Dacarbazine and Ipilimumab vs. Dacarbazine With Placebo in Untreated Unresectable Stage III or IV Melanoma

• ClinicalTrials.gov Identifier: NCT00324155
• Recruitment Status: Completed
• First Posted: May 10, 2006
• Results First Posted: March 10, 2014
• Last Update Posted: November 2, 2014
• Sponsor: Bristol-Myers Squibb
• Collaborator: Medarex
• 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: Melanoma
• Interventions: Drug: Ipilimumab; Drug: Placebo; Drug: Dacarbazine
• Enrollment: 681

Participant Flow

Recruitment Details	The study was initiated on August 8, 2006. Primary endpoint (Survival) was evaluated on February 7, 2011 and again at completion of follow-up period, October 13, 2013. Participants with a histologic diagnosis of untreated, measurable, and unresectable Stage III or Stage IV malignant melanoma were eligible.
Pre-assignment Details	Of 681 patients enrolled, 502 were randomized, and 498 received treatment. Reasons for not starting treatment: 147 no longer met study criteria (including 3 who were randomized but did not receive treatment), 25 withdrew consent, 3 died, 2 had adverse events, 2 lost to follow-up, 2 poor compliance or noncompliance, 1 not reported, and 1 other.

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
Period Title: Enrolled and Randomized
Started	250	252
Completed	247 [1]	251 [2]
Not Completed	3	1
Reason Not Completed
No longer met study criteria	3	0
Lost to Follow-up	0	1
[1] 3 randomized but who did not receive treatment (no longer met study criteria).; [2] 1 randomized but who did not receive treatment (lost to follow-up).
Period Title: Received Treatment in Induction Phase
Started	247	251
Completed	45 [1]	54 [2]
Not Completed	202	197
Reason Not Completed
Disease Progression	88	152
Study Drug Toxicity	83	10
Death	8	15
Deterioration/Undocumented Progression	9	8
Adverse Event	6	7
Withdrawal by Subject	6	5
Physician Decision	2	0
[1] 45 participants on treatment at end of Induction Phase. Study undergoing closure.; [2] 54 participants on treatment at end of Induction Phase. Study undergoing closure.
Period Title: Received Treatment in Maintenance Phase
Started	43 [1]	53 [2]
Completed	11 [3]	6 [4]
Not Completed	32	47
Reason Not Completed
Disease Progression	26	41
Study Drug Toxicity	4	0
Withdrawal by Subject	1	3
Adverse Event	0	3
Deterioration/Undocumented Progression	1	0
[1] 2 completed Induction Phase but did not enter Maintenance Phase; [2] 1 completed Induction Phase but did not enter Maintenance Phase; [3] Study is in closure at this time. 11 in Maintenance Phase not yet summarized.; [4] Study is in closure. 6 participants in Maintenance Phase not yet summarized.
Period Title: Follow-up Phase
Started	247 [1]	251 [1]
Completed	236	245
Not Completed	11	6
Reason Not Completed
On-going participants still on drug	11	6
[1] All participants received study drug. Follow-up was performed for those leaving earlier phases.

Baseline Characteristics

Arm/Group Title		Ipilimumab and Dacarbazine	Placebo and Dacarbazine	Total
Arm/Group Description		Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.	Total of all reporting groups
Overall Number of Baseline Participants		250	252	502
Baseline Analysis Population Description		Number of Randomized Participants
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	250 participants	252 participants	502 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	165 66.0%	177 70.2%	342 68.1%
	>=65 years	85 34.0%	75 29.8%	160 31.9%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	250 participants	252 participants	502 participants
		57.5 (13.51)	56.4 (13.71)	57.0 (13.61)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	250 participants	252 participants	502 participants
	Female	98 39.2%	103 40.9%	201 40.0%
	Male	152 60.8%	149 59.1%	301 60.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	250 participants	252 participants	502 participants
Australia		5	10	15
South Africa		10	12	22
North America		46	46	92
South America		13	9	22
Europe		176	175	351
Melanoma Tumor Stage; Metastasis Classification at Study Entry [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	250 participants	252 participants	502 participants
M0		6	8	14
M1a		37	43	80
M1b		64	62	126
M1c		143	139	282
		[1] Measure Description: Melanoma Tumor Staging: Metastasis (M) classification. M0=No distant metastases; M1a=Distant skin, subcutaneous tissue, or nodal metastases with normal lactic dehydrogenase (LDH); M1b=Lung metastases with normal LDH; M1c=All other visceral metastases with normal LDH or any distant metastasis with elevated LDH. Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma. J Clin Oncol. 2001;19 (16):3635-3648.
Eastern Cooperative Oncology Group Performance Status [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	250 participants	252 participants	502 participants
Category 0		177	179	356
Category 1		73	73	146
		[1] Measure Description: Eastern Cooperative Oncology Group Performance Status. Measured from 0 to 5 with 0=fully active; 1=restricted in physically strenuous activity; 2=ambulatory; 3=limited self care; 4= completely disabled; 5=dead. Lower score=better performance.

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from the date of randomization until the date of death. Analysis of OS was to be done once 416 deaths had occurred (primary endpoint). However, analysis occurred at 414 deaths (February 7, 2011), due to operational timing of the study. Median number of months of OS and associated confidence interval calculated using the method of Brookmeyer and Crowley.
Time Frame	Date of randomization to 37 months through 5-year follow-up and up to approximately 76 months

Outcome Measure Data

Analysis Population Description

All randomized participants whose survival follow-up was current (defined as having died or last known alive date occurring on or after the data cutoff date, which was when a total of 414 deaths occurred).

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks then1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	250	252
Median (95% Confidence Interval); Unit of Measure: Months
	11.17; (9.40 to 13.60)	9.07; (7.75 to 10.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab and Dacarbazine, Placebo and Dacarbazine
	Comments	Analysis stratified for metastasis stage (M0 vs M1a vs M1b vs M1c) and Eastern Cooperative Oncology Group performance status (0 vs 1) recorded at randomization.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	p-value was via stratified log-rank test
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.716
	Confidence Interval	(2-Sided) 95%; 0.588 to 0.872
	Estimation Comments	Hazard ratio via stratified Cox proportional hazards model.

2. Secondary Outcome

Title	Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years
Description	The survival rate (percentage of participants alive) was defined as the probability that a participant is alive at 1 year (or 18 months, 2 years, or 3 years) following randomization and was estimated via the Kaplan-Meier method.
Time Frame	Date of randomization to 3 years following randomization

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent
Overall Number of Participants Analyzed	250	252
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
At 1 year	47.3; (41.0 to 53.6)	36.3; (30.4 to 42.4)
At 18 months	35.6; (29.7 to 41.6)	26.1; (20.7 to 31.6)
At 2 years	28.5; (22.9 to 34.2)	17.9; (13.3 to 22.8)
At 3 years	20.8; (15.7 to 26.1)	12.2; (8.2 to 16.5)

3. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR=number whose best overall response (BOR) was partial response (PR), complete response (CR) or stable disease (SD), divided by all randomized participants (unevaluable participants included). Independent review committee assessment. BOR=date of first dose to last tumor assessment prior to subsequent cancer therapy (including tumor resection, excluding palliative local radiotherapy). Modified World Health Organization criteria: CR=disappearance of all lesions; no evidence of progressive disease (PD); PR=50% or more decrease in the sum of products of the longest diameter and greatest perpendicular diameter of all index lesions compared with baseline; SD=neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD; PD=at least 25% increase in sum of products of all index lesions and/or appearance of any new lesions; nonindex lesions: appearance of any new lesions and/or unequivocal progression of nonindex lesions.
Time Frame	First dose to last tumor assessment prior to subsequent therapy at data cutoff for Primary Endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
Overall Number of Participants Analyzed	250	252
Measure Type: Number; Unit of Measure: Percentage of participants
	33.2	30.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab and Dacarbazine, Placebo and Dacarbazine
	Comments	Analysis stratified for metastasis stage (M0 vs M1a vs M1b vs M1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) recorded at randomization.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4067
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified for metastasis stage (M0 vs M1a vs M1b vs M1c) and ECOG performance status (0 vs 1) recorded at randomization.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.179
	Confidence Interval	(2-Sided) 95%; 0.799 to 1.740
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Median Number of Months of Progression-free Survival (PFS)
Description	PFS=time between randomization and date of progression or death, whichever occurs first. Participants who died without reported prior progression were considered to have progressed on date of death. For those alive and not progressed, PFS was censored on date of last evaluable tumor assessment (TA). Those who have not died and have no recorded postbaseline TA were censored at randomization. Those who died without any recorded postbaseline TA were considered to have progressed on date of death. Evaluation was conducted by both investigator and an independent review committee (IRC), who assessed radiologic imaging studies, photographs of skin lesions, and clinical data. Progressive disease defined using modified criteria of the World Health Organization: demonstration of at least a 25% increase in the sum of products of all index lesions or the appearance of any new lesions. For nonindex lesions: appearance of any new lesions or unequivocal progression of nonindex lesions.
Time Frame	Randomization to date of progression or death to approximately 5 years

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent
Overall Number of Participants Analyzed	250	252
Median (95% Confidence Interval); Unit of Measure: Months
PFS per IRC	2.76; (2.63 to 3.29)	2.60; (2.56 to 2.66)
PFS per investigator	2.73; (2.63 to 3.48)	2.63; (2.60 to 2.73)

5. Secondary Outcome

Title	Progression-free Survival (PFS) Rate Truncated at Week 12
Description	PFS rate=probability patient was progression-free at Day 78, calculated as total patients receiving treatment and with an overall response of stable disease (SD), partial response (PR), or complete response (CR) at Week 12, divided by total patients. For those alive and not progressed at or before Week 12, PFS censored on date of last evaluable tumor assessment (TA) at or before Week 12. Those with an assessment of PD prior to Week 12 and subsequent assessment of SD, PR, or CR at Week 12 were called progression-free at Week 12. Those with no recorded postbaseline TA dated on or before Day 109, and who had not died on or before Day 109, were censored at randomization. PD=at least 25% increase in sum of products of all index lesions or appearance of any new lesions. Both an investigator and independent review committee (IRC) assessed radiologic imaging studies, photographs of skin lesions, and clinical data. IRC assessment was considered primary over that of the investigators.
Time Frame	Day 78

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
Overall Number of Participants Analyzed	250	252
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
PFS rate at Week 12 by IRC	55.4; (48.6 to 62.1)	50.7; (44.2 to 57.3)
PFS rate at Week 12 by Investigator	58.5; (51.9 to 65.0)	54.0; (47.5 to 60.4)

6. Secondary Outcome

Title	Best Overall Response Rate (BORR)
Description	BORR=number with Best Overall Response (BOR) of complete response (CR) or partial response (PR), divided by total number of randomized patients. BOR=date of first dose to the last tumor assessment prior to subsequent cancer therapy (including tumor resection surgery but excluding palliative local radiotherapy for bone lesions). Independent review committee assessment. Modified criteria of the World Health Organization (mWHO): CR=disappearance of all lesions; no evidence of progressive disease; PR=50% or greater decrease in the sum of products of the longest diameter and greatest perpendicular diameter of all index lesions compared with baseline. Immune-related (ir) response criteria (irRC) assess tumor response in patients on immunotherapy: irCR=disappearance of all lesions in 2 consecutive observations at least 4 weeks apart; irPR=50% or greater decrease in total measureable tumor burden compared with peak in 2 observations at least 4 weeks apart.
Time Frame	First dose to last tumor assessment at data cutoff for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1e dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	250	252
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
BORR by mWHO criteria	15.2; (11.0 to 20.3)	10.3; (6.9 to 14.8)
BORR by irRC	16.8; (12.4 to 22.0)	11.1; (7.5 to 15.7)

7. Secondary Outcome

Title	Duration of Response (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (PR)
Description	DOR defined in those with Best Overall Response (BOR)=CR or PR per independent review committee (IRC) as time between date of response of confirmed CR or PR, whichever occurred first, and date of PD or death. If PR assessed before CR, DOR confirmed at earlier time-point showing PR. Modified criteria of the World Health Organization (mWHO): CR=disappearance of all lesions;no evidence of PD; PR=50% or greater decrease in the sum of products of longest and greatest perpendicular diameters (SPD) of all index lesions compared with baseline. PD=an increase of 25% or greater in SPD of index lesions compared with the smallest recorded sum, or appearance of 1 or more new lesions. Immune-related response criteria (irRC): SD=50% decrease in total measurable tumor burden compared with peak cannot be established nor 25% increase compared with nadir, in absence of unequivocal progression of nonindex lesions. Unconfirmed immune-related (ir) CR, irPR, or irPD=irSD.
Time Frame	Day of CR or PR to day of PD or death up to data cutoff for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group and had a response of CR, PR, irCR, or irPR. n=number of participants who responded by mWHO criteria and irRC.

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	42	28
Median (95% Confidence Interval); Unit of Measure: Months
Using mWHO criteria (n=38, 26)	19.3; (12.1 to 26.1)	8.1; (5.2 to 19.8)
Using irRC criteria (n=42, 28)	21.1; (16.5 to 26.1)	10.2; (5.6 to 24.0)

8. Secondary Outcome

Title	Time to Response: All Randomized Participants With Response to Treatment
Description	Time to response was defined as the time between the first dose of study therapy and the date when measurement criteria were met for Best Overall Response (BOR) of partial response (PR) or complete response (CR), whichever occurred first, per independent review committee. Note that if an overall response of PR occurred before confirmation of CR, the time to response endpoint was not determined by the time that the BOR of CR was shown but rather by the earlier time point showing PR. Modified criteria of the World Health Organization: CR=disappearance of all lesions; no evidence of progressive disease (PD); PR=50% or more decrease in the sum of products of the longest and greatest perpendicular diameters (SPD) of all index lesions compared with baseline; PD=an increase of 25% or greater in the SPD of index lesions compared with the smallest recorded sum, or the appearance of 1 or more new lesions.
Time Frame	First dose to date of BOR up to data cutoff for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group and who had a response of CR or PR

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression, (PD) unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	38	26
Median (Full Range); Unit of Measure: Months
	2.6; (2.3 to 3.9)	2.7; (2.5 to 5.7)

9. Secondary Outcome

Title	Duration of Stable Disease (SD): Randomized Participants With Stable Disease
Description	Duration of SD was defined in those whose Best Overall Response (BOR) was SD, per independent review committee (IRC) as the time between Week 12 and date of progressive disease (PD) or death , whichever occurs first. For those who underwent tumor resection following Week 12 but prior to PD, duration of SD was censored on date of last evaluable tumor assessment (TA) prior to resection. For those with BOR of SD at Week 12, date of PD was used in analysis of duration of SD. For those with BOR=SD who have not subsequently progressed and who remain alive, duration of SD censored on date of last evaluable TA. Modified criteria of the World Health Organization (mWHO): SD=insufficient decrease to qualify for partial response or sufficient increase to qualify for PD; PD=an increase of 25% or more in sum of products of longest diameter and greatest perpendicular diameter of index lesions compared with smallest recorded sum, or appearance of 1 or more new lesions.
Time Frame	Week 12 to date of disease progression or death up to data cutoff for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group and had SD

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In maintenance phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	45	57
Median (95% Confidence Interval); Unit of Measure: Months
Duration of SD by mWHO criteria(n=45, 50)	4.7; (1.9 to 9.2)	4.6; (3.2 to 6.9)
Duration of SD by IRC criteria (n=45, 57)	4.8; (2.8 to 7.7)	3.4; (2.5 to 5.2)

10. Secondary Outcome

Title	Percentage of Participants With Brain Metastasis-Free Survival at Time of Data Cutoff
Description	Brain metastasis-free survival was defined as the time from randomization to the date of progression with a new lesion located in the brain. New brain lesions prior to Week 12 constituted a progression event (unlike main progression-free survival analysis). A participant who dies without documentation of a brain lesion was considered to have progressed with brain metastasis on the date of death. Participants who are free of brain metastasis were censored on the date of their last tumor assessment. An independent review committee evaluated images of participants with clinical symptoms to determine the number of those free of brain metastasis. The brain metastasis-free status was reported as a percent of participants (n/N), where n= participants with metastasis-free brains at data cutoff for the Primary Endpoint and N= randomized participants. A 2-sided Clopper and Pearson confidence interval was performed.
Time Frame	Date of randomization up to data cutoff for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment group

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent
Overall Number of Participants Analyzed	250	252
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	93.6; (89.8 to 96.3)	90.9; (86.6 to 94.1)

11. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Drug-related AEs, AEs Leading to Discontinuation, Serious Adverse Events (SAEs), Drug-related SAEs, Drug-related Hypersensitivity, Immune-related AEs/SAEs, and Inflammatory AEs/SAEs
Description	AE=any new undesirable symptom, sign, clinically significant laboratory abnormality, or medical condition occurring after starting study treatment, even if the event was not considered to be drug-related. 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. Treatment-related=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. Randomization=Day 1; start of treatment (first dose)=Week 1. Summarization time frame is from first dose to 70 days after last dose of study at time of 414 deaths.
Time Frame	Week 1 (First Dose) to 70 days after last dose of study up to data cutoff for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of randomized ipilimumab or placebo and/or dacarbazine

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10m g/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	247	251
Measure Type: Number; Unit of Measure: Participants
AEs	244	236
Drug-related AEs	221	192
Discontinuations due to AEs	114	46
SAEs	170	121
Drug-related SAEs	116	17
Drug-related hypersensitivity	5	4
Immune-related AEs	187	77
Immune-related SAEs	91	3
Infammatory AEs	201	117
Inflammatory SAEs	101	9

12. Secondary Outcome

Title	Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved
Description	irAEs included the categories: gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=moderate adverse events (AEs); minimal, local, or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4=life-threatening consequences; urgent intervention indicated. Resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment).
Time Frame	Week 1 (first dose) to 70 days after last dose up to data cutoff for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had this specific event

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
Overall Number of Participants Analyzed	89	8
Measure Type: Number; Unit of Measure: Participants
GI AE Grade 2-4 (n=39, 7)	36	7
GI Grade 3-4 (n=14, 0)	13	0
Liver AE Grade 2-4 (n=89, 8)	81	4
Liver AE Grade 3-4 (n=69, 5)	63	2
Skin AE Grade 2-4 (n=46, 2)	42	2
Skin AE Grade 3-4 (n=8, 0)	6	0
Diarrhea AE Grade 2-3 (n=31, 7)	29	7
Diarrhea AE Grade 3-4 (n=10, 0)	9	0

13. Secondary Outcome

Title	Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs)
Description	irAEs included the categories: gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=Moderate adverse events (AEs); minimal, local or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4=life-threatening consequences; urgent intervention indicated. Time to resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment).
Time Frame	Week 1 (first dose) to 70 days after last dose up to database lock for primary endpoint (approximately 5 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had a specific event that resolved

Arm/Group Title	Ipilimumab and Dacarbazine	Placebo and Dacarbazine
Arm/Group Description:	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	81	7
Median (95% Confidence Interval); Unit of Measure: Weeks
GI AE Grade 2-4 (n=36, 7)	2.00; (1.14 to 2.71)	0.14; (0.14 to 0.29)
GI Grade 3-4 (n=13, 0))	2.14; (2.00 to 4.57)	NA [1]; (NA to NA)
Liver AE Grade 2-4 (n=81, 4)	3.43; (3.14 to 4.43)	NA [1]; (6.86 to NA)
Liver AE Grade 3-4 (n=63, 2)	3.43; (3.00 to 4.43)	NA [1]; (3.57 to NA)
Skin AE Grade 2-4 (n=42, 2)	4.14; (3.14 to 7.00)	0.93; (0.57 to 1.29)
Skin AE Grade 3-4 (n=6, 0)	4.71; (3.14 to 5.29)	NA [1]; (NA to NA)
Diarrhea AE Grade 2-3 (n=29, 7)	1.43; (0.71 to 2.57)	0.14; (0.14 to 0.29)
Diarrhea AE Grade 3-4 (n=9, 0)	2.00; (0.71 to 2.57)	NA [1]; (NA to NA)

[1]

Median time to resolution could not be computed due to low/no occurrence of either the resolution of the AE or low/no occurrence the AE in this arm

Adverse Events

Time Frame	Week 1 (First Dose) to 70 days after last dose of study drug up to last patient, last visit (LPLV) of follow up period; approximately 7 years.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	10 mg/kg Ipilimumab + Dacarbazine	Placebo + Dacarbazine
Arm/Group Description	Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10mg/kg, every 12 wks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.	Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Participants who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
All-Cause Mortality
	10 mg/kg Ipilimumab + Dacarbazine	Placebo + Dacarbazine
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	10 mg/kg Ipilimumab + Dacarbazine	Placebo + Dacarbazine
	Affected / at Risk (%)	Affected / at Risk (%)
Total	170/247 (68.83%)	121/251 (48.21%)
Blood and lymphatic system disorders
Neutropenia † 1	4/247 (1.62%)	5/251 (1.99%)
Coagulopathy † 1	1/247 (0.40%)	0/251 (0.00%)
Febrile bone marrow aplasia † 1	0/247 (0.00%)	1/251 (0.40%)
Lymphadenopathy † 1	1/247 (0.40%)	0/251 (0.00%)
Anaemia † 1	4/247 (1.62%)	4/251 (1.59%)
Eosinophilia † 1	1/247 (0.40%)	0/251 (0.00%)
Thrombocytopenia † 1	6/247 (2.43%)	3/251 (1.20%)
Leukocytosis † 1	0/247 (0.00%)	1/251 (0.40%)
Leukopenia † 1	0/247 (0.00%)	2/251 (0.80%)
Febrile neutropenia † 1	3/247 (1.21%)	0/251 (0.00%)
Cardiac disorders
Acute myocardial infarction † 1	1/247 (0.40%)	0/251 (0.00%)
Myocardial infarction † 1	0/247 (0.00%)	2/251 (0.80%)
Ventricular tachycardia † 1	0/247 (0.00%)	1/251 (0.40%)
Atrial fibrillation † 1	1/247 (0.40%)	0/251 (0.00%)
Pericardial effusion † 1	0/247 (0.00%)	1/251 (0.40%)
Atrial flutter † 1	0/247 (0.00%)	1/251 (0.40%)
Sinus tachycardia † 1	0/247 (0.00%)	1/251 (0.40%)
Arteriosclerosis coronary artery † 1	1/247 (0.40%)	0/251 (0.00%)
Supraventricular tachycardia † 1	1/247 (0.40%)	0/251 (0.00%)
Endocrine disorders
Autoimmune thyroiditis † 1	1/247 (0.40%)	0/251 (0.00%)
Endocrine disorder † 1	1/247 (0.40%)	0/251 (0.00%)
Eye disorders
Vitreous haemorrhage † 1	1/247 (0.40%)	0/251 (0.00%)
Gastrointestinal disorders
Nausea † 1	3/247 (1.21%)	7/251 (2.79%)
Ileus † 1	0/247 (0.00%)	1/251 (0.40%)
Ascites † 1	1/247 (0.40%)	5/251 (1.99%)
Intestinal polyp haemorrhage † 1	1/247 (0.40%)	0/251 (0.00%)
Proctocolitis † 1	1/247 (0.40%)	0/251 (0.00%)
Abdominal distension † 1	0/247 (0.00%)	1/251 (0.40%)
Abdominal pain † 1	3/247 (1.21%)	3/251 (1.20%)
Colitis † 1	8/247 (3.24%)	0/251 (0.00%)
Diarrhoea † 1	16/247 (6.48%)	1/251 (0.40%)
Dysphagia † 1	1/247 (0.40%)	1/251 (0.40%)
Gastrointestinal haemorrhage † 1	0/247 (0.00%)	1/251 (0.40%)
Pancreatitis † 1	1/247 (0.40%)	0/251 (0.00%)
Vomiting † 1	10/247 (4.05%)	4/251 (1.59%)
Abdominal pain upper † 1	0/247 (0.00%)	1/251 (0.40%)
Constipation † 1	1/247 (0.40%)	2/251 (0.80%)
Small intestinal obstruction † 1	0/247 (0.00%)	1/251 (0.40%)
Gastric haemorrhage † 1	0/247 (0.00%)	1/251 (0.40%)
Haematemesis † 1	0/247 (0.00%)	2/251 (0.80%)
Proctitis † 1	1/247 (0.40%)	0/251 (0.00%)
Upper gastrointestinal haemorrhage † 1	0/247 (0.00%)	1/251 (0.40%)
Gastrointestinal obstruction † 1	0/247 (0.00%)	1/251 (0.40%)
General disorders
General physical health deterioration † 1	2/247 (0.81%)	0/251 (0.00%)
Malaise † 1	1/247 (0.40%)	0/251 (0.00%)
Asthenia † 1	0/247 (0.00%)	2/251 (0.80%)
Condition aggravated † 1	0/247 (0.00%)	1/251 (0.40%)
Fatigue † 1	6/247 (2.43%)	5/251 (1.99%)
Pyrexia † 1	19/247 (7.69%)	4/251 (1.59%)
Sudden death † 1	0/247 (0.00%)	1/251 (0.40%)
Hyperpyrexia † 1	1/247 (0.40%)	0/251 (0.00%)
Mucosal inflammation † 1	1/247 (0.40%)	0/251 (0.00%)
Systemic inflammatory response syndrome † 1	1/247 (0.40%)	0/251 (0.00%)
Chills † 1	2/247 (0.81%)	0/251 (0.00%)
Pain † 1	1/247 (0.40%)	3/251 (1.20%)
Performance status decreased † 1	1/247 (0.40%)	0/251 (0.00%)
Chest pain † 1	1/247 (0.40%)	0/251 (0.00%)
Disease progression † 1	0/247 (0.00%)	1/251 (0.40%)
Hyperthermia † 1	1/247 (0.40%)	1/251 (0.40%)
Hernia pain † 1	1/247 (0.40%)	0/251 (0.00%)
Oedema † 1	1/247 (0.40%)	0/251 (0.00%)
Oedema peripheral † 1	1/247 (0.40%)	0/251 (0.00%)
Hepatobiliary disorders
Hepatic function abnormal † 1	2/247 (0.81%)	0/251 (0.00%)
Hepatitis † 1	3/247 (1.21%)	0/251 (0.00%)
Hepatotoxicity † 1	3/247 (1.21%)	0/251 (0.00%)
Hyperbilirubinaemia † 1	1/247 (0.40%)	0/251 (0.00%)
Hepatic failure † 1	1/247 (0.40%)	1/251 (0.40%)
Hepatitis acute † 1	1/247 (0.40%)	0/251 (0.00%)
Cholecystitis acute † 1	0/247 (0.00%)	1/251 (0.40%)
Cholelithiasis † 1	1/247 (0.40%)	0/251 (0.00%)
Autoimmune hepatitis † 1	4/247 (1.62%)	0/251 (0.00%)
Cholecystitis † 1	1/247 (0.40%)	0/251 (0.00%)
Immune system disorders
Autoimmune disorder † 1	2/247 (0.81%)	0/251 (0.00%)
Sarcoidosis † 1	1/247 (0.40%)	0/251 (0.00%)
Hypersensitivity † 1	2/247 (0.81%)	0/251 (0.00%)
Infections and infestations
Urinary tract infection † 1	1/247 (0.40%)	0/251 (0.00%)
Bronchopneumonia † 1	0/247 (0.00%)	1/251 (0.40%)
Device related infection † 1	2/247 (0.81%)	1/251 (0.40%)
Herpes zoster † 1	1/247 (0.40%)	0/251 (0.00%)
Lobar pneumonia † 1	2/247 (0.81%)	0/251 (0.00%)
Meningitis aseptic † 1	1/247 (0.40%)	0/251 (0.00%)
Oral herpes † 1	1/247 (0.40%)	0/251 (0.00%)
Soft tissue infection † 1	1/247 (0.40%)	0/251 (0.00%)
Groin infection † 1	1/247 (0.40%)	0/251 (0.00%)
Kidney infection † 1	0/247 (0.00%)	1/251 (0.40%)
Cellulitis † 1	1/247 (0.40%)	1/251 (0.40%)
Rectal abscess † 1	0/247 (0.00%)	1/251 (0.40%)
Pneumonia † 1	5/247 (2.02%)	2/251 (0.80%)
Anal abscess † 1	1/247 (0.40%)	0/251 (0.00%)
Cardiac infection † 1	1/247 (0.40%)	0/251 (0.00%)
Infection † 1	1/247 (0.40%)	0/251 (0.00%)
Sepsis † 1	0/247 (0.00%)	1/251 (0.40%)
Injury, poisoning and procedural complications
Femoral neck fracture † 1	0/247 (0.00%)	2/251 (0.80%)
Femur fracture † 1	0/247 (0.00%)	1/251 (0.40%)
Fall † 1	0/247 (0.00%)	1/251 (0.40%)
Infusion related reaction † 1	2/247 (0.81%)	0/251 (0.00%)
Clavicle fracture † 1	0/247 (0.00%)	1/251 (0.40%)
Humerus fracture † 1	0/247 (0.00%)	1/251 (0.40%)
Wrist fracture † 1	0/247 (0.00%)	1/251 (0.40%)
Investigations
Blood alkaline phosphatase increased † 1	2/247 (0.81%)	0/251 (0.00%)
Haemoglobin decreased † 1	1/247 (0.40%)	1/251 (0.40%)
Weight decreased † 1	1/247 (0.40%)	0/251 (0.00%)
Aspartate aminotransferase increased † 1	48/247 (19.43%)	1/251 (0.40%)
Blood creatinine increased † 1	0/247 (0.00%)	1/251 (0.40%)
Liver function test abnormal † 1	1/247 (0.40%)	0/251 (0.00%)
Gamma-glutamyltransferase increased † 1	4/247 (1.62%)	1/251 (0.40%)
Glucose tolerance increased † 1	1/247 (0.40%)	0/251 (0.00%)
Hepatic enzyme increased † 1	1/247 (0.40%)	0/251 (0.00%)
Alanine aminotransferase increased † 1	49/247 (19.84%)	1/251 (0.40%)
Platelet count decreased † 1	0/247 (0.00%)	1/251 (0.40%)
Blood bilirubin increased † 1	3/247 (1.21%)	0/251 (0.00%)
Metabolism and nutrition disorders
Hypercalcaemia † 1	1/247 (0.40%)	1/251 (0.40%)
Tumour lysis syndrome † 1	1/247 (0.40%)	0/251 (0.00%)
Hypovolaemia † 1	1/247 (0.40%)	0/251 (0.00%)
Hyperkalaemia † 1	1/247 (0.40%)	0/251 (0.00%)
Decreased appetite † 1	1/247 (0.40%)	2/251 (0.80%)
Dehydration † 1	3/247 (1.21%)	6/251 (2.39%)
Hyponatraemia † 1	1/247 (0.40%)	1/251 (0.40%)
Musculoskeletal and connective tissue disorders
Arthritis † 1	1/247 (0.40%)	0/251 (0.00%)
Pathological fracture † 1	2/247 (0.81%)	0/251 (0.00%)
Bone pain † 1	1/247 (0.40%)	0/251 (0.00%)
Musculoskeletal pain † 1	1/247 (0.40%)	3/251 (1.20%)
Neck mass † 1	1/247 (0.40%)	0/251 (0.00%)
Arthralgia † 1	1/247 (0.40%)	0/251 (0.00%)
Musculoskeletal chest pain † 1	1/247 (0.40%)	0/251 (0.00%)
Back pain † 1	3/247 (1.21%)	3/251 (1.20%)
Flank pain † 1	0/247 (0.00%)	1/251 (0.40%)
Pain in extremity † 1	2/247 (0.81%)	0/251 (0.00%)
Axillary mass † 1	1/247 (0.40%)	0/251 (0.00%)
Muscular weakness † 1	3/247 (1.21%)	3/251 (1.20%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma † 1	1/247 (0.40%)	2/251 (0.80%)
Laryngeal neoplasm † 1	0/247 (0.00%)	1/251 (0.40%)
Neoplasm progression † 1	2/247 (0.81%)	2/251 (0.80%)
Malignant pleural effusion † 1	1/247 (0.40%)	0/251 (0.00%)
Rectal cancer † 1	0/247 (0.00%)	1/251 (0.40%)
Brain neoplasm † 1	0/247 (0.00%)	1/251 (0.40%)
Malignant neoplasm progression † 1	35/247 (14.17%)	58/251 (23.11%)
Transitional cell carcinoma † 1	0/247 (0.00%)	1/251 (0.40%)
Tumour haemorrhage † 1	1/247 (0.40%)	1/251 (0.40%)
Metastases to central nervous system † 1	1/247 (0.40%)	5/251 (1.99%)
Metastases to skin † 1	0/247 (0.00%)	2/251 (0.80%)
Myelodysplastic syndrome † 1	0/247 (0.00%)	1/251 (0.40%)
Malignant ascites † 1	1/247 (0.40%)	0/251 (0.00%)
Tumour pain † 1	1/247 (0.40%)	0/251 (0.00%)
Metastatic malignant melanoma † 1	2/247 (0.81%)	3/251 (1.20%)
Nervous system disorders
Hemiparesis † 1	0/247 (0.00%)	1/251 (0.40%)
Syncope † 1	2/247 (0.81%)	1/251 (0.40%)
Dysarthria † 1	0/247 (0.00%)	1/251 (0.40%)
Epilepsy † 1	0/247 (0.00%)	1/251 (0.40%)
Peripheral motor neuropathy † 1	1/247 (0.40%)	1/251 (0.40%)
Speech disorder † 1	0/247 (0.00%)	1/251 (0.40%)
Aphasia † 1	1/247 (0.40%)	0/251 (0.00%)
Dizziness † 1	2/247 (0.81%)	0/251 (0.00%)
Hypoglycaemic seizure † 1	1/247 (0.40%)	0/251 (0.00%)
Convulsion † 1	0/247 (0.00%)	1/251 (0.40%)
Sciatica † 1	0/247 (0.00%)	1/251 (0.40%)
Cerebral ischaemia † 1	1/247 (0.40%)	1/251 (0.40%)
Headache † 1	5/247 (2.02%)	0/251 (0.00%)
Lethargy † 1	1/247 (0.40%)	0/251 (0.00%)
Nervous system disorder † 1	1/247 (0.40%)	0/251 (0.00%)
Peripheral sensory neuropathy † 1	1/247 (0.40%)	0/251 (0.00%)
Somnolence † 1	1/247 (0.40%)	0/251 (0.00%)
Cerebral haemorrhage † 1	0/247 (0.00%)	4/251 (1.59%)
Presyncope † 1	1/247 (0.40%)	1/251 (0.40%)
Cranial nerve disorder † 1	0/247 (0.00%)	1/251 (0.40%)
Haemorrhage intracranial † 1	0/247 (0.00%)	1/251 (0.40%)
Psychiatric disorders
Confusional state † 1	2/247 (0.81%)	1/251 (0.40%)
Mental status changes † 1	0/247 (0.00%)	2/251 (0.80%)
Completed suicide † 1	0/247 (0.00%)	1/251 (0.40%)
Renal and urinary disorders
Nephritis † 1	0/247 (0.00%)	1/251 (0.40%)
Oliguria † 1	1/247 (0.40%)	0/251 (0.00%)
Proteinuria † 1	0/247 (0.00%)	1/251 (0.40%)
Renal failure acute † 1	2/247 (0.81%)	0/251 (0.00%)
Renal failure † 1	2/247 (0.81%)	2/251 (0.80%)
Urinary retention † 1	2/247 (0.81%)	1/251 (0.40%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm † 1	1/247 (0.40%)	0/251 (0.00%)
Pleuritic pain † 1	0/247 (0.00%)	1/251 (0.40%)
Chronic obstructive pulmonary disease † 1	1/247 (0.40%)	0/251 (0.00%)
Haemoptysis † 1	0/247 (0.00%)	1/251 (0.40%)
Pleural effusion † 1	2/247 (0.81%)	4/251 (1.59%)
Pulmonary sarcoidosis † 1	1/247 (0.40%)	0/251 (0.00%)
Aspiration † 1	0/247 (0.00%)	1/251 (0.40%)
Dyspnoea † 1	3/247 (1.21%)	6/251 (2.39%)
Pneumonitis † 1	2/247 (0.81%)	0/251 (0.00%)
Respiratory failure † 1	1/247 (0.40%)	1/251 (0.40%)
Pulmonary embolism † 1	0/247 (0.00%)	4/251 (1.59%)
Skin and subcutaneous tissue disorders
Pruritus † 1	1/247 (0.40%)	0/251 (0.00%)
Exfoliative rash † 1	1/247 (0.40%)	0/251 (0.00%)
Rash † 1	1/247 (0.40%)	0/251 (0.00%)
Rash erythematous † 1	1/247 (0.40%)	0/251 (0.00%)
Vascular disorders
Hypotension † 1	3/247 (1.21%)	1/251 (0.40%)
Peripheral artery thrombosis † 1	1/247 (0.40%)	0/251 (0.00%)
Phlebitis † 1	0/247 (0.00%)	1/251 (0.40%)
Poor venous access † 1	0/247 (0.00%)	1/251 (0.40%)
Thrombophlebitis † 1	0/247 (0.00%)	1/251 (0.40%)
Haemorrhage † 1	0/247 (0.00%)	1/251 (0.40%)
Thrombosis † 1	1/247 (0.40%)	0/251 (0.00%)
Superior vena cava syndrome † 1	0/247 (0.00%)	1/251 (0.40%)
Aortic disorder † 1	1/247 (0.40%)	0/251 (0.00%)
Deep vein thrombosis † 1	0/247 (0.00%)	1/251 (0.40%)
Hypertension † 1	1/247 (0.40%)	0/251 (0.00%)
† 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%
	10 mg/kg Ipilimumab + Dacarbazine	Placebo + Dacarbazine
	Affected / at Risk (%)	Affected / at Risk (%)
Total	220/247 (89.07%)	218/251 (86.85%)
Blood and lymphatic system disorders
Neutropenia † 1	16/247 (6.48%)	14/251 (5.58%)
Anaemia † 1	20/247 (8.10%)	12/251 (4.78%)
Gastrointestinal disorders
Nausea † 1	119/247 (48.18%)	120/251 (47.81%)
Abdominal pain † 1	28/247 (11.34%)	29/251 (11.55%)
Diarrhoea † 1	83/247 (33.60%)	61/251 (24.30%)
Vomiting † 1	74/247 (29.96%)	69/251 (27.49%)
Constipation † 1	69/247 (27.94%)	68/251 (27.09%)
General disorders
Asthenia † 1	29/247 (11.74%)	32/251 (12.75%)
Fatigue † 1	100/247 (40.49%)	95/251 (37.85%)
Pyrexia † 1	82/247 (33.20%)	20/251 (7.97%)
Chills † 1	27/247 (10.93%)	10/251 (3.98%)
Chest pain † 1	13/247 (5.26%)	8/251 (3.19%)
Influenza like illness † 1	19/247 (7.69%)	11/251 (4.38%)
Oedema peripheral † 1	20/247 (8.10%)	12/251 (4.78%)
Immune system disorders
Hypersensitivity † 1	13/247 (5.26%)	6/251 (2.39%)
Investigations
Blood alkaline phosphatase increased † 1	16/247 (6.48%)	9/251 (3.59%)
Weight decreased † 1	27/247 (10.93%)	13/251 (5.18%)
Aspartate aminotransferase increased † 1	50/247 (20.24%)	14/251 (5.58%)
Gamma-glutamyltransferase increased † 1	19/247 (7.69%)	9/251 (3.59%)
Alanine aminotransferase increased † 1	60/247 (24.29%)	14/251 (5.58%)
Metabolism and nutrition disorders
Decreased appetite † 1	53/247 (21.46%)	47/251 (18.73%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain † 1	18/247 (7.29%)	20/251 (7.97%)
Arthralgia † 1	19/247 (7.69%)	18/251 (7.17%)
Back pain † 1	27/247 (10.93%)	23/251 (9.16%)
Pain in extremity † 1	15/247 (6.07%)	22/251 (8.76%)
Nervous system disorders
Dizziness † 1	16/247 (6.48%)	10/251 (3.98%)
Headache † 1	38/247 (15.38%)	33/251 (13.15%)
Psychiatric disorders
Anxiety † 1	9/247 (3.64%)	13/251 (5.18%)
Insomnia † 1	22/247 (8.91%)	16/251 (6.37%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	25/247 (10.12%)	25/251 (9.96%)
Dyspnoea † 1	25/247 (10.12%)	28/251 (11.16%)
Skin and subcutaneous tissue disorders
Pruritus † 1	73/247 (29.55%)	22/251 (8.76%)
Rash † 1	63/247 (25.51%)	17/251 (6.77%)
† 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.

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

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

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

Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. doi: 10.1200/JCO.2014.56.6018. Epub 2015 Feb 23.

Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol. 2015 Jun 10;33(17):1889-94. doi: 10.1200/JCO.2014.56.2736. Epub 2015 Feb 9.

Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. doi: 10.1056/NEJMoa1104621. Epub 2011 Jun 5.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00324155
• Other Study ID Numbers: CA184-024
• First Submitted: May 8, 2006
• First Posted: May 10, 2006
• Results First Submitted: January 22, 2014
• Results First Posted: March 10, 2014
• Last Update Posted: November 2, 2014