Trial Outcomes & Findings for Phase 3 Trial in Subjects With Metastatic Melanoma Comparing 3 mg/kg Ipilimumab Versus 10 mg/kg Ipilimumab (NCT NCT01515189)

Last Updated: 2019-07-31

Results Overview

OS is defined for each participant as the time between randomization date and death due to any cause. The survival time for participants 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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

831 participants

Primary outcome timeframe

Approximately 48 months (assessed up to February 2016)

Results posted on

2019-07-31

Participant Flow

831 participants were enrolled; 727 were randomized to a treatment group; 726 received at least one dose of study treatment. Of the 105 participants not treated, 81 no longer met study criteria, 11 withdrew consent, 4 suffered an Adverse Event, 4 died, and 5 were not treated due to investigator decision or other reasons.

Participant milestones

Participant milestones
Measure	Ipilimumab (10 mg/kg) Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Induction STARTED	365	362
Induction COMPLETED	128	130
Induction NOT COMPLETED	237	232
First Re-Induction Phase STARTED	23	32
First Re-Induction Phase COMPLETED	9	17
First Re-Induction Phase NOT COMPLETED	14	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Ipilimumab (10 mg/kg) Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Induction Disease Progression	109	155
Induction Study drug toxicity	86	36
Induction Death	24	17
Induction Adverse Event	14	9
Induction Withdrawal by Subject	3	9
Induction No longer meets study criteria	0	2
Induction Lost to Follow-up	1	0
Induction Other	0	4
First Re-Induction Phase Disease progression	6	14
First Re-Induction Phase Study drug toxicity	5	0
First Re-Induction Phase Withdrawal by Subject	1	1
First Re-Induction Phase No longer meets study criteria	1	0
First Re-Induction Phase Other	1	0

Baseline Characteristics

Phase 3 Trial in Subjects With Metastatic Melanoma Comparing 3 mg/kg Ipilimumab Versus 10 mg/kg Ipilimumab

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Total n=727 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	224 Participants n=5 Participants	208 Participants n=7 Participants	432 Participants n=5 Participants
Age, Categorical >=65 years	141 Participants n=5 Participants	154 Participants n=7 Participants	295 Participants n=5 Participants
Age, Continuous	58.6 years STANDARD_DEVIATION 14.52 • n=5 Participants	60.7 years STANDARD_DEVIATION 13.22 • n=7 Participants	59.7 years STANDARD_DEVIATION 13.92 • n=5 Participants
Sex: Female, Male Female	146 Participants n=5 Participants	131 Participants n=7 Participants	277 Participants n=5 Participants
Sex: Female, Male Male	219 Participants n=5 Participants	231 Participants n=7 Participants	450 Participants n=5 Participants

PRIMARY outcome

Timeframe: Approximately 48 months (assessed up to February 2016)

Population: All randomized participants

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Overall Survival (OS)	15.70 months Interval 11.63 to 17.84	11.53 months Interval 9.86 to 13.27

SECONDARY outcome

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

Population: All randomized participants.

PFS was defined as the time between randomization date and the date of progression or death, whichever occurred first. A participant who died without reported prior progression was considered to have progressed on the date of death. For a participant 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. Participants who had not died and had no recorded post-baseline tumor assessment were censored at the day of randomization. For participants 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 participants were censored on the date of their last tumor assessment. Median and 2-sided 95% CIs were calculated with Brookmeyer Crowley method.

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Progression Free Survival (PFS) by mWHO Criteria	2.83 months Interval 2.79 to 2.99	2.79 months Interval 2.76 to 2.83

SECONDARY outcome

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

Population: All randomized participants

BORR by treatment arm was defined as the total number of randomized participants in the arm whose BOR is CR or PR, divided by the total number of randomized participants in the arm. Any participant 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.

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Best Overall Response Rate (BORR) by mWHO Criteria	15.3 percentage of participants with BORR Interval 11.8 to 19.5	12.2 percentage of participants with BORR Interval 9.0 to 16.0

SECONDARY outcome

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

Population: All randomized participants

DCR by treatment arm was defined as the total number of randomized participants in the arm whose BOR is CR, PR or SD, divided by the total number of randomized participants in the arm. Any participant 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.

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Disease Control Rate (DCR) by mWHO Criteria	31.5 percentage of participants with DC Interval 26.8 to 36.5	27.9 percentage of participants with DC Interval 23.3 to 32.8

SECONDARY outcome

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

Population: All randomized participants

Duration of response for participants 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 participants 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 participants 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 participants 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.

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Duration of Response (DOR) by mWHO Criteria	16.33 months Interval 5.98 to 23.98	15.90 months Interval 10.35 to The upper 95% CI for DOR was not reached.

SECONDARY outcome

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

Population: All randomized participants

Duration of stable disease was defined for participants 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 participant 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 participants 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 participants 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.

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Duration of Stable Disease by mWHO Criteria	5.55 months Interval 3.02 to 8.02	3.19 months Interval 2.73 to 5.55

SECONDARY outcome

Timeframe: Approximately 66 months

Population: All randomized participants

OS is defined for each participant as the time between randomization date and death due to any cause. The survival time for participants 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.

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=365 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=362 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Rate of Overall Survival Survival rate at 2 years	38.46 percentage of participants Interval 33.44 to 43.45	30.97 percentage of participants Interval 26.21 to 35.84
Rate of Overall Survival Survival rate at 1 year	54.28 percentage of participants Interval 49.01 to 59.25	47.62 percentage of participants Interval 42.35 to 52.7
Rate of Overall Survival Survival rate at 3 years	31.16 percentage of participants Interval 26.44 to 35.98	23.15 percentage of participants Interval 18.88 to 27.69
Rate of Overall Survival Survival rate at 4 years	26.63 percentage of participants Interval 22.17 to 31.28	20.25 percentage of participants Interval 16.21 to 24.62
Rate of Overall Survival Survival rate at 5 years	24.90 percentage of participants Interval 20.54 to 29.48	18.78 percentage of participants Interval 14.87 to 23.05

SECONDARY outcome

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

Population: All randomized participants with brain metastases at baseline

OS for each participant with brain metastases at baseline was measured as the time between randomization date and death due to any cause. The survival time for participants 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.

Outcome measures

Outcome measures
Measure	Ipilimumab (10 mg/kg) n=65 Participants Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity	Ipilimumab (3 mg/kg) n=62 Participants Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
Overall Survival of Participants With Brain Metastases at Baseline	7.00 months Interval 3.98 to 12.78	5.67 months Interval 4.21 to 6.97

Adverse Events

10 MG/KG IPILIMUMAB

Serious events: 245 serious events

Other events: 319 other events

Deaths: 0 deaths

3 MG/KG IPILIMUMAB

Serious events: 194 serious events

Other events: 302 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 n=364 participants at risk	3 MG/KG IPILIMUMAB n=362 participants at risk
Blood and lymphatic system disorders Anaemia	6.6% 24/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	4.7% 17/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Gastrointestinal disorders Abdominal pain	9.1% 33/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	9.4% 34/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Gastrointestinal disorders Constipation	10.4% 38/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	11.0% 40/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Gastrointestinal disorders Diarrhoea	38.5% 140/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	29.0% 105/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Gastrointestinal disorders Nausea	16.2% 59/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	20.4% 74/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Gastrointestinal disorders Vomiting	11.8% 43/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	9.4% 34/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
General disorders Asthenia	18.7% 68/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	16.6% 60/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
General disorders Fatigue	23.6% 86/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	26.2% 95/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
General disorders Oedema peripheral	6.9% 25/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	6.1% 22/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
General disorders Pyrexia	16.2% 59/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	11.9% 43/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Investigations Alanine aminotransferase increased	7.4% 27/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	3.3% 12/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Investigations Aspartate aminotransferase increased	7.4% 27/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	2.2% 8/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Investigations Weight decreased	8.0% 29/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	6.9% 25/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Metabolism and nutrition disorders Decreased appetite	14.3% 52/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	14.1% 51/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Musculoskeletal and connective tissue disorders Arthralgia	5.2% 19/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	7.2% 26/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Musculoskeletal and connective tissue disorders Back pain	5.8% 21/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	5.5% 20/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Musculoskeletal and connective tissue disorders Pain in extremity	7.1% 26/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	5.8% 21/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Nervous system disorders Dizziness	4.4% 16/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	6.1% 22/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Nervous system disorders Headache	15.4% 56/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	18.2% 66/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Psychiatric disorders Insomnia	5.2% 19/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	4.7% 17/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Respiratory, thoracic and mediastinal disorders Cough	9.1% 33/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	8.8% 32/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.4% 27/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	7.2% 26/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Skin and subcutaneous tissue disorders Pruritus	26.9% 98/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	28.5% 103/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
Skin and subcutaneous tissue disorders Rash	29.1% 106/364 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)	17.7% 64/362 • From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)