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

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT01515189
Collaborator
(none)
831
Enrollment
88
Locations
2
Arms
66
Actual Duration (Months)
9.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether giving Ipilimumab at a dose of 10mg/kg will extend the lives of subjects with unresectable or metastatic melanoma more than giving Ipilimumab at a dose of 3 mg/kg

Condition or Disease Intervention/Treatment Phase
  • Biological: Ipilimumab
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
831 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized Double-Blind Phase III Study of Ipilimumab Administered at 3 mg/kg Versus at 10 mg /kg in Subjects With Previously Treated or Untreated Unresectable or Metastatic Melanoma
Actual Study Start Date :
Feb 17, 2012
Actual Primary Completion Date :
Feb 6, 2016
Actual Study Completion Date :
Aug 17, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm 1: Ipilimumab (3 mg/kg)

Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses; option for Re-induction, until disease progression or unacceptable toxicity

Biological: Ipilimumab
Other Names:
  • Yervoy
  • BMS-734016

    		•
    Experimental: Arm 2: Ipilimumab (10 mg/kg)

    Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses; option for Re-induction, until disease progression or unacceptable toxicity

    Biological: Ipilimumab
    Other Names:
  • Yervoy
  • BMS-734016

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Overall Survival (OS) [Approximately 48 months (assessed up to February 2016)]

      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.

    Secondary Outcome Measures

    1. Progression Free Survival (PFS) by mWHO Criteria [From date of randomization until 540 death events occurred (approximately 48 months)]

      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.

    2. Best Overall Response Rate (BORR) by mWHO Criteria [From date of randomization until 540 death events occurred (approximately 48 months)]

      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.

    3. Disease Control Rate (DCR) by mWHO Criteria [From date of randomization until 540 death events occurred (approximately 48 months)]

      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.

    4. Duration of Response (DOR) by mWHO Criteria [From date of randomization until 540 death events occurred (approximately 48 months)]

      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.

    5. Duration of Stable Disease by mWHO Criteria [From date of randomization until 540 death events occurred (approximately 48 months)]

      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.

    6. Rate of Overall Survival [Approximately 66 months]

      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.

    7. Overall Survival of Participants With Brain Metastases at Baseline [From date of randomization until 540 death events occurred (approximately 48 months)]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

    Inclusion Criteria:

    • Unresectable Stage III or Stage IV melanoma

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

    Exclusion Criteria:

    • Brain metastases with symptoms or requiring treatment

    • History of autoimmune disease

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 The Angeles Clinic And Research Institute Los Angeles California United States 90025
    2 University Of California Los Angeles Los Angeles California United States 90095
    3 Baptist Cancer Institute Jacksonville Florida United States 32207
    4 Orlando Health, Inc Orlando Florida United States 32806
    5 Oncology Specialists, S.C. Park Ridge Illinois United States 60068
    6 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    7 Levine Cancer Institute Charlotte North Carolina United States 28204
    8 Duke University Hospital Durham North Carolina United States 27710
    9 Providence Portland Medical Center Portland Oregon United States 97213
    10 St. Luke's Cancer Center - Anderson Campus Easton Pennsylvania United States 18045
    11 Seattle Cancer Care Alliance Seattle Washington United States 98109
    12 Local Institution San Miguel De Tucuman Tucuman Argentina 4000
    13 Fundacion Cidea Buenos Aires Argentina 1121
    14 Local Institution Camperdown New South Wales Australia 2050
    15 Local Institution Coffs Harbour New South Wales Australia 2450
    16 Local Institution Brisbane Queensland Australia 4102
    17 Local Institution Southport Queensland Australia 4215
    18 Local Institution Adelaide South Australia Australia 5000
    19 Local Institution Heidelberg Victoria Australia 3084
    20 Local Institution Linz Austria 4020
    21 Local Institution Vienna Austria 1090
    22 Local Institution Bruxelles Belgium 1200
    23 Local Institution Leuven Belgium 3000
    24 Local Institution Edmonton Alberta Canada T6G 1Z2
    25 Local Institution Halfax Nova Scotia Canada B3H 2Y9
    26 Local Institution Montreal Quebec Canada H2W1S6
    27 Local Institution Brno Czechia 656 53
    28 Local Institution Olomouc Czechia 775 20
    29 Local Institution Praha 2 Czechia 128 08
    30 Local Institution Aarhus Denmark 8000
    31 Local Institution Herlev Denmark 2730
    32 Local Institution Odense Denmark 5000
    33 Local Institution Bordeaux France 33075
    34 Local Institution Dijon Cedex France 21079
    35 Local Institution Grenoble France 38043
    36 Local Institution Lille France 59037
    37 Local Institution Marseille Cedex 5 France 13385
    38 Local Institution Nantes Cedex 1 France 44093
    39 Local Institution Paris France 75010
    40 Local Institution Pierre Benite France 69495
    41 Local Institution Reims Cedex France 51092
    42 Local Institution Toulouse France 31059
    43 Local Institution Villejuif France 94805
    44 Local Institution Buxtehude Germany 21614
    45 Local Institution Essen Germany 45122
    46 Local Institution Hannover Germany 30625
    47 Local Institution Heidelberg Germany 69120
    48 Local Institution Kiel Germany 24105
    49 Local Institution Mainz Germany 55131
    50 Local Institution Munich Germany 81675
    51 Local Institution Tubingen Germany 72076
    52 Local Institution Budapest Hungary 1122
    53 Local Institution Kaposvar Hungary 7400
    54 Local Institution Szeged Hungary 6720
    55 Local Institution Jerusalem Israel 71908
    56 Local Institution Meldola (fc) Italy 47014
    57 Local Institution Milano Italy 20133
    58 Local Institution Napoli Italy 80131
    59 Local Institution Padova Italy 35128
    60 Local Institution Roma Italy 00144
    61 Local Institution Siena Italy 53100
    62 Local Institution Leon, Guanajato Guanajuato Mexico 37000
    63 Local Institution Amsterdam Netherlands 1081 HV
    64 Local Institution Groningen Netherlands 9713 GZ
    65 Local Institution Leiden Netherlands 2300 RC
    66 Local Institution Bergen Norway 5021
    67 Local Institution Oslo Norway 0379
    68 Local Institution Gdansk Poland 80-219
    69 Local Institution Poznan Poland 60-693
    70 Local Institution Warszawa Poland 02-781
    71 Local Institution Cape Town Western CAPE South Africa 7570
    72 Local Institution George Western CAPE South Africa 6530
    73 Local Institution Rondebosch Western CAPE South Africa 7700
    74 Local Institution Barcelona Spain 08036
    75 Local Institution Barcelona Spain 08908
    76 Local Institution Madrid Spain 28041
    77 Local Institution Navarra Spain 31008
    78 Instituto Valenciano De Oncologia Valencia Spain 46009
    79 Local Institution Valencia Spain 46014
    80 Local Institution Gothenberg Sweden 413 45
    81 Local Institution Lund Sweden 221 85
    82 Local Institution Stockholm Sweden 171 76
    83 Local Institution Umea Sweden 901 85
    84 Local Institution Lausanne Switzerland 1011
    85 Local Institution Manchester Greater Manchester United Kingdom M20 4BX
    86 Local Institution Glasgow, Scotland Strathclyde United Kingdom G12 OYN
    87 Local Institution London United Kingdom SW3 6JJ
    88 Local Institution Swansea United Kingdom SA2 8QA

    Sponsors and Collaborators

    • Bristol-Myers Squibb

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01515189
    Other Study ID Numbers:
    • CA184-169
    • 2011-004029-28
    First Posted:
    Jan 24, 2012
    Last Update Posted:
    Jul 31, 2019
    Last Verified:
    Jul 1, 2019
    Additional relevant MeSH terms:
    Melanoma
    Ipilimumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 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.
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Period Title: Induction
    STARTED 365 362
    COMPLETED 128 130
    NOT COMPLETED 237 232
    Period Title: Induction
    STARTED 23 32
    COMPLETED 9 17
    NOT COMPLETED 14 15

    Baseline Characteristics

    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg) Total
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Total of all reporting groups
    Overall Participants 365 362 727
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    224
    61.4%
    208
    57.5%
    432
    59.4%
    >=65 years
    141
    38.6%
    154
    42.5%
    295
    40.6%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    58.6
    (14.52)
    60.7
    (13.22)
    59.7
    (13.92)
    Sex: Female, Male (Count of Participants)
    Female
    146
    40%
    131
    36.2%
    277
    38.1%
    Male
    219
    60%
    231
    63.8%
    450
    61.9%

    Outcome Measures

    1. Primary Outcome
    Title Overall Survival (OS)
    Description 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.
    Time Frame Approximately 48 months (assessed up to February 2016)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 365 362
    Median (95% Confidence Interval) [months]
    15.70
    11.53
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ipilimumab (10 mg/kg), Ipilimumab (3 mg/kg)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0400
    Comments Analysis stratified by ECOG performance status (0 vs. 1), prior treatment for metastatic melanoma (yes vs. no) and M-stage (M0/M1a/M1b vs. M1c without brain metastases vs. M1c with brain metastases).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.84
    Confidence Interval (2-Sided) 95%
    0.70 to 0.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard of 10 mg/kg ipilimumab over hazard of 3 mg/kg, with 2-sided 95% confidence intervals are based on a Cox proportional hazards model
    2. Secondary Outcome
    Title Progression Free Survival (PFS) by mWHO Criteria
    Description 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.
    Time Frame From date of randomization until 540 death events occurred (approximately 48 months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants.
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 365 362
    Median (95% Confidence Interval) [months]
    2.83
    2.79
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ipilimumab (10 mg/kg), Ipilimumab (3 mg/kg)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1548
    Comments Analysis stratified by ECOG performance status (0 vs. 1), prior treatment for metastatic melanoma (yes vs. no) and M-stage (M0/M1a/M1b vs. M1c without brain metastases vs. M1c with brain metastases).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.89
    Confidence Interval (2-Sided) 95%
    0.76 to 1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard of 10 mg/kg ipilimumab over hazard of 3 mg/kg, with 2-sided 95% confidence intervals are based on a Cox proportional hazards model
    3. Secondary Outcome
    Title Best Overall Response Rate (BORR) by mWHO Criteria
    Description 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.
    Time Frame From date of randomization until 540 death events occurred (approximately 48 months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 365 362
    Number (95% Confidence Interval) [percentage of participants with BORR]
    15.3
    4.2%
    12.2
    3.4%
    4. Secondary Outcome
    Title Disease Control Rate (DCR) by mWHO Criteria
    Description 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.
    Time Frame From date of randomization until 540 death events occurred (approximately 48 months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 365 362
    Number (95% Confidence Interval) [percentage of participants with DC]
    31.5
    8.6%
    27.9
    7.7%
    5. Secondary Outcome
    Title Duration of Response (DOR) by mWHO Criteria
    Description 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.
    Time Frame From date of randomization until 540 death events occurred (approximately 48 months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 365 362
    Median (95% Confidence Interval) [months]
    16.33
    15.90
    6. Secondary Outcome
    Title Duration of Stable Disease by mWHO Criteria
    Description 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.
    Time Frame From date of randomization until 540 death events occurred (approximately 48 months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 365 362
    Median (95% Confidence Interval) [months]
    5.55
    3.19
    7. Secondary Outcome
    Title Rate of Overall Survival
    Description 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.
    Time Frame Approximately 66 months

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 365 362
    Survival rate at 1 year
    54.28
    14.9%
    47.62
    13.2%
    Survival rate at 2 years
    38.46
    10.5%
    30.97
    8.6%
    Survival rate at 3 years
    31.16
    8.5%
    23.15
    6.4%
    Survival rate at 4 years
    26.63
    7.3%
    20.25
    5.6%
    Survival rate at 5 years
    24.90
    6.8%
    18.78
    5.2%
    8. Secondary Outcome
    Title Overall Survival of Participants With Brain Metastases at Baseline
    Description 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.
    Time Frame From date of randomization until 540 death events occurred (approximately 48 months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with brain metastases at baseline
    Arm/Group Title Ipilimumab (10 mg/kg) Ipilimumab (3 mg/kg)
    Arm/Group Description Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses or until disease progression or unacceptable toxicity
    Measure Participants 65 62
    Median (95% Confidence Interval) [months]
    7.00
    5.67
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ipilimumab (10 mg/kg), Ipilimumab (3 mg/kg)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.71
    Confidence Interval (2-Sided) 95%
    0.49 to 1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard of 10 mg/kg ipilimumab over hazard of 3 mg/kg. Based on an unstratified Cox proportional hazards model for subset of participants with brain metastases.

    Adverse Events

    Time Frame From Day 1 of study treatment until 90 days following last day of study treatment, up to study completion (August 2017)
    Adverse Event Reporting Description
    Arm/Group Title 10 MG/KG IPILIMUMAB 3 MG/KG IPILIMUMAB
    Arm/Group Description
    All Cause Mortality
    10 MG/KG IPILIMUMAB 3 MG/KG IPILIMUMAB
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    10 MG/KG IPILIMUMAB 3 MG/KG IPILIMUMAB
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 245/364 (67.3%) 194/362 (53.6%)
    Blood and lymphatic system disorders
    Anaemia 5/364 (1.4%) 4/362 (1.1%)
    Bicytopenia 1/364 (0.3%) 0/362 (0%)
    Disseminated intravascular coagulation 1/364 (0.3%) 0/362 (0%)
    Febrile neutropenia 1/364 (0.3%) 0/362 (0%)
    Pancytopenia 1/364 (0.3%) 0/362 (0%)
    Thrombocytopenia 1/364 (0.3%) 1/362 (0.3%)
    Cardiac disorders
    Atrial fibrillation 3/364 (0.8%) 0/362 (0%)
    Cardiac arrest 1/364 (0.3%) 0/362 (0%)
    Cardiac failure 1/364 (0.3%) 0/362 (0%)
    Cardiac failure congestive 1/364 (0.3%) 0/362 (0%)
    Cardio-respiratory arrest 0/364 (0%) 1/362 (0.3%)
    Myocardial infarction 0/364 (0%) 2/362 (0.6%)
    Pericardial effusion 1/364 (0.3%) 1/362 (0.3%)
    Pericarditis 1/364 (0.3%) 0/362 (0%)
    Supraventricular tachycardia 2/364 (0.5%) 0/362 (0%)
    Tachycardia 1/364 (0.3%) 0/362 (0%)
    Congenital, familial and genetic disorders
    Carney complex 1/364 (0.3%) 0/362 (0%)
    Endocrine disorders
    Adrenal insufficiency 2/364 (0.5%) 0/362 (0%)
    Adrenocortical insufficiency acute 2/364 (0.5%) 1/362 (0.3%)
    Adrenocorticotropic hormone deficiency 2/364 (0.5%) 2/362 (0.6%)
    Autoimmune thyroiditis 1/364 (0.3%) 0/362 (0%)
    Diabetes insipidus 1/364 (0.3%) 0/362 (0%)
    Endocrine disorder 1/364 (0.3%) 0/362 (0%)
    Hyperthyroidism 1/364 (0.3%) 0/362 (0%)
    Hypophysitis 16/364 (4.4%) 9/362 (2.5%)
    Hypopituitarism 5/364 (1.4%) 3/362 (0.8%)
    Hypothalamo-pituitary disorder 0/364 (0%) 1/362 (0.3%)
    Hypothyroidism 0/364 (0%) 1/362 (0.3%)
    Lymphocytic hypophysitis 1/364 (0.3%) 2/362 (0.6%)
    Thyroiditis 2/364 (0.5%) 0/362 (0%)
    Thyrotoxic crisis 0/364 (0%) 1/362 (0.3%)
    Eye disorders
    Eye pain 1/364 (0.3%) 0/362 (0%)
    Periorbital oedema 0/364 (0%) 1/362 (0.3%)
    Gastrointestinal disorders
    Abdominal pain 1/364 (0.3%) 2/362 (0.6%)
    Abdominal pain upper 2/364 (0.5%) 0/362 (0%)
    Ascites 2/364 (0.5%) 3/362 (0.8%)
    Autoimmune colitis 4/364 (1.1%) 4/362 (1.1%)
    Autoimmune pancreatitis 1/364 (0.3%) 0/362 (0%)
    Colitis 33/364 (9.1%) 13/362 (3.6%)
    Colitis ulcerative 2/364 (0.5%) 1/362 (0.3%)
    Constipation 1/364 (0.3%) 3/362 (0.8%)
    Diarrhoea 42/364 (11.5%) 22/362 (6.1%)
    Gastritis 3/364 (0.8%) 0/362 (0%)
    Gastrointestinal haemorrhage 0/364 (0%) 2/362 (0.6%)
    Gastrointestinal perforation 0/364 (0%) 1/362 (0.3%)
    Haematochezia 0/364 (0%) 1/362 (0.3%)
    Haemorrhagic ascites 0/364 (0%) 1/362 (0.3%)
    Hiatus hernia 0/364 (0%) 1/362 (0.3%)
    Intestinal obstruction 0/364 (0%) 1/362 (0.3%)
    Intestinal perforation 2/364 (0.5%) 0/362 (0%)
    Large intestinal obstruction 0/364 (0%) 1/362 (0.3%)
    Large intestine perforation 1/364 (0.3%) 1/362 (0.3%)
    Nausea 2/364 (0.5%) 3/362 (0.8%)
    Pancreatitis 2/364 (0.5%) 0/362 (0%)
    Rectal haemorrhage 1/364 (0.3%) 0/362 (0%)
    Retroperitoneal haematoma 1/364 (0.3%) 0/362 (0%)
    Retroperitoneal haemorrhage 1/364 (0.3%) 0/362 (0%)
    Small intestinal haemorrhage 0/364 (0%) 1/362 (0.3%)
    Small intestinal obstruction 1/364 (0.3%) 1/362 (0.3%)
    Small intestinal perforation 0/364 (0%) 1/362 (0.3%)
    Vomiting 3/364 (0.8%) 3/362 (0.8%)
    General disorders
    Asthenia 2/364 (0.5%) 2/362 (0.6%)
    Chest pain 1/364 (0.3%) 2/362 (0.6%)
    Death 1/364 (0.3%) 0/362 (0%)
    Fatigue 5/364 (1.4%) 1/362 (0.3%)
    General physical health deterioration 10/364 (2.7%) 12/362 (3.3%)
    Generalised oedema 0/364 (0%) 1/362 (0.3%)
    Hyperthermia 2/364 (0.5%) 0/362 (0%)
    Influenza like illness 1/364 (0.3%) 0/362 (0%)
    Multiple organ dysfunction syndrome 1/364 (0.3%) 1/362 (0.3%)
    Oedema 1/364 (0.3%) 0/362 (0%)
    Pain 1/364 (0.3%) 5/362 (1.4%)
    Performance status decreased 0/364 (0%) 1/362 (0.3%)
    Peripheral swelling 0/364 (0%) 1/362 (0.3%)
    Pyrexia 9/364 (2.5%) 5/362 (1.4%)
    Ulcer haemorrhage 1/364 (0.3%) 0/362 (0%)
    Hepatobiliary disorders
    Acute hepatic failure 1/364 (0.3%) 0/362 (0%)
    Autoimmune hepatitis 4/364 (1.1%) 1/362 (0.3%)
    Bile duct obstruction 0/364 (0%) 1/362 (0.3%)
    Biliary dilatation 0/364 (0%) 1/362 (0.3%)
    Cholangitis 0/364 (0%) 1/362 (0.3%)
    Drug-induced liver injury 1/364 (0.3%) 0/362 (0%)
    Hepatic failure 1/364 (0.3%) 0/362 (0%)
    Hepatitis 6/364 (1.6%) 2/362 (0.6%)
    Hepatitis acute 1/364 (0.3%) 0/362 (0%)
    Hepatocellular injury 5/364 (1.4%) 0/362 (0%)
    Hepatorenal syndrome 0/364 (0%) 1/362 (0.3%)
    Hepatotoxicity 2/364 (0.5%) 1/362 (0.3%)
    Hyperbilirubinaemia 0/364 (0%) 1/362 (0.3%)
    Jaundice 0/364 (0%) 1/362 (0.3%)
    Immune system disorders
    Hypersensitivity 2/364 (0.5%) 0/362 (0%)
    Infections and infestations
    Abdominal infection 0/364 (0%) 1/362 (0.3%)
    Bartholinitis 1/364 (0.3%) 0/362 (0%)
    Bronchitis 0/364 (0%) 1/362 (0.3%)
    Cellulitis 1/364 (0.3%) 0/362 (0%)
    Clostridium difficile colitis 0/364 (0%) 1/362 (0.3%)
    Cystitis 0/364 (0%) 1/362 (0.3%)
    Cytomegalovirus colitis 1/364 (0.3%) 1/362 (0.3%)
    Encephalitis 1/364 (0.3%) 0/362 (0%)
    Erysipelas 2/364 (0.5%) 2/362 (0.6%)
    Gastroenteritis viral 1/364 (0.3%) 0/362 (0%)
    Gastrointestinal infection 1/364 (0.3%) 0/362 (0%)
    Hepatitis viral 0/364 (0%) 1/362 (0.3%)
    Herpes zoster 0/364 (0%) 1/362 (0.3%)
    Infection 3/364 (0.8%) 0/362 (0%)
    Liver abscess 1/364 (0.3%) 0/362 (0%)
    Localised infection 0/364 (0%) 1/362 (0.3%)
    Lower respiratory tract infection 1/364 (0.3%) 1/362 (0.3%)
    Lung infection 2/364 (0.5%) 0/362 (0%)
    Lymph node abscess 0/364 (0%) 1/362 (0.3%)
    Necrotising fasciitis 0/364 (0%) 1/362 (0.3%)
    Peritonitis 0/364 (0%) 1/362 (0.3%)
    Pleural infection 1/364 (0.3%) 0/362 (0%)
    Pneumonia 5/364 (1.4%) 4/362 (1.1%)
    Pyelonephritis 1/364 (0.3%) 0/362 (0%)
    Sepsis 0/364 (0%) 2/362 (0.6%)
    Septic shock 2/364 (0.5%) 2/362 (0.6%)
    Staphylococcal infection 1/364 (0.3%) 0/362 (0%)
    Upper respiratory tract infection 0/364 (0%) 1/362 (0.3%)
    Urinary tract infection 0/364 (0%) 2/362 (0.6%)
    Viral infection 1/364 (0.3%) 0/362 (0%)
    Injury, poisoning and procedural complications
    Clavicle fracture 1/364 (0.3%) 0/362 (0%)
    Fibula fracture 0/364 (0%) 1/362 (0.3%)
    Hip fracture 1/364 (0.3%) 0/362 (0%)
    Infusion related reaction 1/364 (0.3%) 1/362 (0.3%)
    Post procedural haemorrhage 1/364 (0.3%) 0/362 (0%)
    Radiation dysphagia 0/364 (0%) 1/362 (0.3%)
    Wound haemorrhage 1/364 (0.3%) 0/362 (0%)
    Investigations
    Alanine aminotransferase increased 6/364 (1.6%) 0/362 (0%)
    Aspartate aminotransferase increased 3/364 (0.8%) 0/362 (0%)
    Blood bilirubin increased 1/364 (0.3%) 0/362 (0%)
    Blood creatinine increased 1/364 (0.3%) 0/362 (0%)
    Blood glucose increased 1/364 (0.3%) 1/362 (0.3%)
    Blood potassium increased 1/364 (0.3%) 0/362 (0%)
    Gamma-glutamyltransferase increased 1/364 (0.3%) 0/362 (0%)
    Hepatic enzyme increased 1/364 (0.3%) 0/362 (0%)
    Liver function test increased 2/364 (0.5%) 0/362 (0%)
    Transaminases increased 3/364 (0.8%) 1/362 (0.3%)
    Metabolism and nutrition disorders
    Decreased appetite 3/364 (0.8%) 0/362 (0%)
    Dehydration 3/364 (0.8%) 2/362 (0.6%)
    Diabetic metabolic decompensation 1/364 (0.3%) 0/362 (0%)
    Hypercalcaemia 1/364 (0.3%) 1/362 (0.3%)
    Hyperglycaemia 1/364 (0.3%) 0/362 (0%)
    Hypokalaemia 1/364 (0.3%) 0/362 (0%)
    Hyponatraemia 3/364 (0.8%) 1/362 (0.3%)
    Ketoacidosis 1/364 (0.3%) 0/362 (0%)
    Tumour lysis syndrome 0/364 (0%) 1/362 (0.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/364 (0%) 1/362 (0.3%)
    Back pain 2/364 (0.5%) 1/362 (0.3%)
    Bone pain 2/364 (0.5%) 1/362 (0.3%)
    Flank pain 1/364 (0.3%) 0/362 (0%)
    Groin pain 2/364 (0.5%) 0/362 (0%)
    Muscular weakness 2/364 (0.5%) 2/362 (0.6%)
    Myalgia 1/364 (0.3%) 0/362 (0%)
    Pain in extremity 2/364 (0.5%) 0/362 (0%)
    Pathological fracture 1/364 (0.3%) 0/362 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 1/364 (0.3%) 0/362 (0%)
    Colon cancer 0/364 (0%) 1/362 (0.3%)
    Endometrial cancer 0/364 (0%) 1/362 (0.3%)
    Intracranial tumour haemorrhage 0/364 (0%) 2/362 (0.6%)
    Malignant melanoma in situ 1/364 (0.3%) 0/362 (0%)
    Malignant neoplasm progression 54/364 (14.8%) 60/362 (16.6%)
    Metastases to central nervous system 1/364 (0.3%) 4/362 (1.1%)
    Metastases to eye 1/364 (0.3%) 0/362 (0%)
    Metastases to meninges 1/364 (0.3%) 0/362 (0%)
    Metastases to muscle 0/364 (0%) 1/362 (0.3%)
    Metastases to skin 0/364 (0%) 1/362 (0.3%)
    Metastasis 0/364 (0%) 1/362 (0.3%)
    Neoplasm progression 0/364 (0%) 3/362 (0.8%)
    Neoplasm swelling 1/364 (0.3%) 0/362 (0%)
    Tumour associated fever 1/364 (0.3%) 0/362 (0%)
    Tumour haemorrhage 0/364 (0%) 3/362 (0.8%)
    Nervous system disorders
    Brain oedema 1/364 (0.3%) 0/362 (0%)
    Central nervous system haemorrhage 2/364 (0.5%) 0/362 (0%)
    Cerebellar haemorrhage 1/364 (0.3%) 1/362 (0.3%)
    Cerebral haematoma 1/364 (0.3%) 1/362 (0.3%)
    Cerebral haemorrhage 1/364 (0.3%) 1/362 (0.3%)
    Cerebrovascular accident 0/364 (0%) 1/362 (0.3%)
    Coma 0/364 (0%) 1/362 (0.3%)
    Epilepsy 1/364 (0.3%) 0/362 (0%)
    Facial nerve disorder 0/364 (0%) 1/362 (0.3%)
    Facial paralysis 1/364 (0.3%) 0/362 (0%)
    Facial paresis 1/364 (0.3%) 0/362 (0%)
    Guillain-barre syndrome 2/364 (0.5%) 0/362 (0%)
    Headache 5/364 (1.4%) 2/362 (0.6%)
    Hemiparesis 1/364 (0.3%) 0/362 (0%)
    Hemiplegia 0/364 (0%) 1/362 (0.3%)
    Intensive care unit acquired weakness 1/364 (0.3%) 0/362 (0%)
    Intracranial pressure increased 3/364 (0.8%) 0/362 (0%)
    Nervous system disorder 0/364 (0%) 1/362 (0.3%)
    Neuralgia 0/364 (0%) 1/362 (0.3%)
    Neurological decompensation 2/364 (0.5%) 0/362 (0%)
    Paralysis recurrent laryngeal nerve 0/364 (0%) 1/362 (0.3%)
    Partial seizures 0/364 (0%) 1/362 (0.3%)
    Peripheral motor neuropathy 1/364 (0.3%) 2/362 (0.6%)
    Sciatica 1/364 (0.3%) 1/362 (0.3%)
    Seizure 1/364 (0.3%) 2/362 (0.6%)
    Spinal cord compression 2/364 (0.5%) 2/362 (0.6%)
    Syncope 3/364 (0.8%) 1/362 (0.3%)
    Vasogenic cerebral oedema 0/364 (0%) 2/362 (0.6%)
    Psychiatric disorders
    Agitation 1/364 (0.3%) 0/362 (0%)
    Bipolar disorder 1/364 (0.3%) 0/362 (0%)
    Completed suicide 0/364 (0%) 1/362 (0.3%)
    Confusional state 2/364 (0.5%) 3/362 (0.8%)
    Depressed mood 2/364 (0.5%) 0/362 (0%)
    Mental status changes 0/364 (0%) 2/362 (0.6%)
    Renal and urinary disorders
    Acute kidney injury 1/364 (0.3%) 3/362 (0.8%)
    Nephritis 1/364 (0.3%) 0/362 (0%)
    Renal failure 3/364 (0.8%) 2/362 (0.6%)
    Tubulointerstitial nephritis 1/364 (0.3%) 0/362 (0%)
    Reproductive system and breast disorders
    Prostatitis 0/364 (0%) 1/362 (0.3%)
    Vaginal haemorrhage 0/364 (0%) 1/362 (0.3%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/364 (0%) 1/362 (0.3%)
    Acute respiratory failure 2/364 (0.5%) 0/362 (0%)
    Atelectasis 1/364 (0.3%) 0/362 (0%)
    Dyspnoea 6/364 (1.6%) 6/362 (1.7%)
    Epistaxis 1/364 (0.3%) 0/362 (0%)
    Haemoptysis 0/364 (0%) 1/362 (0.3%)
    Hydrothorax 0/364 (0%) 1/362 (0.3%)
    Pleural effusion 5/364 (1.4%) 4/362 (1.1%)
    Pneumonia aspiration 1/364 (0.3%) 0/362 (0%)
    Pneumonitis 4/364 (1.1%) 0/362 (0%)
    Pulmonary embolism 9/364 (2.5%) 4/362 (1.1%)
    Pulmonary microemboli 0/364 (0%) 1/362 (0.3%)
    Respiratory distress 1/364 (0.3%) 0/362 (0%)
    Respiratory failure 0/364 (0%) 1/362 (0.3%)
    Skin and subcutaneous tissue disorders
    Dermatitis allergic 1/364 (0.3%) 0/362 (0%)
    Haemorrhage subcutaneous 1/364 (0.3%) 0/362 (0%)
    Rash 1/364 (0.3%) 0/362 (0%)
    Rash pruritic 0/364 (0%) 1/362 (0.3%)
    Toxic skin eruption 1/364 (0.3%) 0/362 (0%)
    Vascular disorders
    Deep vein thrombosis 1/364 (0.3%) 2/362 (0.6%)
    Embolism 1/364 (0.3%) 0/362 (0%)
    Hypotension 1/364 (0.3%) 1/362 (0.3%)
    Thrombosis 1/364 (0.3%) 1/362 (0.3%)
    Other (Not Including Serious) Adverse Events
    10 MG/KG IPILIMUMAB 3 MG/KG IPILIMUMAB
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 319/364 (87.6%) 302/362 (83.4%)
    Blood and lymphatic system disorders
    Anaemia 24/364 (6.6%) 17/362 (4.7%)
    Gastrointestinal disorders
    Abdominal pain 33/364 (9.1%) 34/362 (9.4%)
    Constipation 38/364 (10.4%) 40/362 (11%)
    Diarrhoea 140/364 (38.5%) 105/362 (29%)
    Nausea 59/364 (16.2%) 74/362 (20.4%)
    Vomiting 43/364 (11.8%) 34/362 (9.4%)
    General disorders
    Asthenia 68/364 (18.7%) 60/362 (16.6%)
    Fatigue 86/364 (23.6%) 95/362 (26.2%)
    Oedema peripheral 25/364 (6.9%) 22/362 (6.1%)
    Pyrexia 59/364 (16.2%) 43/362 (11.9%)
    Investigations
    Alanine aminotransferase increased 27/364 (7.4%) 12/362 (3.3%)
    Aspartate aminotransferase increased 27/364 (7.4%) 8/362 (2.2%)
    Weight decreased 29/364 (8%) 25/362 (6.9%)
    Metabolism and nutrition disorders
    Decreased appetite 52/364 (14.3%) 51/362 (14.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 19/364 (5.2%) 26/362 (7.2%)
    Back pain 21/364 (5.8%) 20/362 (5.5%)
    Pain in extremity 26/364 (7.1%) 21/362 (5.8%)
    Nervous system disorders
    Dizziness 16/364 (4.4%) 22/362 (6.1%)
    Headache 56/364 (15.4%) 66/362 (18.2%)
    Psychiatric disorders
    Insomnia 19/364 (5.2%) 17/362 (4.7%)
    Respiratory, thoracic and mediastinal disorders
    Cough 33/364 (9.1%) 32/362 (8.8%)
    Dyspnoea 27/364 (7.4%) 26/362 (7.2%)
    Skin and subcutaneous tissue disorders
    Pruritus 98/364 (26.9%) 103/362 (28.5%)
    Rash 106/364 (29.1%) 64/362 (17.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

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

    Results Point of Contact

    Name/Title Bristol-Myers Squibb Study Director
    Organization Bristol-Myers Squibb
    Phone
    Email Clinical.Trials@bms.com
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01515189
    Other Study ID Numbers:
    • CA184-169
    • 2011-004029-28
    First Posted:
    Jan 24, 2012
    Last Update Posted:
    Jul 31, 2019
    Last Verified:
    Jul 1, 2019