CA184-169

Bristol-Myers Squibb

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

No

No

No

Final

17 Aug 2017

No

Yes

17 Aug 2017

No

To compare the overall survival (OS) of ipilimumab monotherapy at doses of 3 versus (vs) 10 mg/kg in subjects with previously treated (excluding prior BRAF, CTLA-4 and PD-1 inhibitors) or untreated unresectable Stage III or Stage IV melanoma.

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

29 Feb 2012

No

Yes

Argentina: 7

Australia: 49

Austria: 17

Belgium: 9

Canada: 20

Czech Republic: 14

Germany: 83

Denmark: 42

Spain: 57

France: 140

United Kingdom: 24

Hungary: 26

Israel: 4

Italy: 175

Mexico: 3

Netherlands: 9

Norway: 19

Poland: 55

Sweden: 21

United States: 49

South Africa: 8

831

691

0

0

0

0

0

0

492

324

15

Induction

Randomised - controlled

Yes

Ipilimumab

Solution for infusion

Intravenous use

Each subject received ipilimumab (3 or 10 mg/kg) as a single dose via IV infusion. During the Induction Period, subjects received ipilimumab at a dose of 3 or 10 mg/kg via IV infusion every 3 weeks x 4 doses (Weeks 1, 4, 7, and 10) unless there was confirmed disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment. Eligible subjects received ipilimumab again during the Re-induction Phase. During Re-induction, ipilimumab was administered at the same dose level as assigned at randomization once every 3 weeks x 4 for a total of 4 separate doses unless there was disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment.

Ipilimumab

Solution for infusion

Intravenous use

Each subject received ipilimumab (3 or 10 mg/kg) as a single dose via IV infusion. During the Induction Period, subjects received ipilimumab at a dose of 3 or 10 mg/kg via IV infusion every 3 weeks x 4 doses (Weeks 1, 4, 7, and 10) unless there was confirmed disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment. Eligible subjects received ipilimumab again during the Re-induction Phase. During Re-induction, ipilimumab was administered at the same dose level as assigned at randomization once every 3 weeks x 4 for a total of 4 separate doses unless there was disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment.

First Re-Induction Phase

Non-randomised - controlled

Yes

Ipilimumab

Solution for infusion

Intravenous use

Each subject received ipilimumab (3 or 10 mg/kg) as a single dose via IV infusion. During the Induction Period, subjects received ipilimumab at a dose of 3 or 10 mg/kg via IV infusion every 3 weeks x 4 doses (Weeks 1, 4, 7, and 10) unless there was confirmed disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment. Eligible subjects received ipilimumab again during the Re-induction Phase. During Re-induction, ipilimumab was administered at the same dose level as assigned at randomization once every 3 weeks x 4 for a total of 4 separate doses unless there was disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment.

Ipilimumab

Solution for infusion

Intravenous use

Each subject received ipilimumab (3 or 10 mg/kg) as a single dose via IV infusion. During the Induction Period, subjects received ipilimumab at a dose of 3 or 10 mg/kg via IV infusion every 3 weeks x 4 doses (Weeks 1, 4, 7, and 10) unless there was confirmed disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment. Eligible subjects received ipilimumab again during the Re-induction Phase. During Re-induction, ipilimumab was administered at the same dose level as assigned at randomization once every 3 weeks x 4 for a total of 4 separate doses unless there was disease progression (per irRC), unacceptable toxicity, or the subject requested to stop study treatment.

Ipilimumab (10 mg/kg)

Ipilimumab (3 mg/kg)

Ipilimumab (10 mg/kg)

Ipilimumab (3 mg/kg)

Ipilimumab (10 mg/kg)

Ipilimumab (3 mg/kg)

OS is defined for each subject as the time between randomization date and death due to any cause. The survival time for subjects who had not died was censored at the last known alive date. Median and associated 2-sided 95% confidence intervals were calculated using the method of Brookmeyer and Crowley.

Primary

Approximately 48 months (assessed up to February 2016)

Ipilimumab (10 mg/kg) v Ipilimumab (3 mg/kg)

727

Pre-specified

0.84

2-sided

PFS was defined as the time between randomization date and the date of progression or death, whichever occurred first. A subject who died without reported prior progression was considered to have progressed on the date of death. For a subject who underwent resection post randomization, PFS was censored on last tumor assessment date prior to resection. For those who remained alive and had not progressed, PFS was censored on last evaluable tumor assessment date. Subjects who had not died and had no recorded post-baseline tumor assessment were censored at the day of randomization. For subjects who had Progressive Disease (PD) prior to Week 12 and a subsequent assessment of Stable Disease (SD), Partial Response (PR), or Complete Response (CR), the date of PD following response was used in the analysis of PFS; otherwise these subjects were censored on the date of their last tumor assessment. Median and 2-sided 95% CIs were calculated with Brookmeyer Crowley method.

Secondary

From date of randomization until 540 death events occurred (approximately 48 months)

Ipilimumab (10 mg/kg) v Ipilimumab (3 mg/kg)

727

Pre-specified

0.89

2-sided

BORR by treatment arm was defined as the total number of randomized subjects in the arm whose BOR is CR or PR, divided by the total number of randomized subjects in the arm. Any subject who was unevaluable for BOR, e.g. on account of missing or “not evaluable” assessments, was included in the denominator of the calculation (i.e. was considered a non-responder with respect to the BORR endpoint). 95% 2-sided exact confidence intervals were computed using the method of Clopper and Pearson.

Secondary

From date of randomization until 540 death events occurred (approximately 48 months)

DCR by treatment arm was defined as the total number of randomized subjects in the arm whose BOR is CR, PR or SD, divided by the total number of randomized subjects in the arm. Any subject who was unevaluable for Disease Control (DC), (e.g. on account of missing or “not evaluable” assessments), was included in the denominator of the calculation (i.e. was considered a non-responder with respect to the DCR endpoint). 95% 2-sided exact confidence intervals were computed using the Clopper and Pearson method.

Secondary

From date of randomization until 540 death events occurred (approximately 48 months)

Duration of response for subjects whose BOR was CR or PR was defined as the time between the date measurement criteria were first met for overall response of PR or CR (whichever status was recorded first) and the date of disease progression or death (whichever occurred first). For subjects who underwent tumor resection following response but prior to disease progression, duration of response was censored on the date of last evaluable tumor assessment prior to resection. For subjects who had BOR of SD, PR or CR at Week 12, or a confirmed response of PR or CR before Week 12, the date of PD following thereafter (where available) was used in the analysis of duration of response. For those subjects who remained alive and had not progressed following response, duration of response was censored on the date of last evaluable tumor assessment. Median and associated 2-sided 95% confidence intervals were calculated using the Brookmeyer Crowley method.

Secondary

From date of randomization until 540 death events occurred (approximately 48 months)

Duration of stable disease was defined for subjects whose BOR was SD as the time between when SD was first documented and the date of PD or death (whichever occurred first). For a subject who underwent tumor resection following Week 12 but prior to disease progression, duration of stable disease was censored on the date of the last evaluable tumor assessment prior to resection. For subjects who had BOR of SD at Week 12, the date of PD following thereafter (where available) was used in the analysis of duration of stable disease. For subjects with BOR of SD who had not subsequently progressed and who remained alive, duration of stable disease was censored on the date of last evaluable tumor assessment. Median and associated 2-sided 95% confidence intervals were calculated using the Brookmeyer and Crowley method.

Secondary

From date of randomization until 540 death events occurred (approximately 48 months)

OS is defined for each subject as the time between randomization date and death due to any cause. The survival time for subjects who had not died was censored at the last known alive date. Survival rates were calculated based on Kaplan-Meier estimation with log-log transformed confidence intervals. The survival rate at x year(s) is defined as the probability that a subject is alive at x year(s) following randomization.

Secondary

Approximately 66 months

OS for each subject with brain metastases at baseline was measured as the time between randomization date and death due to any cause. The survival time for subjects who had not died was censored at the last known alive date. Median OS, and associated 2-sided 95% confidence intervals were calculated using the Brookmeyer and Crowley method.

Secondary

From date of randomization until 540 death events occurred (approximately 48 months)

Ipilimumab (10 mg/kg) v Ipilimumab (3 mg/kg)

127

Pre-specified

0.71

2-sided

Adverse events occurring on or after Day 1 of study treatment and no later than 90 days following the last day of study treatment were considered.

20.0

10 mg/kg Ipilimumab

3 mg/kg Ipilimumab