A Study of Ramucirumab (IMC-1121B) Drug Product (DP) and Best Supportive Care (BSC) Versus Placebo and BSC as 2nd-Line Treatment in Participants With Hepatocellular Carcinoma After 1st-Line Therapy With Sorafenib (REACH)

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ClinicalTrials.gov Identifier: NCT01140347

Recruitment Status : Completed

First Posted : June 9, 2010

Results First Posted : March 26, 2015

Last Update Posted : December 28, 2015

View this study on the modernized ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Eli Lilly and Company

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Hepatocellular Carcinoma
Interventions	Biological: Placebo Biological: Ramucirumab DP (IMC-1121B) Other: BSC
Enrollment	565

Participant Flow

Recruitment Details
Pre-assignment Details	Participants who died due to any cause or were alive and on study at conclusion but off treatment were considered to have completed the study.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligra...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) intravenous (IV) infusion every 2 weeks. Best supportive care (BSC): Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Period Title: Overall Study
Started	283	282
Received at Least 1 Dose of Study Drug	277	276
Completed	265	268
Not Completed	18	14
Reason Not Completed
Lost to Follow-up	5	6
Withdrawal by Subject	13	8

Baseline Characteristics

Arm/Group Title		Ramucirumab (IMC-1121B) + BSC	Placebo + BSC	Total
Arm/Group Description		Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...	Total of all reporting groups
Arm/Group Description		Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Total of all reporting groups
Overall Number of Baseline Participants		283	282	565
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized participants.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	283 participants	282 participants	565 participants
		62.9 (11.56)	62.5 (11.10)	62.7 (11.33)
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	283 participants	282 participants	565 participants
<65 years		150	162	312
≥65 years		133	120	253
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	283 participants	282 participants	565 participants
	Female	47 16.6%	40 14.2%	87 15.4%
	Male	236 83.4%	242 85.8%	478 84.6%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	283 participants	282 participants	565 participants
	Hispanic or Latino	23 8.1%	20 7.1%	43 7.6%
	Not Hispanic or Latino	253 89.4%	260 92.2%	513 90.8%
	Unknown or Not Reported	7 2.5%	2 0.7%	9 1.6%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	283 participants	282 participants	565 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	131 46.3%	135 47.9%	266 47.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	5 1.8%	3 1.1%	8 1.4%
	White	139 49.1%	137 48.6%	276 48.8%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	8 2.8%	7 2.5%	15 2.7%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	283 participants	282 participants	565 participants
United States		17	20	37
Portugal		0	2	2
Philippines		1	0	1
Taiwan		33	25	58
Hong Kong		14	10	24
Spain		9	12	21
Thailand		5	1	6
Israel		1	1	2
Switzerland		1	1	2
Italy		33	18	51
France		32	27	59
Australia		3	8	11
Netherlands		2	1	3
Korea, Republic of		28	42	70
Finland		0	3	3
Austria		4	4	8
Czech Republic		11	9	20
Hungary		1	0	1
Canada		0	1	1
Belgium		3	5	8
Brazil		15	12	27
Romania		3	4	7
Bulgaria		2	4	6
Germany		19	21	40
Norway		1	1	2
Japan		45	48	93
Sweden		0	2	2

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	OS was defined as the time from the date of randomization to the date ...
Description	OS was defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at the end of the follow-up period or were lost to follow-up were censored on the last date the participant was known to be alive.
Time Frame	Randomization to death from any cause (up to 37 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) Population: All randomized participants. Participants censored: Ramucirumab+BSC (Ram)=65, Placebo+BSC (Pl)=58.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	283	282
Median (95% Confidence Interval) Unit of Measure: months
	9.17 (8.05 to 10.64)	7.62 (6.01 to 9.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab (IMC-1121B) + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1391
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.866
	Confidence Interval	(2-Sided) 95% 0.717 to 1.046
	Estimation Comments	HR with 95% confidence interval (CI) was estimated using a stratified Cox proportional hazards regression model using the Interactive Web Response System (IWRS) stratification factors (geographical regions and etiology of liver disease).

2.Secondary Outcome


Title	Progression-Free Survival (PFS)
Description	PFS was defined as time from date of randomization until date of objec...
Description	PFS was defined as time from date of randomization until date of objectively determined progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or death from any cause. PD was defined as ≥20% increase in sum of diameters (SOD) of target lesions, taking as reference smallest sum on study (including baseline sum if it was smallest). Sum must show a ≥5 millimeter (mm) increase. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. In primary analysis, participants alive and without PD were censored at day of last adequate tumor assessment; progression or deaths without progression occurring immediately after ≥2 missed tumor assessments, were censored at day of the last adequate tumor assessment prior to missing assessments; participants who began new anticancer therapy were censored at day of the last adequate tumor assessment prior to start of new anticancer therapy.
Time Frame	Randomization to PD (up to 36 months)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants. Participants censored: Ram=43, Pl=19.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	283	282
Median (95% Confidence Interval) Unit of Measure: months
	2.79 (2.69 to 3.94)	2.10 (1.58 to 2.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab (IMC-1121B) + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.625
	Confidence Interval	(2-Sided) 95% 0.522 to 0.750
	Estimation Comments	HR with 95% CI was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors (geographical regions and etiology of liver disease).

3.Secondary Outcome


Title	Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
Description	ORR was defined, using RECIST v1.1 criteria, as the percentage of part...
Description	ORR was defined, using RECIST v1.1 criteria, as the percentage of participants who achieved a best overall response of CR or PR. CR was defined as the disappearance of all lesions and any intratumor arterial enhancement in target lesions, the normalization of the tumor marker level and all lymph nodes short axis reduced to <10 mm. PR was defined as ≥30% decrease in the SOD of target lesions, including the short axes of any target lymph nodes, taking as reference the baseline SOD of target lesions, no new lesions and stable nontarget lesions. Percentage of participants was calculated as: (number of participants with CR or PR / number of participants randomized) * 100.
Time Frame	Baseline to the date of first evidence of confirmed CR or PR (up to 37 months)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	283	282
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	7.1 (4.6 to 10.7)	0.7 (0.2 to 2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab (IMC-1121B) + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel (CMH) adjusted for geographic region and etiology liver disease

4.Secondary Outcome


Title	Time to Radiographic Progression (TTP)
Description	TTP was defined as the time from randomization to the first radiograph...
Description	TTP was defined as the time from randomization to the first radiographically documented PD. PD was defined, using RECIST v1.1 criteria, as ≥20% increase in SOD of target lesions, taking as reference smallest sum on study (including baseline sum if it was the smallest). Sum must show an absolute increase of ≥5 mm. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. Participants without PD were censored at the day of the last adequate tumor assessment. Progression occurred immediately after ≥2 missed tumor assessments and were censored at the day of the last adequate tumor assessment prior to the missing assessments. Participants who began new anticancer therapy were censored at the day of their last adequate tumor assessment prior to start of new anticancer therapy.
Time Frame	Randomization to PD (up to 36 months)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants. Participants censored: Ram=86, Pl=52.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	283	282
Median (95% Confidence Interval) Unit of Measure: months
	3.48 (2.76 to 4.47)	2.63 (1.58 to 2.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab (IMC-1121B) + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.593
	Confidence Interval	(2-Sided) 95% 0.487 to 0.722
	Estimation Comments	HR with 95% CI was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors (geographical regions and etiology of liver disease).

5.Secondary Outcome


Title	Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)
Description	The FHSI-8 is a self-administered 8-item questionnaire that measures a...
Description	The FHSI-8 is a self-administered 8-item questionnaire that measures a participant's symptoms in the domains of jaundice, stomach pain/discomfort weight loss, and fatigue. Participants rated each item on a 5-point scale from 0 (not at all) to 4 (very much). Item scores were calculated as outlined in the FACIT manual. FHSI-8 total score was the sum of each item's score with a total score ranging from 0 (highly symptomatic) to 32 (asymptomatic).
Time Frame	Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), and end of treatment (up to 34 months)

Outcome Measure Data

Analysis Population Description

Randomized participants who had FHSI-8 at baseline and the specified time points.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	169	199
Mean (Standard Deviation) Unit of Measure: units on a scale
Cycle 4 (n=166, 147)	-1.26 (3.164)	-0.81 (4.623)
Cycle 10 (n=70, 45)	-1.28 (3.989)	-0.01 (4.378)
Cycle 16 (n=47, 24)	-0.97 (4.095)	0.75 (3.768)
End of Treatment (n=169, 199)	-2.44 (5.561)	-2.86 (5.618)

6.Secondary Outcome


Title	Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score
Description	The EQ-5D is a self-reported, 5-dimension (mobility, self-care, usual ...
Description	The EQ-5D is a self-reported, 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire related to the participant's current health state. Each question was scored using a 3 level scale (no problems, some problems, or extreme problems). EQ-5D health state was defined by combining responses from each of the 5 dimensions into a weighted health-state index score according to the United Kingdom (UK) population based algorithm where 0 = death and 1 = perfect health.
Time Frame	Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), end of treatment (up to 34 months)

Outcome Measure Data

Analysis Population Description

Randomized participants who had an EQ-5D score at baseline and the specified time points.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	166	190
Mean (Standard Deviation) Unit of Measure: units on a scale
Cycle 4 (n=166, 145)	-0.038 (0.189)	-0.046 (0.245)
Cycle 10 (n=71, 45)	-0.054 (0.212)	0.003 (0.148)
Cycle 16 (n=47, 25)	-0.062 (0.214)	-0.012 (0.085)
End of Treatment (n=166, 190)	-0.129 (0.290)	-0.144 (0.280)

7.Secondary Outcome


Title	Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died
Description	The number of participants with serious AEs (SAEs), other non-serious ...
Description	The number of participants with serious AEs (SAEs), other non-serious AEs and participants who died. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time Frame	Baseline to study completion (up to 37 months)

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of study drug.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	277	276
Measure Type: Number Unit of Measure: participants
SAEs	123	92
Other Non-SAEs	254	235
Died	215	220

8.Secondary Outcome


Title	Maximum Concentration (Cmax) of Ramucirumab, Cycle 1
Description	[Not Specified]
Description	[Not Specified]
Time Frame	1 hour following the completion of Cycle 1 (14-day cycle) infusion

Outcome Measure Data

Analysis Population Description

Participants who received Cycle 1 of Ram and had Cmax results.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	247
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: micrograms/milliliter (µg/mL)
	149.6 (36.9%)

9.Secondary Outcome


Title	Cmax of Ramucirumab, Cycle 4
Description	[Not Specified]
Description	[Not Specified]
Time Frame	1 hour following completion of Cycle 4 (14-day cycles) infusion

Outcome Measure Data

Analysis Population Description

Participants who received Cycle 4 of Ram and had Cmax results.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	140
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: µg/mL
	189.5 (39.1%)

10.Secondary Outcome


Title	Cmax of Ramucirumab, Cycle 7
Description	[Not Specified]
Description	[Not Specified]
Time Frame	1 hour following completion of Cycle 7 (14-day cycles) infusion

Outcome Measure Data

Analysis Population Description

Participants who received Cycle 7 of Ram and had Cmax results.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	81
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: µg/mL
	184.4 (56.3%)

11.Secondary Outcome


Title	Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)]
Description	Participants were considered positive for anti-ramucirumab antibodies ...
Description	Participants were considered positive for anti-ramucirumab antibodies [anti-drug antibodies (ADA)] if the post-treatment sample had an increase of at least 4-fold in titer from the pretreatment values. If the pretreatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence of ADA.
Time Frame	Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles)

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of study drug and had post-treatment ADA analysis.


Arm/Group Title	Ramucirumab (IMC-1121B) + BSC	Placebo + BSC
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion eve...	Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description:	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.	Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
Overall Number of Participants Analyzed	241	231
Measure Type: Number Unit of Measure: participants
	10	7

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Ramucirumab (IMC-1121B) + BSC		Placebo + BSC
Arm/Group Description	Ramucirumab 8 mg/kg IV infusion eve...		Placebo: 8 mg/kg IV infusion every ...
Arm/Group Description	Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.		Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
All-Cause Mortality
	Ramucirumab (IMC-1121B) + BSC		Placebo + BSC
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events Serious Adverse Events
	Ramucirumab (IMC-1121B) + BSC		Placebo + BSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	124/277 (44.77%)		92/276 (33.33%)
Blood and lymphatic system disorders
Anaemia ^† 1	0/277 (0.00%)	0	2/276 (0.72%)	2
Disseminated intravascular coagulation ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Neutropenia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Thrombocytopenia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Cardiac disorders
Cardiac failure ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Pericardial effusion ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Supraventricular tachycardia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Eye disorders
Retinal detachment ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Gastrointestinal disorders
Abdominal distension ^† 1	1/277 (0.36%)	2	1/276 (0.36%)	1
Abdominal pain ^† 1	6/277 (2.17%)	7	9/276 (3.26%)	10
Abdominal pain upper ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Ascites ^† 1	8/277 (2.89%)	8	3/276 (1.09%)	4
Colitis ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Diarrhoea ^† 1	1/277 (0.36%)	2	0/276 (0.00%)	0
Duodenal ulcer ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Dysphagia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Food poisoning ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Gastric antral vascular ectasia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Gastric haemorrhage ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Gastric varices haemorrhage ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Gastroduodenitis ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Gastrointestinal haemorrhage ^† 1	7/277 (2.53%)	7	0/276 (0.00%)	0
Haemorrhoids ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	2
Ileus ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Inguinal hernia ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Intestinal obstruction ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Irritable bowel syndrome ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Large intestine perforation ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Melaena ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Nausea ^† 1	2/277 (0.72%)	2	1/276 (0.36%)	1
Oesophageal haemorrhage ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	2
Oesophageal varices haemorrhage ^† 1	4/277 (1.44%)	5	10/276 (3.62%)	12
Pancreatitis ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Peritoneal haemorrhage ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Small intestinal obstruction ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Umbilical hernia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Upper gastrointestinal haemorrhage ^† 1	2/277 (0.72%)	2	1/276 (0.36%)	1
Varices oesophageal ^† 1	1/277 (0.36%)	2	0/276 (0.00%)	0
Vomiting ^† 1	1/277 (0.36%)	2	1/276 (0.36%)	1
General disorders
Asthenia ^† 1	4/277 (1.44%)	5	1/276 (0.36%)	1
Chills ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Death ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Extravasation ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Fatigue ^† 1	1/277 (0.36%)	1	2/276 (0.72%)	2
General physical health deterioration ^† 1	9/277 (3.25%)	9	3/276 (1.09%)	4
Generalised oedema ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hernia obstructive ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hyperthermia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Malaise ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Multi-organ failure ^† 1	2/277 (0.72%)	2	1/276 (0.36%)	2
Non-cardiac chest pain ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Oedema ^† 1	0/277 (0.00%)	0	2/276 (0.72%)	2
Oedema peripheral ^† 1	2/277 (0.72%)	2	1/276 (0.36%)	1
Pyrexia ^† 1	7/277 (2.53%)	8	3/276 (1.09%)	3
Sudden death ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hepatobiliary disorders
Acute hepatic failure ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Bile duct stone ^† 1	1/277 (0.36%)	2	1/276 (0.36%)	1
Cholangitis ^† 1	5/277 (1.81%)	8	1/276 (0.36%)	1
Cholangitis acute ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Hepatic cirrhosis ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Hepatic failure ^† 1	6/277 (2.17%)	9	5/276 (1.81%)	9
Hepatic function abnormal ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Hepatorenal syndrome ^† 1	4/277 (1.44%)	4	1/276 (0.36%)	1
Hyperbilirubinaemia ^† 1	1/277 (0.36%)	1	3/276 (1.09%)	3
Hypertransaminasaemia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Jaundice ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Jaundice cholestatic ^† 1	0/277 (0.00%)	0	2/276 (0.72%)	2
Liver disorder ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Portal vein thrombosis ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Immune system disorders
Anaphylactic reaction ^† 1	2/277 (0.72%)	2	0/276 (0.00%)	0
Infections and infestations
Anal abscess ^† 1	2/277 (0.72%)	2	0/276 (0.00%)	0
Bacteraemia ^† 1	1/277 (0.36%)	2	0/276 (0.00%)	0
Campylobacter infection ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Candida sepsis ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Device related infection ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Device related sepsis ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Infection ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Influenza ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Liver abscess ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Lobar pneumonia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Lung infection ^† 1	2/277 (0.72%)	2	0/276 (0.00%)	0
Peritonitis ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Peritonitis bacterial ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Pneumonia ^† 1	3/277 (1.08%)	3	3/276 (1.09%)	4
Pneumonia bacterial ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Pneumonia klebsiella ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Pulmonary sepsis ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Sepsis ^† 1	3/277 (1.08%)	3	2/276 (0.72%)	3
Septic shock ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	2
Upper respiratory tract infection ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Urinary tract infection ^† 1	3/277 (1.08%)	4	0/276 (0.00%)	0
Injury, poisoning and procedural complications
Fall ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Femur fracture ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Infusion related reaction ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Investigations
Aspartate aminotransferase increased ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Blood bilirubin increased ^† 1	2/277 (0.72%)	2	0/276 (0.00%)	0
Blood creatinine increased ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
General physical condition abnormal ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Liver function test abnormal ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Metabolism and nutrition disorders
Cachexia ^† 1	1/277 (0.36%)	2	1/276 (0.36%)	1
Decreased appetite ^† 1	3/277 (1.08%)	3	0/276 (0.00%)	0
Dehydration ^† 1	2/277 (0.72%)	2	1/276 (0.36%)	1
Diabetes mellitus ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hypercalcaemia ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Hyperglycaemia ^† 1	0/277 (0.00%)	0	2/276 (0.72%)	2
Hyperkalaemia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hypertriglyceridaemia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hypocalcaemia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hypoglycaemia ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Hyponatraemia ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Musculoskeletal and connective tissue disorders
Arthritis ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Back pain ^† 1	0/277 (0.00%)	0	4/276 (1.45%)	4
Flank pain ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Musculoskeletal chest pain ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Neck pain ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Pathological fracture ^† 1	1/277 (0.36%)	2	0/276 (0.00%)	0
Spinal pain ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Liver carcinoma ruptured ^† 1	2/277 (0.72%)	3	2/276 (0.72%)	2
Malignant neoplasm progression ^† 1	23/277 (8.30%)	30	16/276 (5.80%)	22
Metastases to bone ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Metastases to central nervous system ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Metastases to lung ^† 1	1/277 (0.36%)	2	0/276 (0.00%)	0
Small intestine adenocarcinoma ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Tumour associated fever ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Tumour pain ^† 1	0/277 (0.00%)	0	4/276 (1.45%)	5
Nervous system disorders
Central nervous system lesion ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Cerebral infarction ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Coma hepatic ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Convulsion ^† 1	2/277 (0.72%)	2	0/276 (0.00%)	0
Diplegia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Dizziness ^† 1	1/277 (0.36%)	1	1/276 (0.36%)	1
Encephalopathy ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Hepatic encephalopathy ^† 1	12/277 (4.33%)	16	1/276 (0.36%)	1
Mental impairment ^† 1	1/277 (0.36%)	2	0/276 (0.00%)	0
Peripheral motor neuropathy ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Somnolence ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Spinal cord compression ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Subarachnoid haemorrhage ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Tongue biting ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Psychiatric disorders
Mental status changes ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Renal and urinary disorders
Renal failure ^† 1	2/277 (0.72%)	4	0/276 (0.00%)	0
Renal failure acute ^† 1	3/277 (1.08%)	4	1/276 (0.36%)	1
Renal impairment ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	2
Dyspnoea ^† 1	1/277 (0.36%)	1	2/276 (0.72%)	3
Haemoptysis ^† 1	2/277 (0.72%)	2	1/276 (0.36%)	1
Hypoxia ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Pleural effusion ^† 1	2/277 (0.72%)	2	3/276 (1.09%)	5
Pneumonitis ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Pulmonary embolism ^† 1	1/277 (0.36%)	1	2/276 (0.72%)	3
Pulmonary haemorrhage ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Skin and subcutaneous tissue disorders
Dermatitis allergic ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Skin lesion ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Skin ulcer ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
Vascular disorders
Deep vein thrombosis ^† 1	2/277 (0.72%)	2	0/276 (0.00%)	0
Haemorrhage ^† 1	0/277 (0.00%)	0	1/276 (0.36%)	1
Hypertension ^† 1	1/277 (0.36%)	2	0/276 (0.00%)	0
Shock haemorrhagic ^† 1	1/277 (0.36%)	1	0/276 (0.00%)	0
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 16.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ramucirumab (IMC-1121B) + BSC		Placebo + BSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	254/277 (91.70%)		235/276 (85.14%)
Blood and lymphatic system disorders
Anaemia ^† 1	29/277 (10.47%)	54	31/276 (11.23%)	44
Leukopenia ^† 1	14/277 (5.05%)	54	7/276 (2.54%)	19
Neutropenia ^† 1	16/277 (5.78%)	80	4/276 (1.45%)	8
Thrombocytopenia ^† 1	48/277 (17.33%)	189	12/276 (4.35%)	26
Gastrointestinal disorders
Abdominal distension ^† 1	19/277 (6.86%)	27	28/276 (10.14%)	31
Abdominal pain ^† 1	45/277 (16.25%)	63	58/276 (21.01%)	86
Abdominal pain upper ^† 1	26/277 (9.39%)	34	25/276 (9.06%)	32
Ascites ^† 1	72/277 (25.99%)	110	40/276 (14.49%)	47
Constipation ^† 1	36/277 (13.00%)	39	34/276 (12.32%)	39
Diarrhoea ^† 1	50/277 (18.05%)	74	38/276 (13.77%)	52
Gingival bleeding ^† 1	18/277 (6.50%)	22	4/276 (1.45%)	4
Nausea ^† 1	52/277 (18.77%)	71	52/276 (18.84%)	74
Vomiting ^† 1	30/277 (10.83%)	39	40/276 (14.49%)	47
General disorders
Asthenia ^† 1	50/277 (18.05%)	80	36/276 (13.04%)	63
Fatigue ^† 1	66/277 (23.83%)	97	60/276 (21.74%)	99
Oedema peripheral ^† 1	100/277 (36.10%)	151	50/276 (18.12%)	58
Pyrexia ^† 1	42/277 (15.16%)	59	25/276 (9.06%)	32
Hepatobiliary disorders
Hyperbilirubinaemia ^† 1	10/277 (3.61%)	16	15/276 (5.43%)	32
Infections and infestations
Nasopharyngitis ^† 1	15/277 (5.42%)	15	14/276 (5.07%)	16
Investigations
Alanine aminotransferase increased ^† 1	13/277 (4.69%)	34	21/276 (7.61%)	33
Aspartate aminotransferase increased ^† 1	30/277 (10.83%)	59	39/276 (14.13%)	70
Blood alkaline phosphatase increased ^† 1	18/277 (6.50%)	40	14/276 (5.07%)	25
Blood bilirubin increased ^† 1	19/277 (6.86%)	39	24/276 (8.70%)	38
Metabolism and nutrition disorders
Decreased appetite ^† 1	59/277 (21.30%)	81	50/276 (18.12%)	62
Hypoalbuminaemia ^† 1	33/277 (11.91%)	66	14/276 (5.07%)	27
Hyponatraemia ^† 1	13/277 (4.69%)	21	15/276 (5.43%)	20
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	19/277 (6.86%)	26	10/276 (3.62%)	12
Back pain ^† 1	23/277 (8.30%)	27	23/276 (8.33%)	32
Musculoskeletal pain ^† 1	18/277 (6.50%)	26	12/276 (4.35%)	13
Nervous system disorders
Dizziness ^† 1	23/277 (8.30%)	25	16/276 (5.80%)	18
Headache ^† 1	53/277 (19.13%)	69	15/276 (5.43%)	18
Psychiatric disorders
Insomnia ^† 1	19/277 (6.86%)	20	20/276 (7.25%)	20
Renal and urinary disorders
Proteinuria ^† 1	46/277 (16.61%)	117	13/276 (4.71%)	18
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	41/277 (14.80%)	54	25/276 (9.06%)	29
Dyspnoea ^† 1	26/277 (9.39%)	33	26/276 (9.42%)	33
Epistaxis ^† 1	38/277 (13.72%)	48	17/276 (6.16%)	22
Skin and subcutaneous tissue disorders
Dry skin ^† 1	16/277 (5.78%)	17	12/276 (4.35%)	13
Pruritus ^† 1	28/277 (10.11%)	33	29/276 (10.51%)	41
Rash ^† 1	23/277 (8.30%)	27	12/276 (4.35%)	16
Vascular disorders
Hypertension ^† 1	55/277 (19.86%)	104	20/276 (7.25%)	43
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 16.1

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):

Llovet JM, Singal AG, Villanueva A, Finn RS, Kudo M, Galle PR, Ikeda M, Callies S, McGrath LM, Wang C, Abada P, Widau RC, Gonzalez-Gugel E, Zhu AX. Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials. Clin Cancer Res. 2022 Jun 1;28(11):2297-2305. doi: 10.1158/1078-0432.CCR-21-4000.

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.

Zhu AX, Finn RS, Kang YK, Yen CJ, Galle PR, Llovet JM, Assenat E, Brandi G, Motomura K, Ohno I, Daniele B, Vogel A, Yamashita T, Hsu CH, Gerken G, Bilbruck J, Hsu Y, Liang K, Widau RC, Wang C, Abada P, Kudo M. Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab. Br J Cancer. 2021 Apr;124(8):1388-1397. doi: 10.1038/s41416-021-01260-w. Epub 2021 Feb 3.

Reig M, Galle PR, Kudo M, Finn R, Llovet JM, Metti AL, Schelman WR, Liang K, Wang C, Widau RC, Abada P, Zhu AX. Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab. Liver Int. 2021 Mar;41(3):598-607. doi: 10.1111/liv.14731. Epub 2020 Dec 5.

Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. doi: 10.1136/esmoopen-2020-000797.

Kudo M, Okusaka T, Motomura K, Ohno I, Morimoto M, Seo S, Wada Y, Sato S, Yamashita T, Furukawa M, Aramaki T, Nadano S, Ohkawa K, Fujii H, Kudo T, Furuse J, Takai H, Homma G, Yoshikawa R, Zhu AX. Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial. J Gastroenterol. 2020 Jun;55(6):627-639. doi: 10.1007/s00535-020-01668-w. Epub 2020 Feb 27.

Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, Mackey JR, Paz-Ares L, Baron AD, Okusaka T, Yoshino T, Yoon HH, Das M, Ferry D, Zhang Y, Lin Y, Binder P, Sashegyi A, Chau I. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol. 2017 Dec 1;28(12):2932-2942. doi: 10.1093/annonc/mdx514.

Chau I, Peck-Radosavljevic M, Borg C, Malfertheiner P, Seitz JF, Park JO, Ryoo BY, Yen CJ, Kudo M, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Okusaka T, Bowman L, Cui ZL, Girvan AC, Abada PB, Yang L, Zhu AX. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study. Eur J Cancer. 2017 Aug;81:17-25. doi: 10.1016/j.ejca.2017.05.001. Epub 2017 Jun 4. Erratum In: Eur J Cancer. 2018 Sep;100:135-136.

Zhu AX, Baron AD, Malfertheiner P, Kudo M, Kawazoe S, Pezet D, Weissinger F, Brandi G, Barone CA, Okusaka T, Wada Y, Park JO, Ryoo BY, Cho JY, Chung HC, Li CP, Yen CJ, Lee KD, Chang SC, Yang L, Abada PB, Chau I. Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score. JAMA Oncol. 2017 Feb 1;3(2):235-243. doi: 10.1001/jamaoncol.2016.4115.

Kudo M, Hatano E, Ohkawa S, Fujii H, Masumoto A, Furuse J, Wada Y, Ishii H, Obi S, Kaneko S, Kawazoe S, Yokosuka O, Ikeda M, Ukai K, Morita S, Tsuji A, Kudo T, Shimada M, Osaki Y, Tateishi R, Sugiyama G, Abada PB, Yang L, Okusaka T, Zhu AX. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial. J Gastroenterol. 2017 Apr;52(4):494-503. doi: 10.1007/s00535-016-1247-4. Epub 2016 Aug 22.

Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015 Jul;16(7):859-70. doi: 10.1016/S1470-2045(15)00050-9. Epub 2015 Jun 18.

Layout table for additonal information

Responsible Party:	Eli Lilly and Company
ClinicalTrials.gov Identifier:	NCT01140347
Other Study ID Numbers:	13895 CP12-0919 ( Other Identifier: ImClone Systems ) I4T-IE-JVBF ( Other Identifier: Eli Lilly and Company ) 2010-019318-26 ( EudraCT Number )
First Submitted:	June 2, 2010
First Posted:	June 9, 2010
Results First Submitted:	March 13, 2015
Results First Posted:	March 26, 2015
Last Update Posted:	December 28, 2015

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