Efficacy Study of Nivolumab Compared to Ipilimumab in Prevention of Recurrence of Melanoma After Complete Resection of Stage IIIb/c or Stage IV Melanoma (CheckMate 238)

A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage IIIb/c or Stage IV Melanoma in Subjects Who Are at High Risk for Recurrence (CheckMate 238: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 238)

The purpose of this study is to determine whether nivolumab is better than ipilimumab to prevent recurrence of melanoma.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: Ipilimumab; Other: Placebo matching Nivolumab; Drug: Nivolumab; Other: Placebo matching Ipilimumab

• Study Type: Interventional
• Enrollment (Actual): 906
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, 5000
    • Local Institution
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, 1426
      • Local Institution - 0142
  • Tucuman
    • San Miguel de Tucuman, Tucuman, Argentina, 4000
      • Local Institution - 0140
• Australia
  • Camperdown, Australia, 2050
    • Local Institution - 0081
  • New South Wales
    • Gateshead, New South Wales, Australia, 2290
      • Local Institution - 0079
    • Westmead, New South Wales, Australia, 2145
      • Local Institution - 0080
    • Wollstonecraft, New South Wales, Australia, 2065
      • Local Institution - 0078
  • Queensland
    • Greenslopes, Queensland, Australia, 4120
      • Local Institution - 0082
    • Southport, Queensland, Australia, 4215
      • Local Institution - 0083
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Local Institution - 0084
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Local Institution - 0075
    • Prahran, Victoria, Australia, 3181
      • Local Institution - 0077
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Local Institution - 0085
• Austria
  • Graz, Austria, 8036
    • Local Institution - 0169
  • Salzburg, Austria, 5020
    • Local Institution - 0168
• Belgium
  • Brussels, Belgium, 1090
    • Local Institution - 0038
  • Bruxelles, Belgium, 1200
    • Local Institution - 0040
  • Gent, Belgium, 9000
    • Local Institution - 0037
  • Leuven, Belgium, 3000
    • Local Institution - 0039
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Local Institution - 0051
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Local Institution - 0074
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution - 0094
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Local Institution - 0105
    • Quebec City, Quebec, Canada, G1J 1Z4
      • Local Institution - 0046
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Local Institution - 0101
  • Ostrava-Poruba, Czechia, 708 52
    • Local Institution - 0102
  • Praha 1, Czechia, 110 00
    • Local Institution - 0099
  • Praha 2, Czechia, 128 08
    • Local Institution - 0100
• Finland
  • Helsinki, Finland, 00029
    • Local Institution - 0047
  • Tampere, Finland, 33521
    • Local Institution - 0048
• France
  • Lille, France, 59037
    • Local Institution - 0138
  • Marseille Cedex 5, France, 13385
    • Local Institution - 0135
  • Nantes, France, 44000
    • Local Institution - 0134
  • Paris, France, 75010
    • Local Institution - 0136
  • Pierre Benite, France, 69495
    • Local Institution - 0133
  • Toulouse, France, 31059
    • Local Institution - 0137
• Greece
  • Athens, Greece, 11526
    • Local Institution - 0086
  • Neo Faliro, Greece, 18547
    • Local Institution - 0087
• Hungary
  • Budapest, Hungary, 1122
    • Local Institution - 0163
• Ireland
  • Dublin, Ireland, 01
    • Local Institution - 0063
  • Dublin, Ireland, 4
    • Local Institution - 0108
  • Dublin 7, Ireland
    • Local Institution - 0166
  • Galway, Ireland
    • Local Institution - 0064
• Italy
  • Bergamo, Italy, 24127
    • Local Institution - 0112
  • Genova, Italy, 16128
    • Local Institution - 0116
  • Meldola (FC), Italy, 47014
    • Local Institution - 0115
  • Milano, Italy, 20133
    • Local Institution - 0113
  • Napoli, Italy, 80131
    • Local Institution - 0107
  • Padova, Italy, Padova
    • Local Institution - 0111
  • Roma, Italy, 00144
    • Local Institution - 0114
  • Siena, Italy, 53100
    • Local Institution - 0110
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 466-8560
      • Local Institution - 0179
  • Fukuoka
    • Fukuoka-shi, Fukuoka, Japan, 8128582
      • Local Institution - 0161
  • Ibaraki
    • Tsukuba-shi, Ibaraki, Japan, 3058576
      • Local Institution - 0174
  • Kumamoto
    • Kumamoto-shi, Kumamoto, Japan, 8608556
      • Local Institution - 0162
  • Nagano
    • Matsumoto, Nagano, Japan, 3908621
      • Local Institution - 0160
  • Niigata
    • Niigata-shi, Niigata, Japan, 9518566
      • Local Institution - 0175
  • Osaka
    • Osaka-shi, Osaka, Japan, 5400006
      • Local Institution - 0176
  • Shizuoka
    • Sunto-gun, Shizuoka, Japan, 4118777
      • Local Institution - 0159
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 1040045
      • Local Institution - 0158
  • Yamanashi
    • Chuo-shi, Yamanashi, Japan, 4093898
      • Local Institution - 0180
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Local Institution - 0129
  • Seoul, Korea, Republic of, 03722
    • Local Institution - 0127
  • Seoul, Korea, Republic of, 06351
    • Local Institution - 0128
  • Seoul
    • Songpa-gu, Seoul, Korea, Republic of, 05505
      • Local Institution - 0144
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Local Institution - 0042
  • Groningen, Netherlands, 9713 GZ
    • Local Institution - 0045
  • Nijmegen, Netherlands, 6525GA
    • Local Institution - 0043
  • Veldhoven, Netherlands, 5504 DB
    • Local Institution - 0041
• Norway
  • Bergen, Norway, 5021
    • Local Institution - 0098
  • Oslo, Norway, 3100
    • Local Institution - 0109
• Poland
  • Gdansk, Poland, 80-219
    • Local Institution - 0150
  • Krakow, Poland, 31-115
    • Local Institution - 0149
  • Warszawa, Poland, 02-781
    • Local Institution - 0152
• Romania
  • Craiova, Romania, 200542
    • Local Institution - 0156
  • Romania, Romania, 400015
    • Local Institution - 0153
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2196
      • Local Institution - 0148
    • Pretoria, Gauteng, South Africa, 0075
      • Local Institution - 0145
    • Saxonwold, Johannesburg, Gauteng, South Africa, 2196
      • Local Institution - 0147
  • Western CAPE
    • Cape Town, Western CAPE, South Africa, 7700
      • Local Institution - 0181
  • Western Cape
    • Kraaifontein, Western Cape, South Africa, 7570
      • Local Institution - 0146
• Spain
  • Barcelona, Spain, 08036
    • Local Institution - 0120
  • Madrid, Spain, 28007
    • Local Institution - 0119
  • Sevilla, Spain, 41009
    • Local Institution - 0121
  • Valencia, Spain, 46014
    • Local Institution - 0122
• Sweden
  • Gothenberg, Sweden, 413 45
    • Local Institution - 0050
  • Lund, Sweden, 221 85
    • Local Institution - 0096
• Switzerland
  • Zuerich, Switzerland, 8091
    • Local Institution - 0167
• Taiwan
  • Kaohsiung, Taiwan, 833
    • Local Institution - 0131
  • Taichung, Taiwan, 404
    • Local Institution - 0132
  • Taoyuan, Taiwan, 333
    • Local Institution - 0130
• United Kingdom
  • Leicester, United Kingdom, LE15WW
    • Local Institution - 0097
  • Surrey, United Kingdom, SM2 5PT
    • Local Institution - 0053
  • Avon
    • Bristol, Avon, United Kingdom, BS2 8ED
      • Local Institution - 0057
  • Carmarthenshire
    • Swansea, Carmarthenshire, United Kingdom, SA2 8QA
      • Local Institution - 0052
  • Greater London
    • London, Greater London, United Kingdom, SW3 6JJ
      • Local Institution - 0165
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • Local Institution - 0054
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • Local Institution - 0056
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2JR
      • Local Institution - 0177
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LJ
      • Local Institution - 0055
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN
      • Local Institution - 0060
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Local Institution - 0036
  • California
    • La Jolla, California, United States, 92093-0698
      • Local Institution - 0117
    • Los Angeles, California, United States, 90025
      • Local Institution - 0189
    • San Francisco, California, United States, 94109
      • Local Institution - 0021
    • San Francisco, California, United States, 94143
      • Local Institution - 0006
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Local Institution - 0010
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Local Institution - 0004
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Local Institution - 0012
    • Miami Beach, Florida, United States, 33140
      • Local Institution - 0019
    • Orlando, Florida, United States, 32806
      • Local Institution - 0030
    • Tampa, Florida, United States, 33612
      • Local Institution - 0032
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Local Institution - 0016
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Local Institution - 0106
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0013
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0170
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0171
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5869
      • Local Institution - 0015
  • Minnesota
    • Robbinsdale, Minnesota, United States, 55407
      • Local Institution - 0002
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Local Institution - 0017
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Local Institution - 0123
    • New Brunswick, New Jersey, United States, 08903
      • Local Institution - 0095
  • New York
    • New York, New York, United States, 10016
      • Local Institution - 0024
    • New York, New York, United States, 10065
      • Local Institution - 0033
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Local Institution - 0003
    • Durham, North Carolina, United States, 27710
      • Local Institution - 0025
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Local Institution - 0157
  • Oregon
    • Portland, Oregon, United States, 97213
      • Local Institution - 0031
    • Portland, Oregon, United States, 97239
      • Local Institution - 0029
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Local Institution - 0022
    • Bethlehem, Pennsylvania, United States, 18015
      • Local Institution - 0001
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Local Institution - 0026
  • Tennessee
    • Nashville, Tennessee, United States, 37203-1624
      • Local Institution - 0014
  • Texas
    • Dallas, Texas, United States, 75246
      • Local Institution - 0005
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Local Institution - 0027
  • Washington
    • Seattle, Washington, United States, 98109
      • Local Institution - 0126

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At least 15 years of age Except: where local regulations and/or institutional policies do not allow for subjects < 18 years of age (pediatric population) to participate. For those sites, the eligible subject population is ≥ 18 years of age
• Completely removed melanoma by surgery performed within 12 weeks of randomization
• Stage IIIb/C or Stage IV before complete resection
• No previous anti-cancer treatment

Exclusion Criteria:

• Ocular or uveal melanoma
• History of carcinomatosis meningitis
• History of auto-immune disease
• Treatment directed against the resected melanoma that is administrated after the surgery

Other protocol-defined inclusion/exclusion criteria apply

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: Ipilimumab and Placebo matching Nivolumab	Drug: Ipilimumab; Specified dose on specified days; Other: Placebo matching Nivolumab; Specified dose on specified days
Experimental: Nivolumab and Placebo matching Ipilimumab	Drug: Nivolumab; Specified dose on specified days; Other: Placebo matching Ipilimumab; Specified dose on specified days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence-free Survival (RFS)	RFS is defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma, or death (whatever the cause), whichever occurs first.	up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Safety and Tolerability of Nivolumab and Ipilimumab Measured by the Incidence of Adverse Events	the safety and tolerability of Nivolumab and Ipilimumab was measured by the incidence of adverse events	reported between first dose and 30 days after last dose of study therapy
The Safety and Tolerability of Nivolumab and Ipilimumab Measured by the Incidence of Serious Adverse Events	The Safety and Tolerability of nivolumab and ipilimumab was measured by the incidence of serious adverse events	reported between the first dose and 30 days after last dose of study therapy
The Safety and Tolerability of Nivolumab and Ipilimumab Measured by the Incidence of Laboratory Abnormalities	The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of Laboratory abnormalities.	reported after first dose and within 30 days of last dose of the study therapy
Health Related Quality of Life (HRQoL) Evaluation	HRQoL was measured by mean changes from baseline in EORTC-QLQ-C30 global health status/QoL composite scale and in remaining EORTC QLQ-C30 scales in all randomized participants. EORTC QLQ-C30 is the most commonly used QoL instrument in melanoma clinical studies, is a 30-item instrument that has gained wide acceptance in oncology clinical studies and comprises 5 functional scales (physical functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Except for the overall health status and global quality of life items, responses for all items are 4 point categorical scales ranging from 1 (Not at all) to 4 (Very much). The overall health status/quality of life responses are 7-point Likert scales for which higher score reflects higher health status/quality of life for the 7-point Likert scale.	up to 36 months
Overall Survival (OS)	OS is defined as as the time between the date of randomization and the date of death.	up to 106.6 months
the Safety and Tolerability of Nivolumab and Ipilimumab Measured by the Incidence of Deaths	the safety and tolerability of Nivolumab and Ipilimumab was measured by the incidence of Deaths	reported between first dose and 30 to 100 days after last dose of study therapy
Recurrence-free Survival by PD-L1 Expression	Recurrence-free survival by PD-L1 Expression(5% tumor cell membrane expression)	up to 106.6 months

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Ono Pharmaceutical Co. Ltd
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

General Publications

• Larkin J, Weber J, Del Vecchio M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Marquez-Rodas I, Butler MO, Di Giacomo AM, Middleton MR, De la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Long GV, Lobo M, Askelson M, Ascierto PA, Mandala M. Adjuvant nivolumab versus ipilimumab (CheckMate 238 trial): Reassessment of 4-year efficacy outcomes in patients with stage III melanoma per AJCC-8 staging criteria. Eur J Cancer. 2022 Sep;173:285-296. doi: 10.1016/j.ejca.2022.06.041. Epub 2022 Aug 11.
• 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.
• Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbe C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. doi: 10.1056/NEJMoa1709030. Epub 2017 Sep 10.
• Mandala M, Larkin J, Ascierto PA, Del Vecchio M, Gogas H, Cowey CL, Arance A, Dalle S, Schenker M, Grob JJ, Chiarion-Sileni V, Marquez-Rodas I, Butler MO, Di Giacomo AM, Lutzky J, De La Cruz-Merino L, Atkinson V, Arenberger P, Hill A, Fecher L, Millward M, Khushalani NI, de Pril V, Lobo M, Weber J. Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. J Immunother Cancer. 2021 Aug;9(8):e003188. doi: 10.1136/jitc-2021-003188. Erratum In: J Immunother Cancer. 2021 Nov;9(11):e003188corr1. doi: 10.1136/jitc-2021-003188corr1.
• Ascierto PA, Del Vecchio M, Mandala M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Marquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. doi: 10.1016/S1470-2045(20)30494-0. Epub 2020 Sep 19. Erratum In: Lancet Oncol. 2021 Oct;22(10):e428. doi: 10.1016/S1470-2045(21)00537-4.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2015
• Primary Completion (Actual): November 26, 2018
• Study Completion (Actual): October 16, 2024

Study Registration Dates

• First Submitted: March 10, 2015
• First Submitted That Met QC Criteria: March 13, 2015
• First Posted (Estimated): March 17, 2015

Study Record Updates

• Last Update Posted (Actual): April 24, 2025
• Last Update Submitted That Met QC Criteria: April 4, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Recurrence; Melanoma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Nivolumab; Ipilimumab
• Other Study ID Numbers: CA209-238; 2014-002351-26 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No