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

A Randomized Double-Blind Phase III Study of Ipilimumab Administered at 3 mg/kg Versus at 10 mg /kg in Subjects With Previously Treated or Untreated Unresectable or Metastatic Melanoma

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

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Biological: Ipilimumab

• Study Type: Interventional
• Enrollment (Actual): 831
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1121
    • Fundacion Cidea
  • Tucuman
    • San Miguel De Tucuman, Tucuman, Argentina, 4000
      • Local Institution
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Local Institution
    • Coffs Harbour, New South Wales, Australia, 2450
      • Local Institution
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Local Institution
    • Southport, Queensland, Australia, 4215
      • Local Institution
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Local Institution
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Local Institution
• Austria
  • Linz, Austria, 4020
    • Local Institution
  • Vienna, Austria, 1090
    • Local Institution
• Belgium
  • Bruxelles, Belgium, 1200
    • Local Institution
  • Leuven, Belgium, 3000
    • Local Institution
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Local Institution
  • Nova Scotia
    • Halfax, Nova Scotia, Canada, B3H 2Y9
      • Local Institution
  • Quebec
    • Montreal, Quebec, Canada, H2W1S6
      • Local Institution
• Czechia
  • Brno, Czechia, 656 53
    • Local Institution
  • Olomouc, Czechia, 775 20
    • Local Institution
  • Praha 2, Czechia, 128 08
    • Local Institution
• Denmark
  • Aarhus, Denmark, 8000
    • Local Institution
  • Herlev, Denmark, 2730
    • Local Institution
  • Odense, Denmark, 5000
    • Local Institution
• France
  • Bordeaux, France, 33075
    • Local Institution
  • Dijon Cedex, France, 21079
    • Local Institution
  • Grenoble, France, 38043
    • Local Institution
  • Lille, France, 59037
    • Local Institution
  • Marseille Cedex 5, France, 13385
    • Local Institution
  • Nantes Cedex 1, France, 44093
    • Local Institution
  • Paris, France, 75010
    • Local Institution
  • Pierre Benite, France, 69495
    • Local Institution
  • Reims Cedex, France, 51092
    • Local Institution
  • Toulouse, France, 31059
    • Local Institution
  • Villejuif, France, 94805
    • Local Institution
• Germany
  • Buxtehude, Germany, 21614
    • Local Institution
  • Essen, Germany, 45122
    • Local Institution
  • Hannover, Germany, 30625
    • Local Institution
  • Heidelberg, Germany, 69120
    • Local Institution
  • Kiel, Germany, 24105
    • Local Institution
  • Mainz, Germany, 55131
    • Local Institution
  • Munich, Germany, 81675
    • Local Institution
  • Tubingen, Germany, 72076
    • Local Institution
• Hungary
  • Budapest, Hungary, 1122
    • Local Institution
  • Kaposvar, Hungary, 7400
    • Local Institution
  • Szeged, Hungary, 6720
    • Local Institution
• Israel
  • Jerusalem, Israel, 71908
    • Local Institution
• Italy
  • Meldola (fc), Italy, 47014
    • Local Institution
  • Milano, Italy, 20133
    • Local Institution
  • Napoli, Italy, 80131
    • Local Institution
  • Padova, Italy, 35128
    • Local Institution
  • Roma, Italy, 00144
    • Local Institution
  • Siena, Italy, 53100
    • Local Institution
• Mexico
  • Guanajuato
    • Leon, Guanajato, Guanajuato, Mexico, 37000
      • Local Institution
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Local Institution
  • Groningen, Netherlands, 9713 GZ
    • Local Institution
  • Leiden, Netherlands, 2300 RC
    • Local Institution
• Norway
  • Bergen, Norway, 5021
    • Local Institution
  • Oslo, Norway, 0379
    • Local Institution
• Poland
  • Gdansk, Poland, 80-219
    • Local Institution
  • Poznan, Poland, 60-693
    • Local Institution
  • Warszawa, Poland, 02-781
    • Local Institution
• South Africa
  • Western CAPE
    • Cape Town, Western CAPE, South Africa, 7570
      • Local Institution
    • George, Western CAPE, South Africa, 6530
      • Local Institution
    • Rondebosch, Western CAPE, South Africa, 7700
      • Local Institution
• Spain
  • Barcelona, Spain, 08036
    • Local Institution
  • Barcelona, Spain, 08908
    • Local Institution
  • Madrid, Spain, 28041
    • Local Institution
  • Navarra, Spain, 31008
    • Local Institution
  • Valencia, Spain, 46009
    • Instituto Valenciano de Oncología
  • Valencia, Spain, 46014
    • Local Institution
• Sweden
  • Gothenberg, Sweden, 413 45
    • Local Institution
  • Lund, Sweden, 221 85
    • Local Institution
  • Stockholm, Sweden, 171 76
    • Local Institution
  • Umea, Sweden, 901 85
    • Local Institution
• Switzerland
  • Lausanne, Switzerland, 1011
    • Local Institution
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • Local Institution
  • Swansea, United Kingdom, SA2 8QA
    • Local Institution
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • Local Institution
  • Strathclyde
    • Glasgow, Scotland, Strathclyde, United Kingdom, G12 OYN
      • Local Institution
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute
    • Orlando, Florida, United States, 32806
      • Orlando Health, Inc
  • Illinois
    • Park Ridge, Illinois, United States, 60068
      • Oncology Specialists, S.C.
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • Pennsylvania
    • Easton, Pennsylvania, United States, 18045
      • St. Luke's Cancer Center - Anderson Campus
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Inclusion Criteria:

• Unresectable Stage III or Stage IV melanoma
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

• Brain metastases with symptoms or requiring treatment
• History of autoimmune disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Ipilimumab (3 mg/kg); Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses; option for Re-induction, until disease progression or unacceptable toxicity	Biological: Ipilimumab; Other Names: BMS-734016; Yervoy
Experimental: Arm 2: Ipilimumab (10 mg/kg); Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses; option for Re-induction, until disease progression or unacceptable toxicity	Biological: Ipilimumab; Other Names: BMS-734016; Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined for each participant as the time between randomization date and death due to any cause. The survival time for participants who had not died was censored at the last known alive date. Median and associated 2-sided 95% confidence intervals were calculated using the method of Brookmeyer and Crowley.	Approximately 48 months (assessed up to February 2016)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) by mWHO Criteria	PFS was defined as the time between randomization date and the date of progression or death, whichever occurred first. A participant who died without reported prior progression was considered to have progressed on the date of death. For a participant who underwent resection post randomization, PFS was censored on last tumor assessment date prior to resection. For those who remained alive and had not progressed, PFS was censored on last evaluable tumor assessment date. Participants who had not died and had no recorded post-baseline tumor assessment were censored at the day of randomization. For participants who had Progressive Disease (PD) prior to Week 12 and a subsequent assessment of Stable Disease (SD), Partial Response (PR), or Complete Response (CR), the date of PD following response was used in the analysis of PFS; otherwise these participants were censored on the date of their last tumor assessment. Median and 2-sided 95% CIs were calculated with Brookmeyer Crowley method.	From date of randomization until 540 death events occurred (approximately 48 months)
Best Overall Response Rate (BORR) by mWHO Criteria	BORR by treatment arm was defined as the total number of randomized participants in the arm whose BOR is CR or PR, divided by the total number of randomized participants in the arm. Any participant who was unevaluable for BOR, e.g. on account of missing or "not evaluable" assessments, was included in the denominator of the calculation (i.e. was considered a non-responder with respect to the BORR endpoint). 95% 2-sided exact confidence intervals were computed using the method of Clopper and Pearson.	From date of randomization until 540 death events occurred (approximately 48 months)
Disease Control Rate (DCR) by mWHO Criteria	DCR by treatment arm was defined as the total number of randomized participants in the arm whose BOR is CR, PR or SD, divided by the total number of randomized participants in the arm. Any participant who was unevaluable for Disease Control (DC), (e.g. on account of missing or "not evaluable" assessments), was included in the denominator of the calculation (i.e. was considered a non-responder with respect to the DCR endpoint). 95% 2-sided exact confidence intervals were computed using the Clopper and Pearson method.	From date of randomization until 540 death events occurred (approximately 48 months)
Duration of Response (DOR) by mWHO Criteria	Duration of response for participants whose BOR was CR or PR was defined as the time between the date measurement criteria were first met for overall response of PR or CR (whichever status was recorded first) and the date of disease progression or death (whichever occurred first). For participants who underwent tumor resection following response but prior to disease progression, duration of response was censored on the date of last evaluable tumor assessment prior to resection. For participants who had BOR of SD, PR or CR at Week 12, or a confirmed response of PR or CR before Week 12, the date of PD following thereafter (where available) was used in the analysis of duration of response. For those participants who remained alive and had not progressed following response, duration of response was censored on the date of last evaluable tumor assessment. Median and associated 2-sided 95% confidence intervals were calculated using the Brookmeyer Crowley method.	From date of randomization until 540 death events occurred (approximately 48 months)
Duration of Stable Disease by mWHO Criteria	Duration of stable disease was defined for participants whose BOR was SD as the time between when SD was first documented and the date of PD or death (whichever occurred first). For a participant who underwent tumor resection following Week 12 but prior to disease progression, duration of stable disease was censored on the date of the last evaluable tumor assessment prior to resection. For participants who had BOR of SD at Week 12, the date of PD following thereafter (where available) was used in the analysis of duration of stable disease. For participants with BOR of SD who had not subsequently progressed and who remained alive, duration of stable disease was censored on the date of last evaluable tumor assessment. Median and associated 2-sided 95% confidence intervals were calculated using the Brookmeyer and Crowley method.	From date of randomization until 540 death events occurred (approximately 48 months)
Rate of Overall Survival	OS is defined for each participant as the time between randomization date and death due to any cause. The survival time for participants who had not died was censored at the last known alive date. Survival rates were calculated based on Kaplan-Meier estimation with log-log transformed confidence intervals. The survival rate at x year(s) is defined as the probability that a subject is alive at x year(s) following randomization.	Approximately 66 months
Overall Survival of Participants With Brain Metastases at Baseline	OS for each participant with brain metastases at baseline was measured as the time between randomization date and death due to any cause. The survival time for participants who had not died was censored at the last known alive date. Median OS, and associated 2-sided 95% confidence intervals were calculated using the Brookmeyer and Crowley method.	From date of randomization until 540 death events occurred (approximately 48 months)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Ascierto PA, Del Vecchio M, Mackiewicz A, Robert C, Chiarion-Sileni V, Arance A, Lebbe C, Svane IM, McNeil C, Rutkowski P, Loquai C, Mortier L, Hamid O, Bastholt L, Dreno B, Schadendorf D, Garbe C, Nyakas M, Grob JJ, Thomas L, Liszkay G, Smylie M, Hoeller C, Ferraresi V, Grange F, Gutzmer R, Pikiel J, Hosein F, Simsek B, Maio M. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer. 2020 Jun;8(1):e000391. doi: 10.1136/jitc-2019-000391. Erratum In: J Immunother Cancer. 2020 Jul;8(2):
• Feng Y, Wang X, Suryawanshi S, Bello A, Roy A. Linking Tumor Growth Dynamics to Survival in Ipilimumab-Treated Patients With Advanced Melanoma Using Mixture Tumor Growth Dynamic Modeling. CPT Pharmacometrics Syst Pharmacol. 2019 Nov;8(11):825-834. doi: 10.1002/psp4.12454. Epub 2019 Aug 13.
• Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbe C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. doi: 10.1016/S1470-2045(17)30231-0. Epub 2017 Mar 27.

Helpful Links

• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2012
• Primary Completion (Actual): February 6, 2016
• Study Completion (Actual): August 17, 2017

Study Registration Dates

• First Submitted: January 18, 2012
• First Submitted That Met QC Criteria: January 18, 2012
• First Posted (Estimate): January 24, 2012

Study Record Updates

• Last Update Posted (Actual): July 31, 2019
• Last Update Submitted That Met QC Criteria: July 29, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Ipilimumab
• Other Study ID Numbers: CA184-169; 2011-004029-28 (EudraCT Number)