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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: October 24, 2014
Last verified: October 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
The study was initiated on August 8, 2006. Primary endpoint (Survival) was evaluated on February 7, 2011 and again at completion of follow-up period, October 13, 2013. Participants with a histologic diagnosis of untreated, measurable, and unresectable Stage III or Stage IV malignant melanoma were eligible.

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

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 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; 1 dose every 3 weeks for 22 weeks, until 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; 1 dose every 3 weeks for 10 weeks, then 1 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; 1 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 who did not receive treatment (no longer met study criteria).
[2] 1 randomized but who did not receive treatment (lost to follow-up).

Period 2:   Received Treatment 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:   Received Treatment 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] 2 completed Induction Phase but did not enter Maintenance Phase
[2] 1 completed Induction Phase but did not enter Maintenance Phase
[3] Study is in closure at this time. 11 in Maintenance Phase 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 received 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; 1 dose every 3 weeks for 10 weeks, then 1 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; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

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

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent.

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, 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 or any distant metastasis with elevated LDH. Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma. J Clin Oncol. 2001;19 (16):3635-3648.
[2] Eastern Cooperative Oncology Group 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. Lower score=better performance.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Overall Survival (OS)   [ Time Frame: Date of randomization to 37 months through 5-year follow-up and up to approximately 76 months ]

2.  Secondary:   Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years   [ Time Frame: Date of randomization to 3 years following randomization ]

3.  Secondary:   Disease Control Rate (DCR)   [ 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)   [ Time Frame: Randomization to date of progression or death to approximately 5 years ]

5.  Secondary:   Progression-free Survival (PFS) Rate Truncated at Week 12   [ Time Frame: Day 78 ]

6.  Secondary:   Best Overall Response Rate (BORR)   [ Time Frame: First dose to last tumor assessment at data cutoff for primary endpoint (approximately 5 years) ]

7.  Secondary:   Duration of Response (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (PR)   [ Time Frame: Day of CR or PR to day of PD or death up to data cutoff for primary endpoint (approximately 5 years) ]
  Hide Outcome Measure 7

Measure Type Secondary
Measure Title Duration of Response (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (PR)
Measure Description DOR defined in those with Best Overall Response (BOR)=CR or PR per independent review committee (IRC) as time between date of response of confirmed CR or PR, whichever occurred first, and date of PD or death. If PR assessed before CR, DOR confirmed at earlier time-point showing PR. Modified criteria of the World Health Organization (mWHO): CR=disappearance of all lesions;no evidence of PD; PR=50% or greater decrease in the sum of products of longest and greatest perpendicular diameters (SPD) of all index lesions compared with baseline. PD=an increase of 25% or greater in SPD of index lesions compared with the smallest recorded sum, or appearance of 1 or more new lesions. Immune-related response criteria (irRC): SD=50% decrease in total measurable tumor burden compared with peak cannot be established nor 25% increase compared with nadir, in absence of unequivocal progression of nonindex lesions. Unconfirmed immune-related (ir) CR, irPR, or irPD=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 and had a response of CR, PR, irCR, or irPR. n=number of participants who responded by mWHO criteria and irRC.

Reporting Groups
  Description
Ipilimumab and Dacarbazine

Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 10 weeks, then 1 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; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

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

Placebo and Dacarbazine

Placebo: Intravenous solution; intravenous; 0 mg; 1 dose every 3 weeks for 10 weeks, then 1 dose every 12 weeks starting at Week 24; until PD, unacceptable toxicity, or withdrawal of consent

Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, 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 (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (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 (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (PR)



8.  Secondary:   Time to Response: All Randomized Participants With Response to Treatment   [ Time Frame: First dose to date of BOR 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   [ 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 Adverse Events (SAEs), Drug-related SAEs, Drug-related Hypersensitivity, Immune-related AEs/SAEs, and Inflammatory AEs/SAEs   [ 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 Adverse Events (irAEs) With Resolution Resolved   [ 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 Adverse Events (irAEs)   [ 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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  More Information
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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: October 24, 2014
Health Authority: United States: Food and Drug Administration