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

May 8, 2006
March 12, 2014
August 2006
January 2011   (final data collection date for primary outcome measure)
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) ] [ Designated as safety issue: No ]
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.
Overall Progression Free Survival (PFS) - measured when at least 416 events of PFS are observed and followed for 12 weeks.
Complete list of historical versions of study NCT00324155 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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).
  • Progression-Free Survival (PFS) Rate (Percent of Participants) Truncated at Week 12 - All Randomized Participants [ Time Frame: Day 78 ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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 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) ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: No ]
    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.
  • 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) ] [ Designated as safety issue: Yes ]
    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).
  • 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) ] [ Designated as safety issue: Yes ]
    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 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) ] [ Designated as safety issue: Yes ]
    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.
  • Overall Survival
  • Survival at 1 year
  • PFS at Week 12
  • Best Overall Response (BOR) and Duration
  • Disease control rate
  • Time to BOR
  • Safety profile
  • Health-Related QoL
  • Population PK
Not Provided
Not Provided
 
Dacarbazine and Ipilimumab vs. Dacarbazine With Placebo in Untreated Unresectable Stage III or IV Melanoma
A Multi-center, Randomized, Double-Blind, Two-Arm, Phase III Study in Patients With Untreated Stage III (Unresectable) or IV Melanoma Receiving Dacarbazine Plus 10 mg/kg Ipilimumab (MDX-010) vs. Dacarbazine With Placebo

The purpose of this clinical research study is to examine the safety and effectiveness (how well the drug works) of two different treatments for patients with melanoma. One treatment is an investigational compound (a drug that is not currently approved by the United States Food and Drug Administration [FDA]), know as Ipilimumab (also known as MDX-010 or BMS-734016) together with an approved chemotherapy drug called Dacarbazine

For the extension phase:

Allocation: single arm study; Masking: open label; Intervention Model: Single Group

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Melanoma
  • Drug: 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

    In Maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression

    Other Names:
    • MDX-010
    • BMS-734016
  • Drug: 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
  • Drug: 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
  • Experimental: Arm A: Ipilimumab and Dacarbazine
    In Maintenance phase: Ipilimumab will be continued. Dacarbazine was given up to Week 22 and is not given in the Maintenance phase
    Interventions:
    • Drug: Ipilimumab
    • Drug: Dacarbazine
  • Active Comparator: Arm B: Placebo and Dacarbazine
    Interventions:
    • Drug: Placebo
    • Drug: Dacarbazine
Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. doi: 10.1056/NEJMoa1104621. Epub 2011 Jun 5.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
681
October 2013
January 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Informed Consent
  • Measurable Disease
  • Eastern Cooperative Oncology Group (ECOG) 0 or 1
  • Lab / imaging requirements
  • Neg for Human Immunodeficiency Virus (HIV), Hepatitis B (HepB), C
  • Men and Women > 18 years (16 were allowable)
  • Prior therapy restriction (adjuvant only)

Exclusion:

  • Pregnant / nursing
  • Inadequate contraception
  • Brain metastasis
  • Primary ocular or mucosal melanoma
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   Chile,   Czech Republic,   France,   Germany,   Hungary,   Ireland,   Israel,   Italy,   Netherlands,   Norway,   Poland,   Portugal,   Russian Federation,   South Africa,   Spain,   Switzerland,   Ukraine,   United Kingdom
 
NCT00324155
CA184-024
Yes
Bristol-Myers Squibb
Bristol-Myers Squibb
Medarex
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
Bristol-Myers Squibb
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP