Efficacy Study of Ipilimumab Versus Placebo to Prevent Recurrence After Complete Resection of High Risk Stage III Melanoma

Adjuvant Immunotherapy With Anti-CTLA-4 Monoclonal Antibody (Ipilimumab) Versus Placebo After Complete Resection of High Risk Stage III Melanoma: A Randomized, Double-blind Phase 3 Trial of the EORTC Melanoma Group

The purpose of the study is to determine if ipilimumab is effective in preventing or delaying recurrence and prolongs survival after complete resection of high risk stage III melanoma

Study Overview

• Status: Completed
• Conditions: High Risk Stage III Melanoma
• Intervention / Treatment: Drug: ipilimumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 1211
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Waratah, New South Wales, Australia, 2298
      • Local Institution
    • Westmead, New South Wales, Australia, 2145
      • Local Institution
  • Queensland
    • Greenslopes, Queensland, Australia, 4120
      • Local Institution
    • Woolloongabba, Queensland, Australia, 4102
      • Local Institution
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Local Institution
    • Malvern, Victoria, Australia, 3144
      • Local Institution
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Local Institution
• Austria
  • Graz, Austria, A-8036
    • Local Institution
  • Wien, Austria, A-1090
    • Local Institution
• Belgium
  • Gent, Belgium, 9000
    • Local Institution
  • Leuven, Belgium, 3000
    • Local Institution
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Local Institution
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Local Institution
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • Local Institution
• Czechia
  • Praha 2, Czechia, 128 08
    • Local Institution
  • Praha 2, Czechia, 12808
    • Local Institution
• Denmark
  • Aarhus C, Denmark, 8000
    • Local Institution
  • Herlev, Denmark, DK-2730
    • Local Institution
  • Odense C, Denmark, 5000
    • Local Institution
• Finland
  • Helsinki, Finland, 00029
    • Local Institution
  • Turku, Finland, 20520
    • Local Institution
• France
  • Boulogne-billancourt, France, 92104
    • Local Institution
  • Marseille Cedex 5, France, 13885
    • Local Institution
  • Paris, France, 75010
    • Local Institution
  • Paris, France, 75018
    • Local Institution
  • Pierre Benite, France, 69495
    • Local Institution
  • Vandoeuvre Les Nancy, France, 54511
    • Local Institution
  • Villejuif, France, 94805
    • Local Institution
  • Cedex
    • Lillie, Cedex, France, 59037
      • Local Institution
• Germany
  • Berlin, Germany, 10117
    • Local Institution
  • Essen, Germany, 45122
    • Local Institution
  • Gottingen, Germany, 37075
    • Local Institution
  • Heidelberg, Germany, 69120
    • Local Institution
  • Kiel, Germany, 24105
    • Local Institution
  • Koln, Germany, 50937
    • Local Institution
  • Luebeck, Germany, 23538
    • Local Institution
  • Mannheim, Germany, 68167
    • Local Institution
  • Tubingen, Germany, 72076
    • Local Institution
  • Wurzburg, Germany, 97080
    • Local Institution
• Italy
  • Genova, Italy, 16132
    • Local Institution
  • Milano, Italy, 20141
    • Local Institution
  • Napoli, Italy, 80131
    • Local Institution
  • Padova, Italy, 35128
    • Local Institution
  • Roma, Italy, 00144
    • Local Institution
  • Siena, Italy, 53100
    • Local Institution
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Local Institution
  • Amsterdam, Netherlands, 1081 BV
    • Local Institution
  • Leiden, Netherlands, 2333 ZA
    • Local Institution
  • Nijmegen, Netherlands, 6500 HB
    • Local Institution
  • Rotterdam, Netherlands, 3075EA
    • Local Institution
• Norway
  • Oslo, Norway, 0310
    • Local Institution
• Poland
  • Poznan, Poland, 61-866
    • Local Institution
  • Warszawa, Poland, 02-781
    • Local Institution
• Russian Federation
  • Ivanovo, Russian Federation, 153013
    • Local Institution
  • Izhevsk, Russian Federation, 426009
    • Local Institution
  • Krasnodar, Russian Federation, 350040
    • Local Institution
  • Krasnoyarsk, Russian Federation, 660022
    • Local Institution
  • Lipetsk, Russian Federation, 398005
    • Local Institution
  • Moscow, Russian Federation, 115478
    • Local Institution
  • Petrozavodsk, Russian Federation, 185007
    • Local Institution
  • Saratov, Russian Federation, 410004
    • Local Institution
  • St Petersburg, Russian Federation, 194044
    • Local Institution
  • St. Petersburg, Russian Federation, 197022
    • Local Institution
  • St. Petersburg, Russian Federation, 191104
    • Local Institution
  • Tomsk, Russian Federation, 634050
    • Local Institution
  • Ufa, Russian Federation, 450054
    • Local Institution
  • Stavropol Region
    • Pyatigorsk, Stavropol Region, Russian Federation, 357502
      • Local Institution
• Spain
  • Barcelona, Spain, 08036
    • Local Institution
  • Madrid, Spain, 28041
    • Local Institution
  • Zaragoza, Spain, 50009
    • Local Institution
• Sweden
  • Stockholm, Sweden, 171 76
    • Local Institution
• Switzerland
  • Zurich, Switzerland, 8091
    • Local Institution
• United Kingdom
  • Essex
    • Chelmsford, Essex, United Kingdom, CM1 7ET
      • Local Institution
  • Greater London
    • London, Greater London, United Kingdom, SW17 0QT
      • Local Institution
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • Local Institution
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
      • Local Institution
  • Yorkshire
    • Leeds, Yorkshire, United Kingdom, LS9 7TF
      • Local Institution
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic & Research Institute
    • San Diego, California, United States, 92123
      • Sharp Memorial Hospital
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
    • San Francisco, California, United States, 94117
      • North. Cal. Melanoma Center-St. Mary's Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Florida
    • Boca Raton, Florida, United States, 33428
      • Boca Raton Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Cnt And Res Inst
  • Illinois
    • Park Ridge, Illinois, United States, 60068
      • Oncology Specialists, S.C.
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Nevada Cancer Center
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Atlantic Melanoma Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Cancer Center
  • 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
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • St Lukes Hospital And Health Network
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Ctr
  • Texas
    • Dallas, Texas, United States, 75230
      • Center For Oncology Research & Treatment, P.A.
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute At The Univ. Of Utah
  • 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:

• Age ≥ 18 years
• Complete and adequate resection of Stage III melanoma with histologically confirmed melanoma metastatic to lymph node
• Disease-free
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
• Randomization within 12 weeks of surgery

Exclusion Criteria:

• Prior therapy for melanoma except surgery
• Auto-immune disease

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A	Drug: ipilimumab; IV solution, IV, 10 mg/kg, 4x every 21 days, then starting from Week 24 every 12 weeks until Week 156 (3 years), disease recurrence, unacceptable toxicity or patient withdrawal; Other Names: BMS-734016; MDX-010
Placebo Comparator: B	Drug: Placebo; IV solution, IV, 10 mg/kg, 4x every 21 days then starting from Week 24 every 12 weeks until Week 156 (3 years), disease recurrence, unacceptable toxicity or patient withdrawal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence Free Survival (RFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population	Recurrence free survival (RFS) was programmatically determined based on the disease recurrence data provided by the IRC and was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those participants who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. The primary analysis was event-driven and planned when at least 512 RFS events assessed per IRC were collected.	Date of randomization to first date of recurrence or death or last available disease assessment with RFS data up to 5 years. Median follow-up was 2.7 years.
Number of Participants With Recurrence or Death as Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population	Recurrence was defined as appearance of one or more new melanoma lesions: local, regional or distant metastasis. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. A participant who died without reported recurrence was considered to have recurred on the date of death. Disease was assessed at randomization and every 12 weeks (±2 weeks) for 3 years, then every 24 weeks until documented distant progression.	Date of randomization to first date of recurrence or death or last available disease assessment with RFS data upto 5 years. Median follow-up was 2.7 years.
Recurrence-Free Survival (RFS) Rates Per IRC at 1 Year, 2 Years, and 3 Years in the ITT Population	Yearly recurrence-free survival rates, eg. at 1 year, defined as the probability that a participant was recurrence-free at 1 year following randomization, were estimated for each treatment group using the Kaplan-Meier product-limit method, along with their corresponding log-log transformed 95% confidence intervals. RFS was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. CT and MRI were mandatory to establish recurrence.	At years 1, 2, and 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Distant Metastasis-Free Survival (DMFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population	Distant Metastasis-Free Survival (DMFS) was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, DMFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Disease was assessed at baseline (randomization) and every 12 weeks (±2 weeks) for 3 years, then every 24 weeks until documented distant progression.	From June 2008 to January 2016 (approximately 90 months)
Number of Participants With Distant Metastasis-Free Survival (DMFS) Per Independent Review Committee (IRC) in the Intent to Treat (ITT) Population	DMFS was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, DMFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Disease was assessed at baseline (randomization) and every 12 weeks (2 weeks) for 3 years, then every 24 weeks until documented distant progression.	From June 2008 to January 2016 (approximately 90 months)
Distant Metastasis-Free Survival (DMFS) Rates Per IRC at 1 Year, 2 Years, 3 Years, 4 Years and 5 Years in the ITT Population	Yearly distant metastasis-free survival rates, e.g. at 1 year, defined as the probability that a participant was alive at 1 year following randomization, were estimated via the Kaplan-Meier method. Distant Metastasis-Free Survival (DMFS) was programmatically determined based on the first date of distant metastasis provided by the IRC and was defined as the time between the date of randomization and the date of first distant metastasis or death (whatever the cause), whichever occurred first. A participant who died without reported disease distant metastasis was considered to have distant metastasis on the date of death. For those who remained alive and metastasis-free, DMFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment. Participants with disease at baseline were considered to have an event on the day of randomization.	At years 1, 2, 3, 4 and 5
Overall Survival in the Intent to Treat (ITT) Population	OS was defined as the time from the date of randomization to the date of death. For those participants who had not died, OS was censored at the recorded last non-missing date of contact for which the participant was known to be alive.	From June 2008 to January 2016 (approximately 90 months)
Rate of Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death. For those participants who had not died, OS was censored at the recorded last non-missing date of contact for which the participant was known to be alive.Yearly survival rates, e.g. at 3 years, defined as the probability that a participant was alive at 3 years following randomization, were estimated via the Kaplan-Meier method	From date of randomization to date of death, assessed up to 9 years
Number of Participants With On-Study Adverse Events (AEs) Leading to Discontinuation of Treatment, Serious AEs (SAEs), Drug-Related SAEs, Immune-related AEs (irAEs), Immune-mediated Adverse Reactions (imARs), Deaths in Treated Population	AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. irAEs=unknown etiology consistent with an immune phenomenon, considered as causally related to drug. imARs=based on investigator's assessment of immune-mediated etiology [excluding novel maintenance events (ie, patients with imARs occurring for the first time during maintenance)]. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. 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. Drug-related (D-R)=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, Gr 5=Death.	Day 1 up to 70 days after last dose; up to 5 years
Number of Participants With Serious Adverse Events (SAEs), Non-serious AEs (NSAEs) and Number of Deaths: Overall Study	AEs: Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. 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.	SAEs and NSAEs: Day 1 up to 70 days after last dose(safety window). Deaths: All deaths regardless of 70 day safety window.Up to 10 years
Exposure Adjusted Incidence Rate of Adverse Events Including Multiple Occurrences of Unique Events	P-Y = person-years of exposure. Incidence rate per 100 person-years of exposure (IR/100 P-Y) was calculated as event count * 100 /person-years of exposure. MedDRA Version: 19. Duplicate AEs have been eliminated and overlapping and contiguous occurrences of the same event have been collapsed.	Day 1 up to 70 days after last dose; up to 5 years
Mean Change From Baseline in Global Health Status Scores at Each Assessment Timepoint	Global health status was measured using European Organization for Research and Treatment of Cancer (EORTC) Quality Life Questionnaire (QLQ) C-30. This health related quality of life (HRQoL) questionnaire was comprised of 15 questions on functional scales, 13 questions on symptom scales and 2 on global health status scale. Global Health Status used a 7 point Likert-type scale of 1 (Very poor) to 7 (Excellent). All scales linearly transformed to 0-100 scales. Higher scores for Global Health Status indicate better HRQoL. An increase from baseline indicates improvement in HRQoL compared to baseline. HRQoL was administered within 1 week prior to first dose (baseline) and on Days 22, 43, 64 (+/- 3 days), Week 24 and every 12 weeks up to 2 years, independent of disease progression.	Baseline up to 2 years from randomization

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Weber JS, Ascierto PA, Middleton MR, Hennicken D, Zoffoli R, Pieters A, Amadi A, Kupas K, Kotapati S, Moshyk A, Schadendorf D. Indirect treatment comparison of nivolumab versus placebo as adjuvant treatment for resected melanoma. Eur J Cancer. 2021 Nov;158:225-233. doi: 10.1016/j.ejca.2021.08.028. Epub 2021 Oct 15.
• Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AMM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. doi: 10.1016/S1470-2045(17)30015-3. Epub 2017 Feb 3.
• Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. doi: 10.1056/NEJMoa1611299. Epub 2016 Oct 7. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.
• Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. doi: 10.1016/S1470-2045(15)70122-1. Epub 2015 Mar 31. Erratum In: Lancet Oncol. 2015 Jun;16(6):e262. Lancet Oncol. 2016 Jun;17 (6):e223.

Helpful Links

• BMS clinical trial educational resource
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2008
• Primary Completion (Actual): July 26, 2013
• Study Completion (Actual): November 26, 2018

Study Registration Dates

• First Submitted: March 7, 2008
• First Submitted That Met QC Criteria: March 7, 2008
• First Posted (Estimate): March 14, 2008

Study Record Updates

• Last Update Posted (Actual): December 17, 2019
• Last Update Submitted That Met QC Criteria: December 4, 2019
• Last Verified: December 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: CA184-029; EORTC 18071

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes