhage ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Hernial eventration ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Ileus ^† 1	3/529 (0.57%)	5	6/528 (1.14%)	6
Incarcerated inguinal hernia ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Inflammatory bowel disease ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Inguinal hernia ^† 1	2/529 (0.38%)	2	1/528 (0.19%)	1
Intestinal haemorrhage ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Intestinal obstruction ^† 1	8/529 (1.51%)	8	11/528 (2.08%)	11
Intestinal perforation ^† 1	3/529 (0.57%)	3	0/528 (0.00%)	0
Large intestinal haemorrhage ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Large intestinal obstruction ^† 1	3/529 (0.57%)	3	3/528 (0.57%)	3
Large intestinal stenosis ^† 1	0/529 (0.00%)	0	2/528 (0.38%)	2
Large intestine perforation ^† 1	4/529 (0.76%)	4	1/528 (0.19%)	1
Lower gastrointestinal haemorrhage ^† 1	1/529 (0.19%)	1	4/528 (0.76%)	4
Mechanical ileus ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Nausea ^† 1	8/529 (1.51%)	8	6/528 (1.14%)	8
Oesophageal varices haemorrhage ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Oesophagitis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Proctalgia ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Rectal haemorrhage ^† 1	1/529 (0.19%)	1	2/528 (0.38%)	2
Rectal obstruction ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Rectal perforation ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Rectal ulcer ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Small intestinal haemorrhage ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Small intestinal obstruction ^† 1	7/529 (1.32%)	7	5/528 (0.95%)	5
Small intestinal perforation ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Stomatitis ^† 1	0/529 (0.00%)	0	3/528 (0.57%)	3
Subileus ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Vomiting ^† 1	13/529 (2.46%)	14	6/528 (1.14%)	7
General disorders
Asthenia ^† 1	4/529 (0.76%)	4	3/528 (0.57%)	3
Chest pain ^† 1	1/529 (0.19%)	1	3/528 (0.57%)	3
Disease progression ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Fatigue ^† 1	5/529 (0.95%)	5	4/528 (0.76%)	4
General physical health deterioration ^† 1	3/529 (0.57%)	4	5/528 (0.95%)	5
Hernia obstructive ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Malaise ^† 1	3/529 (0.57%)	3	0/528 (0.00%)	0
Mucosal inflammation ^† 1	4/529 (0.76%)	5	2/528 (0.38%)	2
Multi-organ failure ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Non-cardiac chest pain ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Oedema peripheral ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Pyrexia ^† 1	4/529 (0.76%)	5	8/528 (1.52%)	10
Systemic inflammatory response syndrome ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Ulcer haemorrhage ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hepatobiliary disorders
Acute hepatic failure ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Bile duct obstruction ^† 1	2/529 (0.38%)	2	1/528 (0.19%)	1
Bile duct stenosis ^† 1	1/529 (0.19%)	1	2/528 (0.38%)	2
Cholangitis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Cholangitis chronic ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Cholecystitis ^† 1	1/529 (0.19%)	1	2/528 (0.38%)	2
Cholelithiasis obstructive ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Cholestasis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Hepatic cirrhosis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hepatic failure ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hepatic function abnormal ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hepatorenal syndrome ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Hepatotoxicity ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Hyperbilirubinaemia ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	2
Jaundice ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Jaundice cholestatic ^† 1	1/529 (0.19%)	2	2/528 (0.38%)	2
Liver disorder ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Portal hypertension ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Immune system disorders
Anaphylactic reaction ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Drug hypersensitivity ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Infections and infestations
Abdominal infection ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Atypical pneumonia ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Bacteraemia ^† 1	2/529 (0.38%)	2	1/528 (0.19%)	1
Biliary tract infection ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Bronchitis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Bronchopulmonary aspergillosis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Campylobacter gastroenteritis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Cellulitis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Clostridium difficile colitis ^† 1	4/529 (0.76%)	5	1/528 (0.19%)	1
Cystitis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	3
Device related infection ^† 1	1/529 (0.19%)	2	1/528 (0.19%)	1
Device related sepsis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Erysipelas ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Escherichia sepsis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Gastroenteritis ^† 1	0/529 (0.00%)	0	2/528 (0.38%)	2
Herpes zoster ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Infection ^† 1	2/529 (0.38%)	2	1/528 (0.19%)	1
Infective exacerbation of chronic obstructive airways disease ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Influenza ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Klebsiella infection ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Klebsiella sepsis ^† 1	0/529 (0.00%)	0	2/528 (0.38%)	2
Localised infection ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Lung abscess ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Lung infection ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Mastoiditis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Neutropenic infection ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Oral candidiasis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Pelvic abscess ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Pelvic infection ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Perirectal abscess ^† 1	0/529 (0.00%)	0	2/528 (0.38%)	2
Peritonitis ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Peritonitis bacterial ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Pneumonia ^† 1	7/529 (1.32%)	7	7/528 (1.33%)	7
Pyelonephritis ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Respiratory tract infection ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Salmonellosis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Sepsis ^† 1	5/529 (0.95%)	5	11/528 (2.08%)	13
Septic shock ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Sinusitis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Upper respiratory tract infection ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Urinary tract infection ^† 1	4/529 (0.76%)	4	5/528 (0.95%)	6
Wound infection ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Injury, poisoning and procedural complications
Alcohol poisoning ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Ankle fracture ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Compression fracture ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Fall ^† 1	5/529 (0.95%)	5	2/528 (0.38%)	2
Femur fracture ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Fibula fracture ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hepatic haematoma ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Hip fracture ^† 1	2/529 (0.38%)	2	1/528 (0.19%)	1
Lower limb fracture ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Lumbar vertebral fracture ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Post procedural urine leak ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Procedural intestinal perforation ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Spinal fracture ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Stoma site haemorrhage ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Subdural haematoma ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Wound dehiscence ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Investigations
Alanine aminotransferase increased ^† 1	1/529 (0.19%)	1	2/528 (0.38%)	2
Aspartate aminotransferase increased ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Blood bilirubin increased ^† 1	3/529 (0.57%)	3	2/528 (0.38%)	2
Blood creatinine increased ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Blood culture positive ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Eastern cooperative oncology group performance status worsened ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	4
International normalised ratio increased ^† 1	3/529 (0.57%)	3	0/528 (0.00%)	0
Neutrophil count decreased ^† 1	2/529 (0.38%)	3	1/528 (0.19%)	1
Platelet count decreased ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Weight decreased ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Metabolism and nutrition disorders
Cachexia ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Decreased appetite ^† 1	7/529 (1.32%)	8	3/528 (0.57%)	4
Dehydration ^† 1	3/529 (0.57%)	4	6/528 (1.14%)	7
Hyperglycaemia ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Hypoalbuminaemia ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hypokalaemia ^† 1	1/529 (0.19%)	3	3/528 (0.57%)	9
Malnutrition ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Tumour lysis syndrome ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Musculoskeletal and connective tissue disorders
Back pain ^† 1	2/529 (0.38%)	3	1/528 (0.19%)	1
Musculoskeletal pain ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Neuropathic arthropathy ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Rheumatoid arthritis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colorectal cancer metastatic ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Malignant ascites ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Malignant pleural effusion ^† 1	0/529 (0.00%)	0	2/528 (0.38%)	2
Metastases to meninges ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Metastatic neoplasm ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Tumour haemorrhage ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Tumour pain ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Nervous system disorders
Aphasia ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Cerebral haematoma ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Cerebral ischaemia ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Cerebrovascular accident ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Dizziness ^† 1	1/529 (0.19%)	1	2/528 (0.38%)	2
Dysarthria ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Epilepsy ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Headache ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hyperammonaemic encephalopathy ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Ischaemic stroke ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Memory impairment ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Optic neuritis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Posterior reversible encephalopathy syndrome ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Presyncope ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Syncope ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Transient ischaemic attack ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Psychiatric disorders
Alcohol abuse ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Anxiety ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Confusional state ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Delirium ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Depression ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Disorientation ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Mental status changes ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Suicide attempt ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Renal and urinary disorders
Acute prerenal failure ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Haematuria ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	2
Hydronephrosis ^† 1	2/529 (0.38%)	2	1/528 (0.19%)	1
Nephrolithiasis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Nephrotic syndrome ^† 1	3/529 (0.57%)	6	0/528 (0.00%)	0
Prerenal failure ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Renal failure ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Renal failure acute ^† 1	3/529 (0.57%)	4	6/528 (1.14%)	6
Urinary incontinence ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Urinary retention ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Urinary tract obstruction ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
Reproductive system and breast disorders
Pelvic pain ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Dyspnoea ^† 1	1/529 (0.19%)	1	5/528 (0.95%)	6
Haemoptysis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Interstitial lung disease ^† 1	1/529 (0.19%)	3	2/528 (0.38%)	2
Laryngeal inflammation ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Lung infiltration ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Pleural effusion ^† 1	1/529 (0.19%)	1	3/528 (0.57%)	4
Pneumothorax ^† 1	1/529 (0.19%)	1	1/528 (0.19%)	1
Pneumothorax spontaneous ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Pulmonary embolism ^† 1	10/529 (1.89%)	10	6/528 (1.14%)	6
Pulmonary oedema ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Respiratory arrest ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Respiratory distress ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Skin and subcutaneous tissue disorders
Dermal cyst ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Skin ulcer ^† 1	2/529 (0.38%)	2	0/528 (0.00%)	0
Surgical and medical procedures
Cancer surgery ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Colostomy closure ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Enterostomy ^† 1	1/529 (0.19%)	2	0/528 (0.00%)	0
High frequency ablation ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Vascular disorders
Aortic dissection ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Deep vein thrombosis ^† 1	2/529 (0.38%)	2	3/528 (0.57%)	3
Embolism ^† 1	2/529 (0.38%)	2	3/528 (0.57%)	3
Hypertension ^† 1	4/529 (0.76%)	4	0/528 (0.00%)	0
Hypertensive crisis ^† 1	1/529 (0.19%)	1	0/528 (0.00%)	0
Hypotension ^† 1	2/529 (0.38%)	3	1/528 (0.19%)	1
Hypovolaemic shock ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Jugular vein thrombosis ^† 1	1/529 (0.19%)	1	2/528 (0.38%)	2
Lymphoedema ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Subclavian vein thrombosis ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Thrombophlebitis superficial ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Vena cava embolism ^† 1	0/529 (0.00%)	0	1/528 (0.19%)	1
Venous thrombosis ^† 1	3/529 (0.57%)	3	1/528 (0.19%)	1
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 17.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	FOLFIRI + Ramucirumab		FOLFIRI + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	518/529 (97.92%)		510/528 (96.59%)
Blood and lymphatic system disorders
Anaemia ^† 1	93/529 (17.58%)	225	117/528 (22.16%)	270
Neutropenia ^† 1	183/529 (34.59%)	510	131/528 (24.81%)	259
Thrombocytopenia ^† 1	80/529 (15.12%)	177	42/528 (7.95%)	82
Gastrointestinal disorders
Abdominal distension ^† 1	22/529 (4.16%)	26	27/528 (5.11%)	29
Abdominal pain ^† 1	124/529 (23.44%)	178	123/528 (23.30%)	181
Constipation ^† 1	157/529 (29.68%)	227	132/528 (25.00%)	196
Diarrhoea ^† 1	315/529 (59.55%)	881	271/528 (51.33%)	798
Dyspepsia ^† 1	26/529 (4.91%)	28	27/528 (5.11%)	32
Haemorrhoids ^† 1	27/529 (5.10%)	33	6/528 (1.14%)	7
Nausea ^† 1	265/529 (50.09%)	650	274/528 (51.89%)	715
Proctalgia ^† 1	27/529 (5.10%)	35	13/528 (2.46%)	16
Stomatitis ^† 1	166/529 (31.38%)	380	113/528 (21.40%)	235
Vomiting ^† 1	151/529 (28.54%)	299	143/528 (27.08%)	309
General disorders
Asthenia ^† 1	74/529 (13.99%)	228	62/528 (11.74%)	168
Fatigue ^† 1	254/529 (48.02%)	645	225/528 (42.61%)	588
Malaise ^† 1	41/529 (7.75%)	97	38/528 (7.20%)	104
Mucosal inflammation ^† 1	91/529 (17.20%)	218	52/528 (9.85%)	92
Oedema peripheral ^† 1	118/529 (22.31%)	148	50/528 (9.47%)	59
Pyrexia ^† 1	85/529 (16.07%)	135	61/528 (11.55%)	93
Infections and infestations
Upper respiratory tract infection ^† 1	36/529 (6.81%)	44	22/528 (4.17%)	25
Urinary tract infection ^† 1	34/529 (6.43%)	43	21/528 (3.98%)	35
Investigations
Alanine aminotransferase increased ^† 1	28/529 (5.29%)	59	19/528 (3.60%)	59
Aspartate aminotransferase increased ^† 1	34/529 (6.43%)	57	18/528 (3.41%)	42
Blood alkaline phosphatase increased ^† 1	36/529 (6.81%)	66	27/528 (5.11%)	57
Neutrophil count decreased ^† 1	137/529 (25.90%)	437	115/528 (21.78%)	278
Platelet count decreased ^† 1	80/529 (15.12%)	232	36/528 (6.82%)	59
Weight decreased ^† 1	76/529 (14.37%)	124	46/528 (8.71%)	69
White blood cell count decreased ^† 1	49/529 (9.26%)	146	51/528 (9.66%)	136
Metabolism and nutrition disorders
Decreased appetite ^† 1	203/529 (38.37%)	382	149/528 (28.22%)	359
Dehydration ^† 1	32/529 (6.05%)	46	26/528 (4.92%)	32
Hypoalbuminaemia ^† 1	35/529 (6.62%)	59	13/528 (2.46%)	20
Hypokalaemia ^† 1	39/529 (7.37%)	65	38/528 (7.20%)	72
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	33/529 (6.24%)	38	22/528 (4.17%)	26
Back pain ^† 1	43/529 (8.13%)	54	48/528 (9.09%)	128
Pain in extremity ^† 1	36/529 (6.81%)	58	19/528 (3.60%)	25
Nervous system disorders
Dizziness ^† 1	38/529 (7.18%)	46	33/528 (6.25%)	51
Dysgeusia ^† 1	43/529 (8.13%)	57	39/528 (7.39%)	57
Headache ^† 1	80/529 (15.12%)	114	41/528 (7.77%)	69
Peripheral sensory neuropathy ^† 1	33/529 (6.24%)	57	38/528 (7.20%)	49
Psychiatric disorders
Insomnia ^† 1	47/529 (8.88%)	51	54/528 (10.23%)	84
Renal and urinary disorders
Proteinuria ^† 1	94/529 (17.77%)	227	30/528 (5.68%)	40
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	69/529 (13.04%)	88	46/528 (8.71%)	60
Dysphonia ^† 1	31/529 (5.86%)	32	5/528 (0.95%)	6
Dyspnoea ^† 1	56/529 (10.59%)	86	51/528 (9.66%)	70
Epistaxis ^† 1	182/529 (34.40%)	254	80/528 (15.15%)	99
Hiccups ^† 1	30/529 (5.67%)	81	17/528 (3.22%)	22
Skin and subcutaneous tissue disorders
Alopecia ^† 1	156/529 (29.49%)	198	168/528 (31.82%)	191
Dry skin ^† 1	29/529 (5.48%)	35	23/528 (4.36%)	25
Palmar-plantar erythrodysaesthesia syndrome ^† 1	69/529 (13.04%)	108	29/528 (5.49%)	39
Rash ^† 1	42/529 (7.94%)	47	36/528 (6.82%)	45
Vascular disorders
Hypertension ^† 1	147/529 (27.79%)	287	51/528 (9.66%)	108
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 17.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Chief Medical Officer
Organization:	Eli Lilly and Company
Phone:	800-545-5979

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mitani S, Chen Y, Inoue K, Mori J, Gao L, Long A, Wakabayashi S. Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach. Gan To Kagaku Ryoho. 2021 Nov;48(11):1381-1387.

Taniguchi H, Yoshino T, Yamaguchi K, Yamazaki K, Nixon AB, Tabernero J, Van Cutsem E, Robling KR, Abada PB, Hozak RR, Siegel R, Fill JA, Wijayawardana S, Walgren RA, Giles B, Jones A, Pitts KR, Drove N, Muro K. Clinical development and evaluation of a VEGF-D assay in plasma from patients with metastatic colorectal cancer in the RAISE study. Curr Med Res Opin. 2021 Oct;37(10):1769-1778. doi: 10.1080/03007995.2021.1940908. Epub 2021 Jul 28.

Lim HH, Hopkins AM, Rowland A, Yuen HY, Karapetis CS, Sorich MJ. Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab. Target Oncol. 2019 Dec;14(6):743-748. doi: 10.1007/s11523-019-00683-z.

Yoshino T, Portnoy DC, Obermannova R, Bodoky G, Prausova J, Garcia-Carbonero R, Ciuleanu T, Garcia-Alfonso P, Cohn AL, Van Cutsem E, Yamazaki K, Lonardi S, Muro K, Kim TW, Yamaguchi K, Grothey A, O'Connor J, Taieb J, Wijayawardana SR, Hozak RR, Nasroulah F, Tabernero J. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann Oncol. 2019 Jan 1;30(1):124-131. doi: 10.1093/annonc/mdy461.

Grothey A, Yoshino T, Bodoky G, Ciuleanu T, Garcia-Carbonero R, Garcia-Alfonso P, Van Cutsem E, Muro K, Mytelka DS, Li L, Lipkovich O, Hsu Y, Sashegyi A, Ferry D, Nasroulah F, Tabernero J. Association of baseline absolute neutrophil counts and survival in patients with metastatic colorectal cancer treated with second-line antiangiogenic therapies: exploratory analyses of the RAISE trial and validation in an electronic medical record data set. ESMO Open. 2018 Apr 24;3(3):e000347. doi: 10.1136/esmoopen-2018-000347. eCollection 2018.

Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Prausova J, Muro K, Siegel RW, Konrad RJ, Ouyang H, Melemed SA, Ferry D, Nasroulah F, Van Cutsem E. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol. 2018 Mar 1;29(3):602-609. doi: 10.1093/annonc/mdx767.

Obermannova R, Van Cutsem E, Yoshino T, Bodoky G, Prausova J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. doi: 10.1093/annonc/mdw402. Epub 2016 Aug 29.

Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausova J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12. Erratum In: Lancet Oncol. 2015 Jun;16(6):e262.

Layout table for additonal information

Responsible Party:	Eli Lilly and Company
ClinicalTrials.gov Identifier:	NCT01183780
Other Study ID Numbers:	13856 I4T-MC-JVBB ( Other Identifier: Eli Lilly and Company ) CP12-0920 ( Other Identifier: ImClone LLC Trial Number ) 2010-021037-32 ( EudraCT Number ) CTRI/2011/07/001900 ( Registry Identifier: Clinical Trials Registry India )
First Submitted:	August 4, 2010
First Posted:	August 18, 2010
Results First Submitted:	June 19, 2015
Results First Posted:	July 15, 2015
Last Update Posted:	September 25, 2019

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