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) ]

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 ]

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) ]

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) ]

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

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]


  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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