Efficacy Study of Ipilimumab Versus Placebo to Prevent Recurrence After Complete Resection of High Risk Stage III Melanoma

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ClinicalTrials.gov Identifier: NCT00636168

Recruitment Status : Completed

First Posted : March 14, 2008

Results First Posted : August 19, 2014

Last Update Posted : December 17, 2019

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Sponsor:

Information provided by (Responsible Party):

Bristol-Myers Squibb

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	High Risk Stage III Melanoma
Interventions	Drug: ipilimumab Drug: Placebo
Enrollment	1211

Participant Flow

Recruitment Details
Pre-assignment Details	Protocol definition of Enrolled population: All 1211 participants who signed the Informed Consent Form; 951 were randomized to treatment and 945 were treated. Reasons for not being randomized: 193 were ineligible; 42 refused; 19 could not be randomized within 12 weeks after complete lymph node dissection; 6 due to other reasons.


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Period Title: Randomized to Study Drug
Started	475	476
Completed	471	474
Not Completed	4	2
Reason Not Completed
Withdrawal by Subject	2	2
Adverse Event	1	0
No longer meets study criteria	1	0
Period Title: Treated With Study Drug
Started	471	474
Completed ^[1]	63	143
Not Completed	408	331
Reason Not Completed
Recurrence of disease	135	282
Adverse Event	250	22
Participant withdrew consent	16	21
Poor/non-compliance	1	3
Death	3	0
Pregnancy	1	0
No longer meets study criteria	1	0
Other reason	1	3
[1] Normal Completion
Period Title: Long Term Follow-Up
Started ^[1]	141	143
Completed	130	129
Not Completed	11	14
Reason Not Completed
Lost to Follow-up	3	3
Participant withdrew consent	0	2
Death	8	9
[1] Continuing in Long Term Follow Up

Baseline Characteristics

Arm/Group Title		Ipilimumab 10mg/kg	Placebo	Total
Arm/Group Description		Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...	Total of all reporting groups
Arm/Group Description		Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Total of all reporting groups
Overall Number of Baseline Participants		475	476	951
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	475 participants	476 participants	951 participants
		50.7 (12.90)	51.5 (12.82)	51.1 (12.86)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	475 participants	476 participants	951 participants
	Female	179 37.7%	183 38.4%	362 38.1%
	Male	296 62.3%	293 61.6%	589 61.9%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	475 participants	476 participants	951 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 0.2%	0 0.0%	1 0.1%
	Native Hawaiian or Other Pacific Islander	1 0.2%	0 0.0%	1 0.1%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	470 98.9%	476 100.0%	946 99.5%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	3 0.6%	0 0.0%	3 0.3%

Outcome Measures

1.Primary Outcome


Title	Recurrence Free Survival (RFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population
Description	Recurrence free survival (RFS) was programmatically determined based o...
Description	Recurrence free survival (RFS) was programmatically determined based on the disease recurrence data provided by the IRC and was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those participants who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. The primary analysis was event-driven and planned when at least 512 RFS events assessed per IRC were collected.
Time Frame	Date of randomization to first date of recurrence or death or last available disease assessment with RFS data up to 5 years. Median follow-up was 2.7 years.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Median (95% Confidence Interval) Unit of Measure: months
	26.09 (19.32 to 39.26)	17.05 (13.40 to 21.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab 10mg/kg, Placebo
	Comments	The hazard ratio, and its 95 % confidence interval was estimated using a Cox proportional hazards model, stratified by stage (IIIa vs. IIIb vs. IIIc with 1-3 positive lymph-nodes vs. IIIc with >= 4 positive lymph-nodes) as indicated at randomization, with treatment as the single covariate.. The analysis was performed after 528 RFS events per IRC were reported. Two-sided, 95% confidence intervals for median RFS were computed by the Brookmeyer and Crowley method using log-log transformation.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0013
	Comments	[Not Specified]
	Method	Log Rank
	Comments	stratified 2-sided log-rank test

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95% 0.64 to 0.90
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Number of Participants With Recurrence or Death as Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population
Description	Recurrence was defined as appearance of one or more new melanoma lesio...
Description	Recurrence was defined as appearance of one or more new melanoma lesions: local, regional or distant metastasis. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. A participant who died without reported recurrence was considered to have recurred on the date of death. Disease was assessed at randomization and every 12 weeks (±2 weeks) for 3 years, then every 24 weeks until documented distant progression.
Time Frame	Date of randomization to first date of recurrence or death or last available disease assessment with RFS data upto 5 years. Median follow-up was 2.7 years.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Measure Type: Count of Participants Unit of Measure: Participants
	234 49.3%	294 61.8%

3.Primary Outcome


Title	Recurrence-Free Survival (RFS) Rates Per IRC at 1 Year, 2 Years, and 3 Years in the ITT Population
Description	Yearly recurrence-free survival rates, eg. at 1 year, defined as the p...
Description	Yearly recurrence-free survival rates, eg. at 1 year, defined as the probability that a participant was recurrence-free at 1 year following randomization, were estimated for each treatment group using the Kaplan-Meier product-limit method, along with their corresponding log-log transformed 95% confidence intervals. RFS was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. CT and MRI were mandatory to establish recurrence.
Time Frame	At years 1, 2, and 3

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
RFS Rate at 1 Year	63.50 (58.89 to 67.74)	56.13 (51.52 to 60.47)
RFS Rate at 2 Years	51.45 (46.69 to 56.00)	43.83 (39.27 to 48.28)
RFS Rate at 3 Years	46.48 (41.46 to 51.34)	34.79 (30.12 to 39.50)

4.Secondary Outcome


Title	Distant Metastasis-Free Survival (DMFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population
Description	Distant Metastasis-Free Survival (DMFS) was programmatically determine...
Description	Distant Metastasis-Free Survival (DMFS) was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, DMFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Disease was assessed at baseline (randomization) and every 12 weeks (±2 weeks) for 3 years, then every 24 weeks until documented distant progression.
Time Frame	From June 2008 to January 2016 (approximately 90 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Median (95% Confidence Interval) Unit of Measure: Months
	48.30 (35.45 to 71.56)	27.47 (21.91 to 34.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab 10mg/kg, Placebo
	Comments	Medians and associated 2-sided 95% confidence intervals are calculated using the method of Brookmeyer and Crowley. Analysis was stratified for stage (IIIa vs. IIIb vs. IIIc with 1-3 positive lymph-nodes vs. IIIc with >= 4 positive lymph-nodes) as recorded at randomization. P-value was based on stratified 2-sided log-rank test. Hazard of 10 mg/kg Ipilimumab over hazard of Placebo, with 2-sided 95.8% confidence interval are based on a stratified Cox proportional hazards model
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0024
	Comments	[Not Specified]
	Method	Log Rank
	Comments	stratified 2-sided log-rank test

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95.8% 0.64 to 0.92
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Number of Participants With Distant Metastasis-Free Survival (DMFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population
Description	DMFS was programmatically determined based on the first date of distan...
Description	DMFS was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, DMFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Disease was assessed at baseline (randomization) and every 12 weeks (2 weeks) for 3 years, then every 24 weeks until documented distant progression.
Time Frame	From June 2008 to January 2016 (approximately 90 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Measure Type: Count of Participants Unit of Measure: Participants
	227 47.8%	279 58.6%

6.Secondary Outcome


Title	Distant Metastasis-Free Survival (DMFS) Rates Per IRC at 1 Year, 2 Years, 3 Years, 4 Years and 5 Years in the ITT Population
Description	Yearly distant metastasis-free survival rates, e.g. at 1 year, defined...
Description	Yearly distant metastasis-free survival rates, e.g. at 1 year, defined as the probability that a participant was alive at 1 year following randomization, were estimated via the Kaplan-Meier method. Distant Metastasis-Free Survival (DMFS) was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment. Participants with disease at baseline were considered to have an event on the day of randomization.
Time Frame	At years 1, 2, 3, 4 and 5

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
DMFS Rate at 1 Year	74.27 (69.98 to 78.04)	65.77 (61.27 to 69.88)
DMFS Rate at 2 Years	61.48 (56.75 to 65.85)	53.26 (48.58 to 57.70)
DMFS Rate at 3 Years	53.90 (49.04 to 58.50)	45.17 (40.53 to 49.70)
DMFS Rate at 4 Years	50.19 (45.30 to 54.87)	41.48 (36.87 to 46.02)
DMFS Rate at 5 Years	48.29 (43.36 to 53.04)	38.90 (34.29 to 43.47)

7.Secondary Outcome


Title	Overall Survival in the Intent to Treat (ITT) Population
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. For those participants who had not died, OS was censored at the recorded last non-missing date of contact for which the participant was known to be alive.
Time Frame	From June 2008 to January 2016 (approximately 90 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Median (95% Confidence Interval) Unit of Measure: Months
	86.60 ^[1] (86.60 to NA)	NA ^[2] (59.30 to NA)

[1]

Upper limit was not reached because the number of participants with a followup of more than 7 years was too small

[2]

Median and upper limit were not reached because the number of participants with a followup of more than 7 years was too small

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab 10mg/kg, Placebo
	Comments	Medians and associated 2-sided 95% confidence intervals are calculated using the method of Brookmeyer and Crowley. Analysis was stratified for stage (IIIa vs. IIIb vs. IIIc with 1-3 positive lymph-nodes vs. IIIc with >= 4 positive lymph-nodes) as recorded at randomization. P-value was based on stratified 2-sided log-rank test. Hazard of 10 mg/kg Ipilimumab over hazard of Placebo, with 2-sided 95.1% confidence interval are based on a stratified Cox proportional hazards model
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0013
	Comments	[Not Specified]
	Method	Log Rank
	Comments	stratified 2-sided log-rank test

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95.1% 0.58 to 0.88
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Rate of 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. For those participants who had not died, OS was censored at the recorded last non-missing date of contact for which the participant was known to be alive.Yearly survival rates, e.g. at 3 years, defined as the probability that a participant was alive at 3 years following randomization, were estimated via the Kaplan-Meier method
Time Frame	From date of randomization to date of death, assessed up to 9 years

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: All randomized participants,analyzed in the arm to which they were allocated by randomization


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	475	476
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
OS Rate at 1 year	93.53 (90.88 to 95.43)	87.72 (84.40 to 90.37)
OS Rate at 2 years	82.55 (78.76 to 85.73)	75.27 (71.10 to 78.92)
OS Rate at 3 years	74.20 (69.90 to 77.98)	65.43 (60.91 to 69.56)
OS Rate at 4 years	67.79 (63.24 to 71.90)	60.34 (55.72 to 64.64)
OS Rate at 5 years	65.42 (60.80 to 69.64)	54.43 (49.71 to 58.89)
OS Rate at 7 years	60.0 (55.0 to 64.7)	51.3 (46.5 to 55.9)

9.Secondary Outcome


Title	Number of Participants With On-Study Adverse Events (AEs) Leading to Discontinuation of Treatment, Serious AEs (SAEs), Drug-Related SAEs, Immune-related AEs (irAEs), Immune-mediated Adverse Reactions (imARs), Deaths in Treated Population
Description	AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16....
Description	AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. irAEs=unknown etiology consistent with an immune phenomenon, considered as causally related to drug. imARs=based on investigator's assessment of immune-mediated etiology [excluding novel maintenance events (ie, patients with imARs occurring for the first time during maintenance)]. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related (D-R)=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death.
Time Frame	Day 1 up to 70 days after last dose; up to 5 years

Outcome Measure Data

Analysis Population Description

Safety population: All randomized participants who received at least 1 dose of study therapy


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	471	474
Measure Type: Count of Participants Unit of Measure: Participants
On-study AE leading to Discontinuation (Any Grade)	247 52.4%	43 9.1%
On-study SAE (At least 5%, Any Grade)	257 54.6%	128 27.0%
On-study D-R SAE (Any Grade)	217 46.1%	10 2.1%
On-study irAE (Any Grade)	426 90.4%	188 39.7%
On-study gastrointestinal irAE (Any Grade)	217 46.1%	85 17.9%
On-study endocrine irAE (Any Grade)	178 37.8%	38 8.0%
On-study liver irAE (Any Grade)	115 24.4%	20 4.2%
On-study skin irAE (Any Grade)	298 63.3%	99 20.9%
On-study neurological irAE (Any Grade)	21 4.5%	9 1.9%
On-study other irAE (Any Grade)	111 23.6%	23 4.9%
On-study imAR (Grade 3-4)	194 41.2%	16 3.4%
On-study imAR (Grade 5)	1 0.2%	0 0.0%
On-study enterocolitis imAR (Grade 5)	1 0.2%	0 0.0%
On-study enterocolitis imAR (Grade 3-4)	76 16.1%	4 0.8%
On-study endocrinopathy imAR (Grade 3-4)	39 8.3%	1 0.2%
On-study hepatitis imAR (Grade 3-4)	51 10.8%	1 0.2%
On-study dermatitis imAR (Grade 3-4)	19 4.0%	2 0.4%
On-study neuropathy imAR (Grade 3-4)	10 2.1%	0 0.0%
On-study other imAR (Grade 3-4)	30 6.4%	9 1.9%
Any Death	162 34.4%	214 45.1%
Death within 70 days of last dose study drug	6 1.3%	6 1.3%
Death within 30 days of last dose study drug	1 0.2%	0 0.0%
Drug-related Deaths	4 0.8%	0 0.0%

10.Secondary Outcome


Title	Number of Participants With Serious Adverse Events (SAEs), Non-serious AEs (NSAEs) and Number of Deaths: Overall Study
Description	AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16....
Description	AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
Time Frame	SAEs and NSAEs: Day 1 up to 70 days after last dose(safety window). Deaths: All deaths regardless of 70 day safety window.Up to 10 years

Outcome Measure Data

Analysis Population Description

Safety population: All randomized participants who received at least 1 dose of study therapy


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	471	474
Measure Type: Count of Participants Unit of Measure: Participants
No. of deaths	173 36.7%	223 47.0%
No. of participants with SAEs	257 54.6%	128 27.0%
No of participants with NSAEs	441 93.6%	382 80.6%

11.Secondary Outcome


Title	Exposure Adjusted Incidence Rate of Adverse Events Including Multiple Occurrences of Unique Events
Description	P-Y = person-years of exposure. Incidence rate per 100 person-years of...
Description	P-Y = person-years of exposure. Incidence rate per 100 person-years of exposure (IR/100 P-Y) was calculated as event count * 100 /person-years of exposure. MedDRA Version: 19. Duplicate AEs have been eliminated and overlapping and contiguous occurrences of the same event have been collapsed.
Time Frame	Day 1 up to 70 days after last dose; up to 5 years

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of ipilimumab or placebo, adjusted for person-years (P-Y) of exposure; P-Y=467.4; P-Y=781.7 for ipilimumab and placebo, respectively.


Arm/Group Title	Ipilimumab 10mg/kg	Placebo
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:	Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed	471	474
Measure Type: Number Unit of Measure: Events per 100 person-years of exposure
	1171.8	465.0

12.Secondary Outcome


Title	Mean Change From Baseline in Global Health Status Scores at Each Assessment Timepoint
Description	Global health status was measured using European Organization for Rese...
Description	Global health status was measured using European Organization for Research and Treatment of Cancer (EORTC) Quality Life Questionnaire (QLQ) C-30. This health related quality of life (HRQoL) questionnaire was comprised of 15 questions on functional scales, 13 questions on symptom scales and 2 on global health status scale. Global Health Status used a 7 point Likert-type scale of 1 (Very poor) to 7 (Excellent). All scales linearly transformed to 0-100 scales. Higher scores for Global Health Status indicate better HRQoL. An increase from baseline indicates improvement in HRQoL compared to baseline. HRQoL was administered within 1 week prior to first dose (baseline) and on Days 22, 43, 64 (+/- 3 days), Week 24 and every 12 weeks up to 2 years, independent of disease progression.
Time Frame	Baseline up to 2 years from randomization

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT) analyzed in the arm to which they were allocated by randomization were analyzed. At timepoint level, all randomized participants (ITT) with a measurement at the timepoint were analyzed.


Arm/Group Title		Ipilimumab 10mg/kg	Placebo
Arm/Group Description:		Ipilimumab (10 mg/kg) as a single d...	Placebo as a single dose via a 90 m...
Arm/Group Description:		Ipilimumab (10 mg/kg) as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (every 21 days in the Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, Ipilimumab was administered at a dose of 10 mg/kg, by IV infusion, every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).	Placebo as a single dose via a 90 minute intravenous (IV) infusion (not as bolus or IV push) during Days 1, 22, 43 and 64 (Induction Phase) for a total of four separate doses, until disease recurrence, unacceptable toxicity or withdrawal of consent. During the maintenance phase, placebo was administered by IV infusion every 12 weeks, beginning at Week 24, until disease recurrence, unacceptable toxicity or withdrawal of consent, for a maximum of 3 years (Week 156).
Overall Number of Participants Analyzed		400	421
Mean (Standard Deviation) Unit of Measure: units on a scale
Week 4 Day 22	Number Analyzed	400 participants	421 participants
Week 4 Day 22		-2.29 (15.96)	1.33 (14.02)
Week 7, Day 43	Number Analyzed	360 participants	412 participants
Week 7, Day 43		-6.64 (20.44)	-0.10 (16.75)
Week 10 Day 64	Number Analyzed	356 participants	405 participants
Week 10 Day 64		-9.06 (23.56)	-0.23 (16.18)
Week 24 Day 162 (300, 347)	Number Analyzed	300 participants	347 participants
Week 24 Day 162 (300, 347)		-4.33 (21.55)	1.37 (17.00)
Week 36 Day 246	Number Analyzed	290 participants	307 participants
Week 36 Day 246		-5.09 (21.32)	1.52 (18.52)
Week 48 Day 330	Number Analyzed	275 participants	276 participants
Week 48 Day 330		-3.67 (20.17)	1.54 (18.87)
Week 60 Day 414	Number Analyzed	242 participants	255 participants
Week 60 Day 414		-5.30 (21.34)	2.84 (17.05)
Week 72 day 498	Number Analyzed	217 participants	248 participants
Week 72 day 498		-4.07 (23.19)	1.18 (17.46)
Week 84 Day 582	Number Analyzed	205 participants	227 participants
Week 84 Day 582		-3.90 (22.06)	1.84 (17.08)
Week 96 Day 666	Number Analyzed	199 participants	214 participants
Week 96 Day 666		-4.48 (21.71)	1.36 (18.67)
Week 108 Day 750	Number Analyzed	162 participants	177 participants
Week 108 Day 750		-4.27 (20.35)	2.45 (16.72)

Adverse Events

Time Frame	Day 1 up to 70 days after last dose. Up to 10 years.
Adverse Event Reporting Description	Adverse Events were collected for the safety population which included all 945 randomized subjects who received at least 1 dose of study therapy (471 in the ipilimumab group and 474 in the placebo group)

Arm/Group Title	IPILIMUMAB 10 MG/KG	PLACEBO
Arm/Group Description	[Not Specified]	[Not Specified]
Arm/Group Description	[Not Specified]	[Not Specified]
All-Cause Mortality
	IPILIMUMAB 10 MG/KG	PLACEBO
	Affected / at Risk (%)	Affected / at Risk (%)
Total	173/471 (36.73%)	223/474 (47.05%)
Serious Adverse Events Serious Adverse Events
	IPILIMUMAB 10 MG/KG	PLACEBO
	Affected / at Risk (%)	Affected / at Risk (%)
Total	257/471 (54.56%)	128/474 (27.00%)
Blood and lymphatic system disorders
Lymphadenopathy ^† 1	5/471 (1.06%)	3/474 (0.63%)
Lymphoid tissue hyperplasia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Thrombocytopenia ^† 1	1/471 (0.21%)	1/474 (0.21%)
Cardiac disorders
Acute coronary syndrome ^† 1	0/471 (0.00%)	1/474 (0.21%)
Atrial fibrillation ^† 1	3/471 (0.64%)	1/474 (0.21%)
Atrial flutter ^† 1	0/471 (0.00%)	1/474 (0.21%)
Atrial tachycardia ^† 1	0/471 (0.00%)	1/474 (0.21%)
Bifascicular block ^† 1	0/471 (0.00%)	1/474 (0.21%)
Cardiac arrest ^† 1	1/471 (0.21%)	0/474 (0.00%)
Cardiac failure ^† 1	1/471 (0.21%)	0/474 (0.00%)
Cardiopulmonary failure ^† 1	1/471 (0.21%)	0/474 (0.00%)
Coronary artery disease ^† 1	0/471 (0.00%)	1/474 (0.21%)
Silent myocardial infarction ^† 1	1/471 (0.21%)	0/474 (0.00%)
Tachycardia ^† 1	0/471 (0.00%)	1/474 (0.21%)
Ear and labyrinth disorders
Deafness unilateral ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hypoacusis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Endocrine disorders
Adrenal insufficiency ^† 1	4/471 (0.85%)	0/474 (0.00%)
Adrenocorticotropic hormone deficiency ^† 1	1/471 (0.21%)	0/474 (0.00%)
Autoimmune thyroiditis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Basedow's disease ^† 1	1/471 (0.21%)	0/474 (0.00%)
Endocrine disorder ^† 1	1/471 (0.21%)	1/474 (0.21%)
Hyperadrenocorticism ^† 1	0/471 (0.00%)	1/474 (0.21%)
Hyperthyroidism ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hypophysitis ^† 1	37/471 (7.86%)	0/474 (0.00%)
Hypopituitarism ^† 1	10/471 (2.12%)	0/474 (0.00%)
Hypothyroidism ^† 1	3/471 (0.64%)	0/474 (0.00%)
Lymphocytic hypophysitis ^† 1	5/471 (1.06%)	0/474 (0.00%)
Thyroiditis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Eye disorders
Autoimmune uveitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Episcleritis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Ulcerative keratitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Uveitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Gastrointestinal disorders
Abdominal hernia ^† 1	0/471 (0.00%)	1/474 (0.21%)
Abdominal pain ^† 1	3/471 (0.64%)	1/474 (0.21%)
Abdominal pain lower ^† 1	1/471 (0.21%)	0/474 (0.00%)
Anal fissure ^† 1	1/471 (0.21%)	0/474 (0.00%)
Autoimmune colitis ^† 1	4/471 (0.85%)	0/474 (0.00%)
Colitis ^† 1	51/471 (10.83%)	1/474 (0.21%)
Colitis ulcerative ^† 1	2/471 (0.42%)	1/474 (0.21%)
Constipation ^† 1	1/471 (0.21%)	0/474 (0.00%)
Diarrhoea ^† 1	36/471 (7.64%)	6/474 (1.27%)
Diverticulum intestinal haemorrhagic ^† 1	1/471 (0.21%)	0/474 (0.00%)
Duodenal ulcer ^† 1	1/471 (0.21%)	0/474 (0.00%)
Dysphagia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Enteritis ^† 1	2/471 (0.42%)	0/474 (0.00%)
Enterocolitis haemorrhagic ^† 1	1/471 (0.21%)	0/474 (0.00%)
Gastric haemorrhage ^† 1	1/471 (0.21%)	0/474 (0.00%)
Gastritis ^† 1	2/471 (0.42%)	0/474 (0.00%)
Gastrointestinal haemorrhage ^† 1	1/471 (0.21%)	0/474 (0.00%)
Haemorrhoids ^† 1	0/471 (0.00%)	1/474 (0.21%)
Inguinal hernia ^† 1	1/471 (0.21%)	2/474 (0.42%)
Intestinal perforation ^† 1	2/471 (0.42%)	0/474 (0.00%)
Nausea ^† 1	4/471 (0.85%)	1/474 (0.21%)
Oesophageal haemorrhage ^† 1	1/471 (0.21%)	0/474 (0.00%)
Pancreatitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Pancreatitis acute ^† 1	1/471 (0.21%)	0/474 (0.00%)
Rectal haemorrhage ^† 1	1/471 (0.21%)	0/474 (0.00%)
Umbilical hernia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Vomiting ^† 1	8/471 (1.70%)	1/474 (0.21%)
General disorders
Adverse event ^† 1	1/471 (0.21%)	0/474 (0.00%)
Asthenia ^† 1	3/471 (0.64%)	0/474 (0.00%)
Chest pain ^† 1	3/471 (0.64%)	2/474 (0.42%)
Disease progression ^† 1	1/471 (0.21%)	4/474 (0.84%)
Disease recurrence ^† 1	0/471 (0.00%)	3/474 (0.63%)
Fatigue ^† 1	5/471 (1.06%)	1/474 (0.21%)
Influenza like illness ^† 1	1/471 (0.21%)	0/474 (0.00%)
Multiple organ dysfunction syndrome ^† 1	1/471 (0.21%)	0/474 (0.00%)
Pyrexia ^† 1	18/471 (3.82%)	1/474 (0.21%)
Retention cyst ^† 1	0/471 (0.00%)	1/474 (0.21%)
Sudden death ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	12/471 (2.55%)	1/474 (0.21%)
Cholecystitis ^† 1	0/471 (0.00%)	1/474 (0.21%)
Hepatitis ^† 1	4/471 (0.85%)	0/474 (0.00%)
Hepatocellular injury ^† 1	2/471 (0.42%)	0/474 (0.00%)
Hepatotoxicity ^† 1	5/471 (1.06%)	0/474 (0.00%)
Hyperbilirubinaemia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Immune system disorders
Anaphylactoid reaction ^† 1	1/471 (0.21%)	0/474 (0.00%)
Autoimmune disorder ^† 1	1/471 (0.21%)	0/474 (0.00%)
Drug hypersensitivity ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hypersensitivity ^† 1	3/471 (0.64%)	0/474 (0.00%)
Sarcoidosis ^† 1	3/471 (0.64%)	1/474 (0.21%)
Infections and infestations
Appendicitis ^† 1	3/471 (0.64%)	1/474 (0.21%)
Appendicitis perforated ^† 1	0/471 (0.00%)	3/474 (0.63%)
Bacteraemia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Bacterial infection ^† 1	1/471 (0.21%)	1/474 (0.21%)
Beta haemolytic streptococcal infection ^† 1	1/471 (0.21%)	0/474 (0.00%)
Bronchitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Cellulitis ^† 1	1/471 (0.21%)	4/474 (0.84%)
Cystitis ^† 1	3/471 (0.64%)	0/474 (0.00%)
Diarrhoea infectious ^† 1	1/471 (0.21%)	0/474 (0.00%)
Endocarditis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Erysipelas ^† 1	2/471 (0.42%)	7/474 (1.48%)
External ear cellulitis ^† 1	0/471 (0.00%)	1/474 (0.21%)
Gastroenteritis ^† 1	1/471 (0.21%)	1/474 (0.21%)
Gastroenteritis viral ^† 1	0/471 (0.00%)	1/474 (0.21%)
Gastrointestinal infection ^† 1	1/471 (0.21%)	0/474 (0.00%)
Groin infection ^† 1	0/471 (0.00%)	1/474 (0.21%)
H1N1 influenza ^† 1	1/471 (0.21%)	0/474 (0.00%)
Herpes ophthalmic ^† 1	1/471 (0.21%)	0/474 (0.00%)
Herpes zoster ^† 1	1/471 (0.21%)	0/474 (0.00%)
Infection ^† 1	1/471 (0.21%)	0/474 (0.00%)
Laryngitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Localised infection ^† 1	1/471 (0.21%)	1/474 (0.21%)
Lung infection ^† 1	1/471 (0.21%)	0/474 (0.00%)
Meningitis ^† 1	2/471 (0.42%)	0/474 (0.00%)
Meningitis aseptic ^† 1	2/471 (0.42%)	0/474 (0.00%)
Meningitis bacterial ^† 1	0/471 (0.00%)	1/474 (0.21%)
Neuroborreliosis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Osteomyelitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Otitis externa ^† 1	0/471 (0.00%)	1/474 (0.21%)
Perirectal abscess ^† 1	1/471 (0.21%)	0/474 (0.00%)
Pneumonia ^† 1	4/471 (0.85%)	1/474 (0.21%)
Post procedural infection ^† 1	0/471 (0.00%)	1/474 (0.21%)
Sepsis ^† 1	2/471 (0.42%)	0/474 (0.00%)
Septic embolus ^† 1	1/471 (0.21%)	0/474 (0.00%)
Skin infection ^† 1	1/471 (0.21%)	1/474 (0.21%)
Staphylococcal infection ^† 1	2/471 (0.42%)	0/474 (0.00%)
Tooth infection ^† 1	1/471 (0.21%)	0/474 (0.00%)
Urinary tract infection ^† 1	1/471 (0.21%)	0/474 (0.00%)
Viral infection ^† 1	0/471 (0.00%)	1/474 (0.21%)
Wound infection ^† 1	0/471 (0.00%)	1/474 (0.21%)
Injury, poisoning and procedural complications
Femoral neck fracture ^† 1	0/471 (0.00%)	1/474 (0.21%)
Fracture displacement ^† 1	0/471 (0.00%)	1/474 (0.21%)
Gastrointestinal stoma complication ^† 1	1/471 (0.21%)	0/474 (0.00%)
Incisional hernia ^† 1	0/471 (0.00%)	1/474 (0.21%)
Infusion related reaction ^† 1	1/471 (0.21%)	0/474 (0.00%)
Post procedural complication ^† 1	1/471 (0.21%)	0/474 (0.00%)
Radius fracture ^† 1	0/471 (0.00%)	1/474 (0.21%)
Respiratory tract procedural complication ^† 1	1/471 (0.21%)	0/474 (0.00%)
Seroma ^† 1	0/471 (0.00%)	1/474 (0.21%)
Investigations
Alanine aminotransferase increased ^† 1	17/471 (3.61%)	0/474 (0.00%)
Aspartate aminotransferase increased ^† 1	15/471 (3.18%)	0/474 (0.00%)
Blood corticotrophin decreased ^† 1	0/471 (0.00%)	1/474 (0.21%)
Blood creatinine increased ^† 1	1/471 (0.21%)	0/474 (0.00%)
Ejection fraction decreased ^† 1	0/471 (0.00%)	1/474 (0.21%)
Gamma-glutamyltransferase increased ^† 1	1/471 (0.21%)	0/474 (0.00%)
Influenza A virus test positive ^† 1	0/471 (0.00%)	1/474 (0.21%)
Lipase increased ^† 1	1/471 (0.21%)	0/474 (0.00%)
Liver function test increased ^† 1	1/471 (0.21%)	0/474 (0.00%)
Lymph nodes scan abnormal ^† 1	1/471 (0.21%)	1/474 (0.21%)
Thyroid function test abnormal ^† 1	2/471 (0.42%)	0/474 (0.00%)
Transaminases increased ^† 1	3/471 (0.64%)	0/474 (0.00%)
Weight decreased ^† 1	1/471 (0.21%)	0/474 (0.00%)
Metabolism and nutrition disorders
Dehydration ^† 1	4/471 (0.85%)	0/474 (0.00%)
Hypercalcaemia ^† 1	0/471 (0.00%)	1/474 (0.21%)
Hyperglycaemia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hypoglycaemia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hypokalaemia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hyponatraemia ^† 1	2/471 (0.42%)	1/474 (0.21%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	2/471 (0.42%)	0/474 (0.00%)
Arthritis ^† 1	1/471 (0.21%)	2/474 (0.42%)
Back pain ^† 1	0/471 (0.00%)	1/474 (0.21%)
Intervertebral disc protrusion ^† 1	1/471 (0.21%)	0/474 (0.00%)
Neck mass ^† 1	1/471 (0.21%)	0/474 (0.00%)
Osteoarthritis ^† 1	0/471 (0.00%)	3/474 (0.63%)
Pain in extremity ^† 1	0/471 (0.00%)	1/474 (0.21%)
Synovial cyst ^† 1	0/471 (0.00%)	1/474 (0.21%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma ^† 1	0/471 (0.00%)	1/474 (0.21%)
Adrenal adenoma ^† 1	0/471 (0.00%)	1/474 (0.21%)
Basal cell carcinoma ^† 1	2/471 (0.42%)	12/474 (2.53%)
Benign lung neoplasm ^† 1	1/471 (0.21%)	0/474 (0.00%)
Central nervous system melanoma ^† 1	0/471 (0.00%)	1/474 (0.21%)
Endobronchial lipoma ^† 1	1/471 (0.21%)	0/474 (0.00%)
Liposarcoma ^† 1	1/471 (0.21%)	0/474 (0.00%)
Malignant melanoma ^† 1	1/471 (0.21%)	9/474 (1.90%)
Malignant melanoma in situ ^† 1	1/471 (0.21%)	3/474 (0.63%)
Malignant neoplasm progression ^† 1	4/471 (0.85%)	6/474 (1.27%)
Malignant pleural effusion ^† 1	0/471 (0.00%)	1/474 (0.21%)
Melanocytic naevus ^† 1	0/471 (0.00%)	1/474 (0.21%)
Melanoma recurrent ^† 1	1/471 (0.21%)	7/474 (1.48%)
Metastases to adrenals ^† 1	1/471 (0.21%)	0/474 (0.00%)
Metastases to bone ^† 1	0/471 (0.00%)	1/474 (0.21%)
Metastases to central nervous system ^† 1	0/471 (0.00%)	2/474 (0.42%)
Metastases to lung ^† 1	1/471 (0.21%)	0/474 (0.00%)
Metastases to lymph nodes ^† 1	1/471 (0.21%)	2/474 (0.42%)
Metastases to skin ^† 1	0/471 (0.00%)	1/474 (0.21%)
Metastasis ^† 1	0/471 (0.00%)	1/474 (0.21%)
Metastatic malignant melanoma ^† 1	2/471 (0.42%)	11/474 (2.32%)
Neoplasm progression ^† 1	0/471 (0.00%)	2/474 (0.42%)
Oncocytoma ^† 1	0/471 (0.00%)	1/474 (0.21%)
Papillary cystadenoma lymphomatosum ^† 1	1/471 (0.21%)	0/474 (0.00%)
Parathyroid tumour benign ^† 1	0/471 (0.00%)	1/474 (0.21%)
Prostate cancer ^† 1	0/471 (0.00%)	1/474 (0.21%)
Rectal cancer stage 0 ^† 1	0/471 (0.00%)	1/474 (0.21%)
Second primary malignancy ^† 1	1/471 (0.21%)	0/474 (0.00%)
Squamous cell carcinoma ^† 1	0/471 (0.00%)	6/474 (1.27%)
Squamous cell carcinoma of skin ^† 1	0/471 (0.00%)	4/474 (0.84%)
Nervous system disorders
Ataxia ^† 1	0/471 (0.00%)	1/474 (0.21%)
Autoimmune neuropathy ^† 1	1/471 (0.21%)	0/474 (0.00%)
Axonal neuropathy ^† 1	1/471 (0.21%)	0/474 (0.00%)
Carotid artery stenosis ^† 1	0/471 (0.00%)	1/474 (0.21%)
Cerebral thrombosis ^† 1	0/471 (0.00%)	1/474 (0.21%)
Cranial nerve disorder ^† 1	1/471 (0.21%)	1/474 (0.21%)
Guillain-Barre syndrome ^† 1	1/471 (0.21%)	0/474 (0.00%)
Haemorrhage intracranial ^† 1	1/471 (0.21%)	0/474 (0.00%)
Headache ^† 1	6/471 (1.27%)	2/474 (0.42%)
Meningoradiculitis ^† 1	1/471 (0.21%)	0/474 (0.00%)
Neuropathy peripheral ^† 1	1/471 (0.21%)	0/474 (0.00%)
Peripheral motor neuropathy ^† 1	1/471 (0.21%)	0/474 (0.00%)
Peripheral sensory neuropathy ^† 1	1/471 (0.21%)	0/474 (0.00%)
Polyneuropathy ^† 1	1/471 (0.21%)	0/474 (0.00%)
Presyncope ^† 1	1/471 (0.21%)	0/474 (0.00%)
Seizure ^† 1	0/471 (0.00%)	2/474 (0.42%)
Spinal cord compression ^† 1	0/471 (0.00%)	1/474 (0.21%)
Syncope ^† 1	2/471 (0.42%)	0/474 (0.00%)
Trigeminal nerve disorder ^† 1	1/471 (0.21%)	0/474 (0.00%)
Psychiatric disorders
Confusional state ^† 1	1/471 (0.21%)	0/474 (0.00%)
Depression ^† 1	2/471 (0.42%)	0/474 (0.00%)
Mental status changes ^† 1	1/471 (0.21%)	1/474 (0.21%)
Substance-induced psychotic disorder ^† 1	1/471 (0.21%)	0/474 (0.00%)
Renal and urinary disorders
Cystitis haemorrhagic ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hydronephrosis ^† 1	0/471 (0.00%)	1/474 (0.21%)
Renal failure ^† 1	2/471 (0.42%)	0/474 (0.00%)
Urinary tract obstruction ^† 1	1/471 (0.21%)	0/474 (0.00%)
Reproductive system and breast disorders
Endometrial hyperplasia ^† 1	0/471 (0.00%)	1/474 (0.21%)
Ovarian cyst ^† 1	0/471 (0.00%)	1/474 (0.21%)
Respiratory, thoracic and mediastinal disorders
Eosinophilic pneumonia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Hypoxia ^† 1	1/471 (0.21%)	0/474 (0.00%)
Interstitial lung disease ^† 1	1/471 (0.21%)	0/474 (0.00%)
Lung infiltration ^† 1	1/471 (0.21%)	0/474 (0.00%)
Oropharyngeal pain ^† 1	1/471 (0.21%)	0/474 (0.00%)
Pneumonitis ^† 1	3/471 (0.64%)	0/474 (0.00%)
Pneumothorax ^† 1	0/471 (0.00%)	1/474 (0.21%)
Pulmonary embolism ^† 1	1/471 (0.21%)	2/474 (0.42%)
Pulmonary granuloma ^† 1	1/471 (0.21%)	0/474 (0.00%)
Pulmonary sarcoidosis ^† 1	2/471 (0.42%)	0/474 (0.00%)
Skin and subcutaneous tissue disorders
Actinic keratosis ^† 1	0/471 (0.00%)	1/474 (0.21%)
Angioedema ^† 1	1/471 (0.21%)	0/474 (0.00%)
Drug eruption ^† 1	1/471 (0.21%)	0/474 (0.00%)
Exfoliative rash ^† 1	0/471 (0.00%)	1/474 (0.21%)
Pruritus ^† 1	1/471 (0.21%)	0/474 (0.00%)
Rash ^† 1	1/471 (0.21%)	0/474 (0.00%)
Rash maculo-papular ^† 1	1/471 (0.21%)	0/474 (0.00%)
Skin exfoliation ^† 1	0/471 (0.00%)	1/474 (0.21%)
Vascular disorders
Circulatory collapse ^† 1	0/471 (0.00%)	1/474 (0.21%)
Haematoma ^† 1	0/471 (0.00%)	2/474 (0.42%)
Hypotension ^† 1	4/471 (0.85%)	0/474 (0.00%)
Lymphoedema ^† 1	1/471 (0.21%)	1/474 (0.21%)
Withdrawal hypertension ^† 1	0/471 (0.00%)	1/474 (0.21%)
1 Term from vocabulary, 22.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	IPILIMUMAB 10 MG/KG	PLACEBO
	Affected / at Risk (%)	Affected / at Risk (%)
Total	441/471 (93.63%)	382/474 (80.59%)
Endocrine disorders
Hypophysitis ^† 1	56/471 (11.89%)	2/474 (0.42%)
Hypothyroidism ^† 1	47/471 (9.98%)	7/474 (1.48%)
Gastrointestinal disorders
Abdominal pain ^† 1	64/471 (13.59%)	44/474 (9.28%)
Colitis ^† 1	43/471 (9.13%)	5/474 (1.05%)
Constipation ^† 1	31/471 (6.58%)	30/474 (6.33%)
Diarrhoea ^† 1	229/471 (48.62%)	141/474 (29.75%)
Nausea ^† 1	117/471 (24.84%)	82/474 (17.30%)
Vomiting ^† 1	61/471 (12.95%)	27/474 (5.70%)
General disorders
Asthenia ^† 1	29/471 (6.16%)	38/474 (8.02%)
Fatigue ^† 1	188/471 (39.92%)	143/474 (30.17%)
Influenza like illness ^† 1	35/471 (7.43%)	30/474 (6.33%)
Oedema peripheral ^† 1	21/471 (4.46%)	27/474 (5.70%)
Pyrexia ^† 1	73/471 (15.50%)	22/474 (4.64%)
Infections and infestations
Nasopharyngitis ^† 1	21/471 (4.46%)	31/474 (6.54%)
Investigations
Alanine aminotransferase increased ^† 1	95/471 (20.17%)	26/474 (5.49%)
Aspartate aminotransferase increased ^† 1	72/471 (15.29%)	26/474 (5.49%)
Blood lactate dehydrogenase increased ^† 1	33/471 (7.01%)	12/474 (2.53%)
Blood testosterone decreased ^† 1	29/471 (6.16%)	8/474 (1.69%)
Lipase increased ^† 1	42/471 (8.92%)	30/474 (6.33%)
Weight decreased ^† 1	149/471 (31.63%)	42/474 (8.86%)
Weight increased ^† 1	71/471 (15.07%)	114/474 (24.05%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	65/471 (13.80%)	16/474 (3.38%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	34/471 (7.22%)	45/474 (9.49%)
Back pain ^† 1	29/471 (6.16%)	41/474 (8.65%)
Musculoskeletal pain ^† 1	16/471 (3.40%)	26/474 (5.49%)
Myalgia ^† 1	21/471 (4.46%)	24/474 (5.06%)
Pain in extremity ^† 1	21/471 (4.46%)	36/474 (7.59%)
Nervous system disorders
Dizziness ^† 1	29/471 (6.16%)	18/474 (3.80%)
Headache ^† 1	150/471 (31.85%)	85/474 (17.93%)
Psychiatric disorders
Anxiety ^† 1	21/471 (4.46%)	25/474 (5.27%)
Insomnia ^† 1	45/471 (9.55%)	21/474 (4.43%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	68/471 (14.44%)	48/474 (10.13%)
Dyspnoea ^† 1	31/471 (6.58%)	16/474 (3.38%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform ^† 1	26/471 (5.52%)	6/474 (1.27%)
Pruritus ^† 1	203/471 (43.10%)	70/474 (14.77%)
Rash ^† 1	186/471 (39.49%)	80/474 (16.88%)
1 Term from vocabulary, 22.0 † Indicates events were collected by systematic assessment

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.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Bristol-Myers Squibb Study Director
Organization:	Bristol-Myers Squibb
Phone:	Please email
EMail:	Clinical.Trials@bms.com

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

Weber JS, Ascierto PA, Middleton MR, Hennicken D, Zoffoli R, Pieters A, Amadi A, Kupas K, Kotapati S, Moshyk A, Schadendorf D. Indirect treatment comparison of nivolumab versus placebo as adjuvant treatment for resected melanoma. Eur J Cancer. 2021 Nov;158:225-233. doi: 10.1016/j.ejca.2021.08.028. Epub 2021 Oct 15.

Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AMM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. doi: 10.1016/S1470-2045(17)30015-3. Epub 2017 Feb 3.

Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. doi: 10.1056/NEJMoa1611299. Epub 2016 Oct 7. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.

Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. doi: 10.1016/S1470-2045(15)70122-1. Epub 2015 Mar 31. Erratum In: Lancet Oncol. 2015 Jun;16(6):e262. Lancet Oncol. 2016 Jun;17 (6):e223.

Layout table for additonal information

Responsible Party:	Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT00636168
Other Study ID Numbers:	CA184-029 EORTC 18071
First Submitted:	March 7, 2008
First Posted:	March 14, 2008
Results First Submitted:	July 25, 2014
Results First Posted:	August 19, 2014
Last Update Posted:	December 17, 2019

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