Trial Outcomes & Findings for Dacarbazine and Ipilimumab vs. Dacarbazine With Placebo in Untreated Unresectable Stage III or IV Melanoma (NCT NCT00324155)

Last Updated: 2014-11-03

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

681 participants

Primary outcome timeframe

Date of randomization to 37 months through 5-year follow-up and up to approximately 76 months

Results posted on

2014-11-03

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Ipilimumab and Dacarbazine 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 and Dacarbazine 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.
Enrolled and Randomized STARTED	250	252
Enrolled and Randomized COMPLETED	247	251
Enrolled and Randomized NOT COMPLETED	3	1
Received Treatment in Induction Phase STARTED	247	251
Received Treatment in Induction Phase COMPLETED	45	54
Received Treatment in Induction Phase NOT COMPLETED	202	197
Received Treatment in Maintenance Phase STARTED	43	53
Received Treatment in Maintenance Phase COMPLETED	11	6
Received Treatment in Maintenance Phase NOT COMPLETED	32	47
Follow-up Phase STARTED	247	251
Follow-up Phase COMPLETED	236	245
Follow-up Phase NOT COMPLETED	11	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Ipilimumab and Dacarbazine 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 and Dacarbazine 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.
Enrolled and Randomized No longer met study criteria	3	0
Enrolled and Randomized Lost to Follow-up	0	1
Received Treatment in Induction Phase Disease Progression	88	152
Received Treatment in Induction Phase Study Drug Toxicity	83	10
Received Treatment in Induction Phase Death	8	15
Received Treatment in Induction Phase Deterioration/Undocumented Progression	9	8
Received Treatment in Induction Phase Adverse Event	6	7
Received Treatment in Induction Phase Withdrawal by Subject	6	5
Received Treatment in Induction Phase Physician Decision	2	0
Received Treatment in Maintenance Phase Disease Progression	26	41
Received Treatment in Maintenance Phase Study Drug Toxicity	4	0
Received Treatment in Maintenance Phase Withdrawal by Subject	1	3
Received Treatment in Maintenance Phase Adverse Event	0	3
Received Treatment in Maintenance Phase Deterioration/Undocumented Progression	1	0
Follow-up Phase On-going participants still on drug	11	6

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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 n=502 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	165 Participants n=5 Participants	177 Participants n=7 Participants	342 Participants n=5 Participants
Age, Categorical >=65 years	85 Participants n=5 Participants	75 Participants n=7 Participants	160 Participants n=5 Participants
Age, Continuous	57.5 years STANDARD_DEVIATION 13.51 • n=5 Participants	56.4 years STANDARD_DEVIATION 13.71 • n=7 Participants	57.0 years STANDARD_DEVIATION 13.61 • n=5 Participants
Sex: Female, Male Female	98 Participants n=5 Participants	103 Participants n=7 Participants	201 Participants n=5 Participants
Sex: Female, Male Male	152 Participants n=5 Participants	149 Participants n=7 Participants	301 Participants n=5 Participants
Region of Enrollment Australia	5 participants n=5 Participants	10 participants n=7 Participants	15 participants n=5 Participants
Region of Enrollment South Africa	10 participants n=5 Participants	12 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment North America	46 participants n=5 Participants	46 participants n=7 Participants	92 participants n=5 Participants
Region of Enrollment South America	13 participants n=5 Participants	9 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment Europe	176 participants n=5 Participants	175 participants n=7 Participants	351 participants n=5 Participants
Melanoma Tumor Stage; Metastasis Classification at Study Entry M0	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Melanoma Tumor Stage; Metastasis Classification at Study Entry M1a	37 Participants n=5 Participants	43 Participants n=7 Participants	80 Participants n=5 Participants
Melanoma Tumor Stage; Metastasis Classification at Study Entry M1b	64 Participants n=5 Participants	62 Participants n=7 Participants	126 Participants n=5 Participants
Melanoma Tumor Stage; Metastasis Classification at Study Entry M1c	143 Participants n=5 Participants	139 Participants n=7 Participants	282 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status Category 0	177 Participants n=5 Participants	179 Participants n=7 Participants	356 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status Category 1	73 Participants n=5 Participants	73 Participants n=7 Participants	146 Participants n=5 Participants

PRIMARY outcome

Timeframe: Date of randomization to 37 months through 5-year follow-up and up to approximately 76 months

Population: 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).

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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 Survival (OS)	11.17 Months Interval 9.4 to 13.6	9.07 Months Interval 7.75 to 10.51

SECONDARY outcome

Timeframe: Date of randomization to 3 years following randomization

Population: All participants who were randomized to a treatment group

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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
Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years At 1 year	47.3 Percentage of participants Interval 41.0 to 53.6	36.3 Percentage of participants Interval 30.4 to 42.4
Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years At 18 months	35.6 Percentage of participants Interval 29.7 to 41.6	26.1 Percentage of participants Interval 20.7 to 31.6
Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years At 2 years	28.5 Percentage of participants Interval 22.9 to 34.2	17.9 Percentage of participants Interval 13.3 to 22.8
Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years At 3 years	20.8 Percentage of participants Interval 15.7 to 26.1	12.2 Percentage of participants Interval 8.2 to 16.5

SECONDARY outcome

Timeframe: First dose to last tumor assessment prior to subsequent therapy at data cutoff for Primary Endpoint (approximately 5 years)

Population: All participants who were randomized to a treatment group

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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
Disease Control Rate (DCR)	33.2 Percentage of participants	30.2 Percentage of participants

SECONDARY outcome

Timeframe: Randomization to date of progression or death to approximately 5 years

Population: All participants who were randomized to a treatment group

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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
Median Number of Months of Progression-free Survival (PFS) PFS per IRC	2.76 Months Interval 2.63 to 3.29	2.60 Months Interval 2.56 to 2.66
Median Number of Months of Progression-free Survival (PFS) PFS per investigator	2.73 Months Interval 2.63 to 3.48	2.63 Months Interval 2.6 to 2.73

SECONDARY outcome

Timeframe: Day 78

Population: All participants who were randomized to a treatment group

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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
Progression-free Survival (PFS) Rate Truncated at Week 12 PFS rate at Week 12 by IRC	55.4 Percentage of participants Interval 48.6 to 62.1	50.7 Percentage of participants Interval 44.2 to 57.3
Progression-free Survival (PFS) Rate Truncated at Week 12 PFS rate at Week 12 by Investigator	58.5 Percentage of participants Interval 51.9 to 65.0	54.0 Percentage of participants Interval 47.5 to 60.4

SECONDARY outcome

Timeframe: First dose to last tumor assessment at data cutoff for primary endpoint (approximately 5 years)

Population: All participants who were randomized to a treatment group

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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
Best Overall Response Rate (BORR) BORR by mWHO criteria	15.2 Percentage of participants Interval 11.0 to 20.3	10.3 Percentage of participants Interval 6.9 to 14.8
Best Overall Response Rate (BORR) BORR by irRC	16.8 Percentage of participants Interval 12.4 to 22.0	11.1 Percentage of participants Interval 7.5 to 15.7

SECONDARY outcome

Timeframe: Day of CR or PR to day of PD or death up to data cutoff for primary endpoint (approximately 5 years)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=42 Participants 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 and Dacarbazine n=28 Participants 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
Duration of Response (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (PR) Using mWHO criteria (n=38, 26)	19.3 Months Interval 12.1 to 26.1	8.1 Months Interval 5.2 to 19.8
Duration of Response (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (PR) Using irRC criteria (n=42, 28)	21.1 Months Interval 16.5 to 26.1	10.2 Months Interval 5.6 to 24.0

SECONDARY outcome

Timeframe: First dose to date of BOR up to data cutoff for primary endpoint (approximately 5 years)

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

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=38 Participants 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 and Dacarbazine n=26 Participants 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
Time to Response: All Randomized Participants With Response to Treatment	2.6 Months Interval 2.3 to 3.9	2.7 Months Interval 2.5 to 5.7

SECONDARY outcome

Timeframe: Week 12 to date of disease progression or death up to data cutoff for primary endpoint (approximately 5 years)

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

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=45 Participants 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 and Dacarbazine n=57 Participants 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
Duration of Stable Disease (SD): Randomized Participants With Stable Disease Duration of SD by mWHO criteria(n=45, 50)	4.7 Months Interval 1.9 to 9.2	4.6 Months Interval 3.2 to 6.9
Duration of Stable Disease (SD): Randomized Participants With Stable Disease Duration of SD by IRC criteria (n=45, 57)	4.8 Months Interval 2.8 to 7.7	3.4 Months Interval 2.5 to 5.2

SECONDARY outcome

Timeframe: Date of randomization up to data cutoff for primary endpoint (approximately 5 years)

Population: All participants who were randomized to a treatment group

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=250 Participants 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 and Dacarbazine n=252 Participants 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
Percentage of Participants With Brain Metastasis-Free Survival at Time of Data Cutoff	93.6 Percentage of participants Interval 89.8 to 96.3	90.9 Percentage of participants Interval 86.6 to 94.1

SECONDARY outcome

Timeframe: Week 1 (First Dose) to 70 days after last dose of study up to data cutoff for primary endpoint (approximately 5 years)

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

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.

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=247 Participants 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 and Dacarbazine n=251 Participants 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
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 AEs	244 Participants	236 Participants
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 Drug-related AEs	221 Participants	192 Participants
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 Discontinuations due to AEs	114 Participants	46 Participants
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 SAEs	170 Participants	121 Participants
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 Drug-related SAEs	116 Participants	17 Participants
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 Drug-related hypersensitivity	5 Participants	4 Participants
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 Immune-related AEs	187 Participants	77 Participants
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 Immune-related SAEs	91 Participants	3 Participants
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 Infammatory AEs	201 Participants	117 Participants
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 Inflammatory SAEs	101 Participants	9 Participants

SECONDARY outcome

Timeframe: Week 1 (first dose) to 70 days after last dose up to data cutoff for primary endpoint (approximately 5 years)

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

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).

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=89 Participants 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 and Dacarbazine n=8 Participants 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
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved GI AE Grade 2-4 (n=39, 7)	36 Participants	7 Participants
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved GI Grade 3-4 (n=14, 0)	13 Participants	0 Participants
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved Liver AE Grade 2-4 (n=89, 8)	81 Participants	4 Participants
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved Liver AE Grade 3-4 (n=69, 5)	63 Participants	2 Participants
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved Skin AE Grade 2-4 (n=46, 2)	42 Participants	2 Participants
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved Skin AE Grade 3-4 (n=8, 0)	6 Participants	0 Participants
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved Diarrhea AE Grade 2-3 (n=31, 7)	29 Participants	7 Participants
Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved Diarrhea AE Grade 3-4 (n=10, 0)	9 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 1 (first dose) to 70 days after last dose up to database lock for primary endpoint (approximately 5 years)

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

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).

Outcome measures

Outcome measures
Measure	Ipilimumab and Dacarbazine n=81 Participants 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 and Dacarbazine n=7 Participants 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
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) GI AE Grade 2-4 (n=36, 7)	2.00 Weeks Interval 1.14 to 2.71	0.14 Weeks Interval 0.14 to 0.29
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) GI Grade 3-4 (n=13, 0))	2.14 Weeks Interval 2.0 to 4.57	NA Weeks 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
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) Liver AE Grade 2-4 (n=81, 4)	3.43 Weeks Interval 3.14 to 4.43	NA Weeks Interval 6.86 to 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
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) Liver AE Grade 3-4 (n=63, 2)	3.43 Weeks Interval 3.0 to 4.43	NA Weeks Interval 3.57 to 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
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) Skin AE Grade 2-4 (n=42, 2)	4.14 Weeks Interval 3.14 to 7.0	0.93 Weeks Interval 0.57 to 1.29
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) Skin AE Grade 3-4 (n=6, 0)	4.71 Weeks Interval 3.14 to 5.29	NA Weeks 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
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) Diarrhea AE Grade 2-3 (n=29, 7)	1.43 Weeks Interval 0.71 to 2.57	0.14 Weeks Interval 0.14 to 0.29
Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs) Diarrhea AE Grade 3-4 (n=9, 0)	2.00 Weeks Interval 0.71 to 2.57	NA Weeks 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

10 mg/kg Ipilimumab + Dacarbazine

Serious events: 170 serious events

Other events: 220 other events

Deaths: 0 deaths

Placebo + Dacarbazine

Serious events: 121 serious events

Other events: 218 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	10 mg/kg Ipilimumab + Dacarbazine n=247 participants at risk 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 + Dacarbazine n=251 participants at risk 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.
Investigations Blood alkaline phosphatase increased	6.5% 16/247 • 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.	3.6% 9/251 • 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.
Gastrointestinal disorders Nausea	48.2% 119/247 • 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.	47.8% 120/251 • 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.
Blood and lymphatic system disorders Neutropenia	6.5% 16/247 • 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.	5.6% 14/251 • 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.
Skin and subcutaneous tissue disorders Pruritus	29.6% 73/247 • 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.	8.8% 22/251 • 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.
Investigations Weight decreased	10.9% 27/247 • 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.	5.2% 13/251 • 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.
Investigations Aspartate aminotransferase increased	20.2% 50/247 • 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.	5.6% 14/251 • 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.
General disorders Asthenia	11.7% 29/247 • 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.	12.7% 32/251 • 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.
Respiratory, thoracic and mediastinal disorders Cough	10.1% 25/247 • 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.	10.0% 25/251 • 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.
General disorders Fatigue	40.5% 100/247 • 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.	37.8% 95/251 • 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.
Nervous system disorders Dizziness	6.5% 16/247 • 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.	4.0% 10/251 • 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.
General disorders Pyrexia	33.2% 82/247 • 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.	8.0% 20/251 • 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.
Gastrointestinal disorders Abdominal pain	11.3% 28/247 • 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.	11.6% 29/251 • 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.
Blood and lymphatic system disorders Anaemia	8.1% 20/247 • 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.	4.8% 12/251 • 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.
Psychiatric disorders Anxiety	3.6% 9/247 • 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.	5.2% 13/251 • 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.
Gastrointestinal disorders Diarrhoea	33.6% 83/247 • 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.	24.3% 61/251 • 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.
Investigations Gamma-glutamyltransferase increased	7.7% 19/247 • 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.	3.6% 9/251 • 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.
Psychiatric disorders Insomnia	8.9% 22/247 • 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.	6.4% 16/251 • 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.3% 18/247 • 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.	8.0% 20/251 • 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.
Musculoskeletal and connective tissue disorders Arthralgia	7.7% 19/247 • 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.	7.2% 18/251 • 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.
General disorders Chills	10.9% 27/247 • 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.	4.0% 10/251 • 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.
Gastrointestinal disorders Vomiting	30.0% 74/247 • 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.	27.5% 69/251 • 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.
Investigations Alanine aminotransferase increased	24.3% 60/247 • 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.	5.6% 14/251 • 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.
Musculoskeletal and connective tissue disorders Back pain	10.9% 27/247 • 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.	9.2% 23/251 • 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.
General disorders Chest pain	5.3% 13/247 • 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.	3.2% 8/251 • 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.
Gastrointestinal disorders Constipation	27.9% 69/247 • 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.	27.1% 68/251 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.1% 25/247 • 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.	11.2% 28/251 • 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.
Nervous system disorders Headache	15.4% 38/247 • 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.	13.1% 33/251 • 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.
Musculoskeletal and connective tissue disorders Pain in extremity	6.1% 15/247 • 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.	8.8% 22/251 • 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.
Skin and subcutaneous tissue disorders Rash	25.5% 63/247 • 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.	6.8% 17/251 • 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.
Immune system disorders Hypersensitivity	5.3% 13/247 • 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.	2.4% 6/251 • 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.
General disorders Influenza like illness	7.7% 19/247 • 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.	4.4% 11/251 • 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.
Metabolism and nutrition disorders Decreased appetite	21.5% 53/247 • 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.	18.7% 47/251 • 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.
General disorders Oedema peripheral	8.1% 20/247 • 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.	4.8% 12/251 • 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.