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

This study has been completed.
Sponsor:
Collaborator:
Medarex
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00324155
First received: May 8, 2006
Last updated: March 12, 2014
Last verified: March 2014
Results First Received: January 22, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Melanoma
Interventions: Drug: Ipilimumab
Drug: Placebo
Drug: Dacarbazine

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study initiated 8 August 2006; maintenance phase undergoing closure. Primary endpoint (Survival) was evaluated at 7 February (FEB) 2011. Participants with a histologic diagnosis of malignant melanoma which was untreated, measurable, and unresectable Stage III or Stage IV melanoma were eligible.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
681 enrolled; 502 randomized; 498 treated. Reasons for not starting treatment: 147 no longer met criteria (including 3 participants who were randomized but not treated), 25 withdrew consent, 3 died, 2 had adverse events (AEs), 2 lost to follow up (including 1 randomized but not treated), 2 had poor or non-compliance, 1 not reported, 1 other.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one 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; one dose every 3 weeks for 22 weeks, until disease progression (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; one dose every 3 weeks for 10 weeks then one 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; one 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.


Participant Flow for 4 periods

Period 1:   Enrolled and Randomized
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
STARTED     250     252  
COMPLETED     247 [1]   251 [2]
NOT COMPLETED     3     1  
No longer met study criteria                 3                 0  
Lost to Follow-up                 0                 1  
[1] 3 randomized but not treated (no longer met study criteria).
[2] 1 randomized but not treated (lost to follow up).

Period 2:   Treated in Induction Phase
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
STARTED     247     251  
COMPLETED     45 [1]   54 [2]
NOT COMPLETED     202     197  
Disease Progression                 88                 152  
Study Drug Toxicity                 83                 10  
Death                 8                 15  
Deterioration/Undocumented Progression                 9                 8  
Adverse Event                 6                 7  
Withdrawal by Subject                 6                 5  
Physician Decision                 2                 0  
[1] 45 participants on treatment at end of induction phase. Study undergoing closure.
[2] 54 participants on treatment at end of induction phase. Study undergoing closure.

Period 3:   Treated in Maintenance Phase
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
STARTED     43 [1]   53 [2]
COMPLETED     11 [3]   6 [4]
NOT COMPLETED     32     47  
Disease Progression                 26                 41  
Study Drug Toxicity                 4                 0  
Withdrawal by Subject                 1                 3  
Adverse Event                 0                 3  
Deterioration/Undocumented Progression                 1                 0  
[1] Two completed induction phase but did not enter maintenance phase.
[2] One participant completed induction phase but did not enter maintenance phase.
[3] Study is in closure at this time. 11 in Maintenance Phase treatment not yet summarized.
[4] Study is in closure. 6 participants in Maintenance Phase not yet summarized.

Period 4:   Follow up Phase
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
STARTED     247 [1]   251 [1]
COMPLETED     236     245  
NOT COMPLETED     11     6  
On-going participants still on drug                 11                 6  
[1] All participants treated with study drug. Follow up was performed for those leaving earlier phases.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Randomized Participants

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In Maintenance phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the Maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

Total Total of all reporting groups

Baseline Measures
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine     Total  
Number of Participants  
[units: participants]
  250     252     502  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     165     177     342  
>=65 years     85     75     160  
Age  
[units: years]
Mean ± Standard Deviation
  57.5  ± 13.51     56.4  ± 13.71     57.0  ± 13.61  
Gender  
[units: participants]
     
Female     98     103     201  
Male     152     149     301  
Region of Enrollment  
[units: participants]
     
Australia     5     10     15  
South Africa     10     12     22  
North America     46     46     92  
South America     13     9     22  
Europe     176     175     351  
Melanoma Tumor Stage; Metastasis Classification at Study Entry [1]
[units: participants]
     
M0     6     8     14  
M1a     37     43     80  
M1b     64     62     126  
M1c     143     139     282  
Eastern Cooperative Oncology Group Performance Status [2]
[units: participants]
     
Category 0     177     179     356  
Category 1     73     73     146  
[1] Melanoma Tumor Staging: Metastasis (M) classification. M0: No distant metastases; M1a: Distant skin, subcutaneous tissue, or nodal metastases with normal lactic dehydrogenase (LDH); M1b: Lung metastases with normal LDH; M1c: All other visceral metastases with normal LDH; Any distant metastasis with elevated LDH. Final Version of the American Joint Committee on Cancer Staging System for Cutaneous melanoma. Journal of Clinical Oncology, 2001. (Vol. 19 No.16): p. 3635-3648.
[2] Eastern Cooperative Oncology Group (ECOG) Performance Status. Measured from 0 to 5 with 0=Fully active; 1= restricted in physically strenuous activity; 2= ambulatory; 3=limited self care; 4= completely disabled; 5=dead.



  Outcome Measures
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1.  Primary:   Overall Survival in Participants Randomized to Either Ipilimumab Plus Dacarbazine or Dacarbazine Plus Placebo   [ Time Frame: Date of Randomization to Date of Death at Primary Endpoint Data cutoff (at 414 deaths; approximately 5 years) ]

Measure Type Primary
Measure Title Overall Survival in Participants Randomized to Either Ipilimumab Plus Dacarbazine or Dacarbazine Plus Placebo
Measure Description Overall Survival (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 events (deaths) had occurred (primary endpoint); analysis occurred at 414 events (7 FEB 2011) which differed slightly from the projected 416 events due to operational timing of the study. Median number of Months of OS and associated confidence interval (CI) calculated using the method of Brookmeyer and Crowley. Study is undergoing closure with OS of remaining participants being summarized.
Time Frame Date of Randomization to Date of Death at Primary Endpoint Data cutoff (at 414 deaths; approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group 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 events (deaths) occurred.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  196     218  
Overall Survival in Participants Randomized to Either Ipilimumab Plus Dacarbazine or Dacarbazine Plus Placebo  
[units: months]
Median ( 95% Confidence Interval )
  11.17  
  ( 9.40 to 13.60 )  
  9.07  
  ( 7.75 to 10.51 )  


Statistical Analysis 1 for Overall Survival in Participants Randomized to Either Ipilimumab Plus Dacarbazine or Dacarbazine Plus Placebo
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0009
Hazard Ratio (HR) [4] 0.716
95% Confidence Interval ( 0.588 to 0.872 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified for M-stage (M0 vs M1a vs M1b vs M1c) and ECOG performance status (0 vs 1) recorded at randomization.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value was via stratified log-rank test
[4] Other relevant estimation information:
  Hazard ratio via stratified Cox proportional hazards model.



2.  Secondary:   Survival Rate (Percent of Participants) at 1 Year, 18 Months, 2 Years, and 3 Years Post Randomization - Randomized Participants   [ Time Frame: Date of Randomization to 3 Years Post Randomization ]

Measure Type Secondary
Measure Title Survival Rate (Percent of Participants) at 1 Year, 18 Months, 2 Years, and 3 Years Post Randomization - Randomized Participants
Measure Description The survival rate (percent of participants) was defined as the probability that a participant is alive at one year (or 18 months or 2 years or 3 years) following randomization and was estimated via the Kaplan-Meier method.
Time Frame Date of Randomization to 3 Years Post Randomization  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group (ie, on an intent-to-treat basis).

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  250     252  
Survival Rate (Percent of Participants) at 1 Year, 18 Months, 2 Years, and 3 Years Post Randomization - Randomized Participants  
[units: percentage of Participants]
Number ( 95% Confidence Interval )
   
Survival rate at 1 year     47.3  
  ( 41.0 to 53.6 )  
  36.3  
  ( 30.4 to 42.4 )  
Survival rate at 18 Months     35.6  
  ( 29.7 to 41.6 )  
  26.1  
  ( 20.7 to 31.6 )  
Survival rate at 2 Years     28.5  
  ( 22.9 to 34.2 )  
  17.9  
  ( 13.3 to 22.8 )  
Survival rate at 3 Years     20.8  
  ( 15.7 to 26.1 )  
  12.2  
  ( 8.2 to 16.5 )  

No statistical analysis provided for Survival Rate (Percent of Participants) at 1 Year, 18 Months, 2 Years, and 3 Years Post Randomization - Randomized Participants



3.  Secondary:   Disease Control Rate (DCR) - All Randomized Participants   [ Time Frame: First dose to last tumor assessment prior to subsequent therapy at data cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Disease Control Rate (DCR) - All Randomized Participants
Measure Description DCR=number whose best overall response (BOR) was partial response (PR), complete response (CR) or stable disease (SD), divided by all randomized participants (unevaluable participants included). Independent review committee (IRC) assessment. BOR=between date of first dose and last tumor assessment (TA) prior to subsequent cancer therapy (including tumor resection, excluding palliative local radiotherapy). Modified World Health Organization (mWHO) 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 (SPD) of all index lesions compared to 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 non-index lesions.
Time Frame First dose to last tumor assessment prior to subsequent therapy at data cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group (ie, on an intent-to-treat basis).

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10mg/kg; one dose every 3 weeks for 10 weeks, then one 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; one dose every 3 weeks for 22 weeks, until disease progression (PD), unacceptable toxicity or withdrawal of consent.

In Maintenance phase: Only Ipilimumab: 10mg/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; one dose every 3 weeks for 10 weeks then one 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; one 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.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  250     252  
Disease Control Rate (DCR) - All Randomized Participants  
[units: percent of participants]
  33.2     30.2  


Statistical Analysis 1 for Disease Control Rate (DCR) - All Randomized Participants
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.4067
Odds Ratio (OR) [4] 1.179
95% Confidence Interval ( 0.799 to 1.740 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis stratified for M-stage (M0 vs M1a vs M1b vs M1c) and ECOG performance status (0 vs 1) recorded at randomization.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified for M-stage (M0 vs M1a vs M1b vs M1c) and ECOG performance status (0 vs 1) recorded at randomization.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Median Number of Months of Progression-free Survival (PFS) - All Randomized Participants   [ Time Frame: Randomization to Date of Progression or Death by Data Cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Median Number of Months of Progression-free Survival (PFS) - All Randomized Participants
Measure Description PFS=time between randomization and date of progression or death, whichever occurs first. A participant who died without reported prior progression was considered to have progressed on date of death. For those alive and not progressed, PFS was censored on date of last evaluable TA. Those who have not died and have no recorded post-baseline TA were censored at day of randomization. Those who died without any recorded post-baseline TA were considered to have progressed on date of death. Evaluation was conducted by both investigator and an independent review committee (IRC) who provided an independent assessment of radiologic imaging studies, photographs of skin lesions and clinical data). Progressive Disease (PD) defined using mWHO criteria: demonstration of at least a 25% increase in the sum of products of all index lesions and/or appearance of any new lesion(s). For nonindex lesions: appearance of any any new lesion(s) and/or unequivocal progression of non-index lesion(s).
Time Frame Randomization to Date of Progression or Death by Data Cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group (ie, on an intent-to-treat basis).

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In Maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  250     252  
Median Number of Months of Progression-free Survival (PFS) - All Randomized Participants  
[units: Months]
Median ( 95% Confidence Interval )
   
PFS per IRC     2.76  
  ( 2.63 to 3.29 )  
  2.60  
  ( 2.56 to 2.66 )  
PFS per Investigator     2.73  
  ( 2.63 to 3.48 )  
  2.63  
  ( 2.60 to 2.73 )  

No statistical analysis provided for Median Number of Months of Progression-free Survival (PFS) - All Randomized Participants



5.  Secondary:   Progression-Free Survival (PFS) Rate (Percent of Participants) Truncated at Week 12 - All Randomized Participants   [ Time Frame: Day 78 ]

Measure Type Secondary
Measure Title Progression-Free Survival (PFS) Rate (Percent of Participants) Truncated at Week 12 - All Randomized Participants
Measure Description PFS rate at Week 12 = probability participant was progression-free at Day 78 post treatment (ie, total number of treated participants with OR of SD, PR or CR at Week 12, divided by total number of participants); estimated via Kaplan-Meier method, truncated at Week 12 (up to, including Week 12). For participants alive and not progressed at or before Week 12, PFS was censored on the date of the last evaluable TA occurring at or before Week 12. Those who had an assessment of PD prior to Week 12 and subsequent assessment of SD, PR or CR at Week 12 were censored as progression-free at Week 12. Those with no recorded post-baseline TA dated on or before Day 109, and who had not died on or before Day 109, were censored at date of randomization. Evaluation by IRC and investigator. PD= at least a 25% increase in sum of the products of all index lesions and/or appearance of any new lesions; nonindex lesions: the appearance of any new lesions and/or unequivocal progression of non-index lesions.
Time Frame Day 78  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group (ie, on an intent-to-treat basis).

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one 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; one dose every 3 weeks for 22 weeks, until disease progression (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; one dose every 3 weeks for 10 weeks then one 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; one 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.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  250     252  
Progression-Free Survival (PFS) Rate (Percent of Participants) Truncated at Week 12 - All Randomized Participants  
[units: percent of participants]
Number ( 95% Confidence Interval )
   
PFS rate at Week 12 by IRC     55.4  
  ( 48.6 to 62.1 )  
  50.7  
  ( 44.2 to 57.3 )  
PFS rate at Week 12 by Investigator     58.5  
  ( 51.9 to 65.0 )  
  54.0  
  ( 47.5 to 60.4 )  

No statistical analysis provided for Progression-Free Survival (PFS) Rate (Percent of Participants) Truncated at Week 12 - All Randomized Participants



6.  Secondary:   Best Overall Response Rate (BORR) - All Randomized Participants   [ Time Frame: First Dose to last Tumor Assessment at Data Cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Best Overall Response Rate (BORR) - All Randomized Participants
Measure Description BORR=number of participants whose BOR was CR or PR, divided by total number of randomized participants (percent). Anyone unevaluable for BOR was included in the denominator. 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). IRC assessment. mWHO criteria: CR: disappearance of all lesions; no evidence of PD; PR: 50% or more decrease in the sum of products of the longest diameter and greatest perpendicular diameter (SPD) of all index lesions compared to baseline. Immune related (ir) response criteria (RC) (irRC), a refinement of mWHO criteria which captures tumor response in patients on immunotherapy: irCR: Disappearance of all lesions in 2 consecutive observations not less than 4 weeks apart; irPR: 50% or more decrease in total measureable tumor burden (TMTB) compared to peak in 2 observations at least 4 weeks apart, in absence of unequivocal progress.
Time Frame First Dose to last Tumor Assessment at Data Cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who were randomized to a treatment group (ie, on an intent-to-treat basis).

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  250     252  
Best Overall Response Rate (BORR) - All Randomized Participants  
[units: Percentage of participants]
Number ( 95% Confidence Interval )
   
BORR using mWHO criteria     15.2  
  ( 11.0 to 20.3 )  
  10.3  
  ( 6.9 to 14.8 )  
BORR using irRC criteria     16.8  
  ( 12.4 to 22.0 )  
  11.1  
  ( 7.5 to 15.7 )  

No statistical analysis provided for Best Overall Response Rate (BORR) - All Randomized Participants



7.  Secondary:   Duration of Response - Randomized Participants With Response of CR or PR   [ Time Frame: Day of CR or PR to Day of PD or Death up to Data Cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Duration of Response - Randomized Participants With Response of CR or PR
Measure Description Duration of response defined in those with BOR=CR or PR (per IRC assessment) as time between date of response of confirmed CR or PR (whichever occurred first) and date of PD or death (whichever occurred first). If assessment of PR occurred before confirmation of CR, the duration of response endpoint was shown at the earlier time-point showing PR. Duration of response was measured in months. mWHO criteria: CR: disappearance of all lesions;no evidence of PD; PR: 50% or more decrease in the sum of products of the longest diameter and SPD of all index lesions compared to baseline. PD: An increase of 25% or more in the SPD of index lesions compared to the smallest recorded sum, or appearance of 1 or more new lesions. irRC criteria: SD: 50% decrease (confirmed) in TMTB compared to peak cannot be established nor 25% increase (confirmed) compared to nadir, in absence of unequivocal progression of non-index lesions [unconfirmed irCR, irPR or immune-related PD (irPD) counts as irSD]
Time Frame Day of CR or PR to Day of PD or Death up to Data Cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group (ie, on an intent-to-treat basis) and responded to study treatment with either CR or PR (irCR or irPR). n= number of participants who responded via mWHO: n=38, 26 in ipilimumab+dacarbazine and dacarbazine+placebo, respectively; irRC: n=42, 28 in each arm, respectively.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  42     28  
Duration of Response - Randomized Participants With Response of CR or PR  
[units: Months]
Median ( 95% Confidence Interval )
   
Using mWHO criteria (n=38, 26)     19.3  
  ( 12.1 to 26.1 )  
  8.1  
  ( 5.2 to 19.8 )  
Using irRC criteria (n=42, 28)     21.1  
  ( 16.5 to 26.1 )  
  10.2  
  ( 5.6 to 24.0 )  

No statistical analysis provided for Duration of Response - Randomized Participants With Response of CR or PR



8.  Secondary:   Time to Response - All Randomized Participants With Response to Treatment   [ Time Frame: First Dose to date of Best Overall Response up to Data Cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Time to Response - All Randomized Participants With Response to Treatment
Measure Description Time to response was defined as the time between the first dose of study therapy and the date when measurement criteria were met for best overall response (BOR) of partial response (PR) or complete response (CR) (whichever occurred first), as per IRC assessment. Note that if an overall response (OR) assessment 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. Time to Response was measured in months. mWHO 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 (SPD) of all index lesions compared to baseline; PD: An increase of 25% or more in the SPD of index lesions compared to the smallest recorded sum, or appearance of 1 or more new lesions.
Time Frame First Dose to date of Best Overall Response up to Data Cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group (ie, on an intent-to-treat basis) and who had a response (CR or PR) to study treatment were analyzed.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  38     26  
Time to Response - All Randomized Participants With Response to Treatment  
[units: Months]
Median ( Full Range )
  2.6  
  ( 2.3 to 3.9 )  
  2.7  
  ( 2.5 to 5.7 )  

No statistical analysis provided for Time to Response - All Randomized Participants With Response to Treatment



9.  Secondary:   Duration of Stable Disease (SD) - Randomized Participants With Stable Disease   [ Time Frame: Week 12 to Date of Disease Progression or Death Up to Data Cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Duration of Stable Disease (SD) - Randomized Participants With Stable Disease
Measure Description Duration of SD was defined in those whose BOR was SD (as per IRC assessment) as the time between Week 12 and date of 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 TA prior to resection. For those with BOR of SD at Week 12, date of PD following this (where available) 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. Duration of SD measured in months. mWHO: SD=Neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD; PD=An increase of 25% or more in SPD of index lesions compared to the smallest recorded sum, or appearance of 1 or more new lesions. ir RC: irSD: 50% decrease in TMTB compared to peak cannot be established nor 25% increase compared to nadir, in absence of unequivocal progression of non-index lesions.
Time Frame Week 12 to Date of Disease Progression or Death Up to Data Cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to a treatment group (ie, on an intent-to-treat basis) and had Stable Disease were analyzed.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  45     57  
Duration of Stable Disease (SD) - Randomized Participants With Stable Disease  
[units: Months]
Median ( 95% Confidence Interval )
   
Duration of SD using mWHO (n=45, 50)     4.7  
  ( 1.9 to 9.2 )  
  4.6  
  ( 3.2 to 6.9 )  
Duration of SD using ir RC (n=45, 57)     4.8  
  ( 2.8 to 7.7 )  
  3.4  
  ( 2.5 to 5.2 )  

No statistical analysis provided for Duration of Stable Disease (SD) - Randomized Participants With Stable Disease



10.  Secondary:   Percentage of Participants With Brain Metastasis-Free Survival at Time of Data Cutoff - All Randomized Participants   [ Time Frame: Date of Randomization Up to Data Cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Percentage of Participants With Brain Metastasis-Free Survival at Time of Data Cutoff - All Randomized Participants
Measure Description Brain metastasis-free survival was defined as the time from randomization to the date of progression with a new lesion located in the brain. New brain lesions prior to Week 12 constituted a progression event (unlike main PFS 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. The IRC evaluated images of participants with clinical symptoms to determine the number of participants free of brain metastasis. The brain metastasis-free status was reported as a percent of participants (n/N); n= participants with metastasis-free brains at data cutoff for the Primary Endpoint; N= randomized participants. A 2-sided Clopper and Pearson confidence interval was performed.
Time Frame Date of Randomization Up to Data Cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
N= All participants who were randomized to a treatment group (ie, on an intent-to-treat basis) were analyzed.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  250     252  
Percentage of Participants With Brain Metastasis-Free Survival at Time of Data Cutoff - All Randomized Participants  
[units: percentage of participants]
Number ( 95% Confidence Interval )
  93.6  
  ( 89.8 to 96.3 )  
  90.9  
  ( 86.6 to 94.1 )  

No statistical analysis provided for Percentage of Participants With Brain Metastasis-Free Survival at Time of Data Cutoff - All Randomized Participants



11.  Secondary:   Number of Participants With Adverse Events (AEs), Drug-Related AEs, AEs Leading to Discontinuation, Serious AEs, Drug-Related SAEs, Drug-Related Hypersensitivity, Immune Related AEs/SAEs, and Inflammatory AEs/SAEs - All Treated Participants   [ Time Frame: Week 1 (First Dose) to 70 days after last dose of study Up to Data Cutoff for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Number of Participants With Adverse Events (AEs), Drug-Related AEs, AEs Leading to Discontinuation, Serious AEs, Drug-Related SAEs, Drug-Related Hypersensitivity, Immune Related AEs/SAEs, and Inflammatory AEs/SAEs - All Treated Participants
Measure Description AE=any new undesirable symptom, sign, clinically significant laboratory abnormality, or medical condition occurring after starting study treatment, even if the event was not considered to be drug-related. Serious AE (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. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 12.1. 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 (7 FEB 2011 data cut-off).
Time Frame Week 1 (First Dose) to 70 days after last dose of study Up to Data Cutoff for Primary Endpoint (approximately 5 years)  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated Participants includes all participants who received at least 1 dose of their randomized ipilimumab or placebo and/or dacarbazine were analyzed.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10m g/kg; one dose every 3 weeks for 10weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  247     251  
Number of Participants With Adverse Events (AEs), Drug-Related AEs, AEs Leading to Discontinuation, Serious AEs, Drug-Related SAEs, Drug-Related Hypersensitivity, Immune Related AEs/SAEs, and Inflammatory AEs/SAEs - All Treated Participants  
[units: participants]
   
Adverse Events     244     236  
Drug-Related Adverse Events     221     192  
Discontinued due to AEs     114     46  
Serious Adverse Events     170     121  
Drug-Related Serious Adverse Events     116     17  
Drug-related Hypersensitivity     5     4  
Immune related AEs     187     77  
Immune related SAEs     91     3  
Infammatory AEs     201     117  
Inflammatory SAEs     101     9  

No statistical analysis provided for Number of Participants With Adverse Events (AEs), Drug-Related AEs, AEs Leading to Discontinuation, Serious AEs, Drug-Related SAEs, Drug-Related Hypersensitivity, Immune Related AEs/SAEs, and Inflammatory AEs/SAEs - All Treated Participants



12.  Secondary:   Number of Participants With Grade 2-3 and Grade 3-4 Immune Related (ir) AEs With Resolution Resolved - All Treated Participants   [ Time Frame: Week 1 (First Dose) to 70 Days after last dose up to data cutoff for primary endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Number of Participants With Grade 2-3 and Grade 3-4 Immune Related (ir) AEs With Resolution Resolved - All Treated Participants
Measure Description Immune related (ir) AEs included the categories: Gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=Moderate AEs, minimal, local or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4= Life-threatening consequences; urgent intervention indicated. Resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment).
Time Frame Week 1 (First Dose) to 70 Days after last dose up to data cutoff for primary endpoint (approximately 5 years)  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
n=all participants receiving at least 1 dose of study drug who had this specific event.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one 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; one dose every 3 weeks for 22 weeks, until disease progression (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; one dose every 3 weeks for 10 weeks then one 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; one 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.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  89     8  
Number of Participants With Grade 2-3 and Grade 3-4 Immune Related (ir) AEs With Resolution Resolved - All Treated Participants  
[units: participants]
   
GI AE Grade 2-4 (n=39, 7)     36     7  
GI Grade 3-4 (n=14, 0)     13     0  
Liver AE Grade 2-4 (n=89, 8)     81     4  
Liver AE Grade 3-4 (n=69, 5)     63     2  
Skin AE Grade 2-4 (n=46, 2)     42     2  
Skin AE Grade 3-4 (n=8, 0)     6     0  
Diarrhea AE Grade 2-3 (n=31, 7)     29     7  
Diarrhea AE Grade 3-4 (n=10, 0)     9     0  

No statistical analysis provided for Number of Participants With Grade 2-3 and Grade 3-4 Immune Related (ir) AEs With Resolution Resolved - All Treated Participants



13.  Secondary:   Time to Resolution of Grade 2-3, Grade 3-4 Immune Related AEs - All Treated Participants   [ Time Frame: Week 1 (First Dose) to 70 Days after last dose up to database lock for Primary Endpoint (approximately 5 years) ]

Measure Type Secondary
Measure Title Time to Resolution of Grade 2-3, Grade 3-4 Immune Related AEs - All Treated Participants
Measure Description Immune related (ir) AEs included the categories: Gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=Moderate AEs, minimal, local or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4= Life-threatening consequences; urgent intervention indicated. Time to resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment). Time to resolution is reported in Weeks.
Time Frame Week 1 (First Dose) to 70 Days after last dose up to database lock for Primary Endpoint (approximately 5 years)  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants receiving at least 1 dose of study drug with a specific event which resolved.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; one dose every 3 weeks for 10 weeks, then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.

In maintenance phase: Only Ipilimumab: 10 mg/kg, every 12 weeks will be continued until disease progression. Dacarbazine was given up to Week 22 and was not given in the maintenance phase.

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent.


Measured Values
    Ipilimumab and Dacarbazine     Placebo and Dacarbazine  
Number of Participants Analyzed  
[units: participants]
  81     7  
Time to Resolution of Grade 2-3, Grade 3-4 Immune Related AEs - All Treated Participants  
[units: Weeks]
Median ( 95% Confidence Interval )
   
GI AE Grade 2-4 (n=36, 7)     2.00  
  ( 1.14 to 2.71 )  
  0.14  
  ( 0.14 to 0.29 )  
GI Grade 3-4 (n=13, 0))     2.14  
  ( 2.00 to 4.57 )  
  NA  
  ( NA to NA ) [1]
Liver AE Grade 2-4 (n=81, 4)     3.43  
  ( 3.14 to 4.43 )  
  NA  
  ( 6.86 to NA ) [1]
Liver AE Grade 3-4 (n=63, 2)     3.43  
  ( 3.00 to 4.43 )  
  NA  
  ( 3.57 to NA ) [1]
Skin AE Grade 2-4 (n=42, 2)     4.14  
  ( 3.14 to 7.00 )  
  0.93  
  ( 0.57 to 1.29 )  
Skin AE Grade 3-4 (n=6, 0)     4.71  
  ( 3.14 to 5.29 )  
  NA  
  ( NA to NA ) [1]
Diarrhea AE Grade 2-3 (n=29, 7)     1.43  
  ( 0.71 to 2.57 )  
  0.14  
  ( 0.14 to 0.29 )  
Diarrhea AE Grade 3-4 (n=9, 0)     2.00  
  ( 0.71 to 2.57 )  
  NA  
  ( NA to NA ) [1]
[1] Median time to resolution could not be computed due to low/no occurrence of either the resolution of the AE or low/no occurrence the AE in this arm

No statistical analysis provided for Time to Resolution of Grade 2-3, Grade 3-4 Immune Related AEs - All Treated Participants




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided by Bristol-Myers Squibb

Publications automatically indexed to this study:

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00324155     History of Changes
Other Study ID Numbers: CA184-024
Study First Received: May 8, 2006
Results First Received: January 22, 2014
Last Updated: March 12, 2014
Health Authority: United States: Food and Drug Administration