Various Advanced CancerPhase 3CheckMate 648NCT03143153
A Study to Evaluate Efficacy in Subjects With Esophageal Cancer Treated With Nivolumab and Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin
A Phase 3 study testing Nivolumab, Ipilimumab and Cisplatin in people with Various Advanced Cancer, run by Bristol-Myers Squibb at 190 sites in 27 countries.
Trial summary
The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Various Advanced Cancer
- What is being tested?
- Nivolumab, Ipilimumab and Cisplatin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 970 participants
- Where
- 190 sitesin 27 countries
- Study dates
- 29 Jun 2017to 13 Jan 2025
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Must have histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of esophagus
- Male or Female at least 18 years of age
- Must have esophageal cancer that cannot be operated on, or treated with definitive chemoradiation with curative intent, that is advanced, reoccurring or has spread out
- Must have full activity or, if limited, must be able to walk and carry out light activities such as light house work or office work
- Must agree to provide tumor tissue sample, either from a previous surgery or biopsy within 6 months or fresh, prior to the start of treatment in this study
Who cannot join
- Presence of tumor cells in the brain or spinal cord which are symptomatic or require treatment
- Active known or suspected autoimmune disease
- Any serious or uncontrolled medical disorder or active infection
- Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Any positive test result for hepatitis B or C indicating acute or chronic infection and/or detectable virus
- Other protocol defined inclusion/exclusion criteria apply
Trial locations and contacts
190 sites in 27 countries.
190 sites in 27 countries
Japan54 sites
Local Institution - 0170
Akashi-shi, Hyōgo, 6738558
Local Institution - 0152
Akita, Akita, 010-8543
Local Institution - 0106
Bunkyo-ku, Tokyo, 1138519
Local Institution - 0110
Bunkyo-ku, Tokyo, 1138677
Local Institution - 0101
Chiba, Chiba, 260-8717
Local Institution - 0153
Chiba, Chiba, 2608670
Local Institution - 0136
Chuo-ku, Tokyo, 1040045
Local Institution - 0128
Chuo-ku, Tokyo, 1048560
Local Institution - 0174
Fukuoka, Fukuoka, 8111395
Local Institution - 0142
Fukuoka, Fukuoka, 8128582
Local Institution - 0103
Fukushima, Fukushima, 9601295
Local Institution - 0154
Gifu, Gifu, 5011194
Local Institution - 0230
Hidaka-shi, Saitama, 3501298
Local Institution - 0221
Hirakata, Osaka, 573-1191
Local Institution - 0104
Hirosaki-shi, Aomori, 0368563
Local Institution - 0100
Hiroshima, Hiroshima, 7348551
Local Institution - 0127
Isehara, Kanagawa, 259-1193
Local Institution - 0229
Kagoshima, Kagoshima-ken, 8908520
Local Institution - 0120
Kamigyō-ku, Kyoto, 602-8566
Local Institution - 0171
Kanazawa, Ishikawa-ken, 920-8530
Local Institution - 0173
Kashiwa-shi, Chiba, 2778577
Local Institution - 0109
Kawasaki-shi, Kanagawa, 216-8511
Local Institution - 0175
Kitaadachi-gun, Saitama, 3620806
Local Institution - 0172
Kobe, Hyōgo, 6500017
Local Institution - 0118
Kobe, Hyōgo, 6500047
Local Institution - 0126
Koto-ku, Tokyo, 1358550
Local Institution - 0141
Kumamoto, Kumamoto, 8608556
Local Institution - 0135
Kurashiki-shi, Okayama-ken, 7010192
Local Institution - 0145
Kyoto, Kyoto, 606-8507
Local Institution - 0169
Matsuyama, Ehime, 7900024
Local Institution - 0119
Matsuyama, Ehime, 7910280
Local Institution - 0156
Minato-ku, Tokyo, 1058470
Local Institution - 0146
Niigata, Niigata, 9518566
Local Institution - 0137
Okayama, Okayama-ken, 7008558
Local Institution - 0138
Osaka, Osaka, 5418567
Local Institution - 0176
Ōta, Gunma, 3738550
Local Institution - 0245
Ōta-ku, Tokyo, 1438541
Local Institution - 0105
Sagamihara-shi, Kanagawa, 2520375
Local Institution - 0111
Sapporo, Hokkaido, 060-8648
Local Institution - 0098
Sayama, Osaka, 589-8511
Local Institution - 0144
Sendai, Miyagi, 9808575
Local Institution - 0148
Shimotsuga-gun, Tochigi, 321-0293
Local Institution - 0140
Shinagawa-ku, Tokyo, 142-8666
Local Institution - 0155
Shinjuku-ku, Tokyo, 1628666
Local Institution - 0196
Shinjuku-Ku, Tokyo, 1608582
Local Institution - 0108
Shizuoka, Shizuoka, 4208527
Local Institution - 0107
Suita, Osaka, 5650871
Local Institution - 0143
Sunto-gun, Shizuoka, 411-8777
Local Institution - 0139
Takatsuki, Osaka, 569-8686
Local Institution - 0231
Toyama, Toyama, 9300194
Local Institution - 0238
Ube-shi, Yamaguchi, 7558505
Local Institution - 0178
Wakayama, Wakayama, 641-8510
Local Institution - 0147
Yokohama, Kanagawa, 2360004
Local Institution - 0117
Yokohama, Kanagawa, 2418515
China23 sites
Local Institution - 0182
Beijing, Beijing Municipality, 100032
Local Institution - 0179
Beijing, Beijing Municipality, 100071
Local Institution - 0216
Beijing, Beijing Municipality, 100853
Local Institution - 0180
Changchun, Jilin, 130021
Local Institution - 0249
Changsha, Hunan, 410000
Local Institution - 0212
Changsha, Hunan, 410008
Local Institution - 0217
Fuzhou, Fujian, 350014
Local Institution - 0219
Fuzhou, Fujian, 350025
Local Institution - 0184
Hangzhou, Zhejiang, 310003
Local Institution - 0185
Harbin, Heilongjiang, 155040
Local Institution - 0207
Hefei, Anhui, 230022
Local Institution - 0197
Hefei, Anhui, 230061
Local Institution - 0247
Linhai, Zhejiang, 317000
Local Institution - 0201
Nanjing, Jiangsu, 210000
Local Institution - 0215
Shanghai, Shanghai Municipality, 200030
Local Institution - 0200
Shanghai, Shanghai Municipality, 200032
Local Institution - 0199
Shantou, Guangdong, 515041
Local Institution - 0220
Shenyang, 110042
Local Institution - 0183
Xi'an, Shan3xi, 710038
Local Institution - 0248
Xi'an, 0
Local Institution - 0193
Zhengzhou, Henan, 0
Local Institution - 0195
Zhengzhou, Henan, 450008
Local Institution - 0194
Zhengzhou, Henan, 450052
United States16 sites
Local Institution - 0074
Atlanta, Georgia, 30322
Local Institution - 0210
Dallas, Texas, 75246
Local Institution - 0188
Denver, Colorado, 80218
Oncology Associates Of Oregon, Pc
Eugene, Oregon, 97401
Local Institution - 0028
Houston, Texas, 77030
Usc/Norris Comprehensive Cancer Center
Los Angeles, California, 90033
Local Institution - 0032
Marietta, Georgia, 30060
University Of Miami Sylvester Comprehensive Cancer Center
Miami, Florida, 33136
Local Institution - 0186
Miami, Florida, 33176
Local Institution - 0191
Mobile, Alabama, 36608
Local Institution - 0203
Morgantown, West Virginia, 26506-9162
Hackensack Meridian Jersey Shore University Medical Center
Neptune City, New Jersey, 07753
Northwest Cancer Specialists, P.C.
Portland, Oregon, 97227
Local Institution - 0190
Roanoke, Virginia, 24014
Local Institution - 0225
Tampa, Florida, 33612
Arizona Cancer Center
Tucson, Arizona, 85724
South Korea14 sites
Local Institution - 0166
Busan, 49241
Local Institution - 0150
Daegu, 41404
Local Institution - 0149
Daejeon, 35015
Local Institution - 0236
Jeonju, 54907
Local Institution - 0129
Seongnam-si, Kyǒnggi-do, 13620
Local Institution - 0165
Seoul, Seoul-teukbyeolsi [Seoul], 02841
Local Institution - 0235
Seoul, 01812
Local Institution - 0130
Seoul, 05505
Local Institution - 0177
Seoul, 06351
Local Institution - 0168
Seoul, 06591
Local Institution - 0151
Seoul, 07345
Local Institution - 0131
Seoul, 08308
Local Institution - 0123
Seoul, 120-752
Local Institution - 0157
Ulsan, 44033
Taiwan12 sites
Local Institution - 0158
Changhua County, Changhua, 50006
Local Institution - 0167
Kaohsiung City, 807
Local Institution - 0133
Kaohsiung City, 833
Local Institution - 0163
Kaohsiung County, 0
Local Institution - 0164
Keelung, 204
Local Institution - 0132
Taichung, 40447
Local Institution - 0161
Tainan, TNN, 704
Local Institution - 0160
Tainan, 71004
Local Institution - 0124
Taipei, 100
Local Institution - 0162
Taipei, 10449
Local Institution - 0134
Taipei, 11217
Local Institution - 0159
Taoyuan, 333
Brazil9 sites
Local Institution - 0019
Barretos, São Paulo, 14780-070
Local Institution - 0021
Ijuí, Rio Grande do Sul, 98700-000
Local Institution - 0227
Ipatinga, Minas Gerais, 35160-158
Local Institution - 0226
Jaú, São Paulo, 17210-080
Local Institution - 0016
Porto Alegre, Rio Grande do Sul, 90610-000
Local Institution - 0228
Rio de Janeiro, Rio de Janeiro, 22793-080
Local Institution - 0017
Salvador, Estado de Bahia, 41950-640
Local Institution - 0018
São José do Rio Preto, São Paulo, 15090000
Local Institution - 0020
São Paulo, São Paulo, 01246-000
France6 sites
Local Institution - 0114
Caen, 14076
Local Institution - 0116
Lille, Nord, 59000
Local Institution - 0112
Montpellier, 34090
Local Institution - 0113
Rennes, 35042
Local Institution - 0242
Toulouse, 31059
Local Institution - 0115
Villejuif, 94800
United Kingdom5 sites
Local Institution - 0069
London, Greater London, NW1 2PG
Local Institution - 0066
London, Greater London, SW3 6JJ
Local Institution - 0237
London, EC1A 7BE
Local Institution - 0031
Manchester, Greater Manchester, M20 4BX
Local Institution - 0029
Surrey, SM2 5PT
Argentina4 sites
Local Institution - 0048
Buenos Aires, Buenos Aires, 1417
Local Institution - 0050
Capital Federal, Buenos Aires, 1264
Local Institution - 0087
La Rioja, La Rioja Province, 5300
Local Institution - 0086
Rosario, Santa Fe Province, 2000
Canada4 sites
Local Institution - 0095
Moncton, New Brunswick, E1C 6Z8
Local Institution - 0082
Montreal, Quebec, H3T 1E2
Local Institution - 0222
Montreal, Quebec, H4A 3J1
Local Institution - 0037
Trois-Rivières, Quebec, G8Z 3R9
Colombia4 sites
Local Institution - 0059
Bogotá, Bogota D.C., 0
Local Institution - 0058
Medellín, 050034
Local Institution - 0224
Montería, 230001
Local Institution - 0094
Pereira, 660004
Italy4 sites
Local Institution - 0085
Bergamo, 24127
Local Institution - 0039
Milan, 20133
Local Institution - 0084
Padova, Padova
Local Institution - 0240
Pisa, 56126
Mexico4 sites
Local Institution - 0071
Mérida, Yucatán, 97138
Local Institution - 0102
Mexico City, Mexico City, 14000
Local Institution - 0234
San Luis Potosí City, San Luis Potosí, 78200
Local Institution - 0090
Tuxtla Gutiérrez, Chiapas, 29038
Romania4 sites
Local Institution - 0081
Bucharest, 021389
Local Institution - 0079
Cluj-Napoca, 400015
Local Institution - 0076
Craiova, 200347
Local Institution - 0080
Suceava, 720237
Australia3 sites
Local Institution - 0011
Douglas, Queensland, 4814
Local Institution - 0010
Murdoch, Western Australia, 6150
Local Institution - 0232
Tamworth, New South Wales, 2340
Czechia3 sites
Local Institution - 0083
Brno, 625 00
Local Institution - 0008
Brno, 656 53
Local Institution - 0006
Nový Jičín, 741 01
Peru3 sites
Local Institution - 0092
Callao, Provincia Constitucional del Callao, 02
Local Institution - 0060
Lima, Lima Province, 34
Local Institution - 0093
Lima, Lima Province, Lima 11
Turkey (Türkiye)3 sites
Local Institution - 0096
Ankara, 06100
Local Institution - 0125
Diyarbakır, 21280
Local Institution - 0122
Edrine, 22010
Chile2 sites
Local Institution - 0053
Santiago, Santiago Metropolitan, 8320000
Local Institution - 0214
Santiago, Santiago Metropolitan
Hong Kong2 sites
Local Institution - 0035
Hong Kong, 0
Local Institution - 0070
Kowloon
Poland2 sites
Local Institution - 0024
Lublin, 20-081
Local Institution - 0022
Warsaw, 02-781
Russia2 sites
Local Institution - 0089
Moscow, 121309
Local Institution - 0088
Saint Petersburg, 198255
Singapore2 sites
Local Institution - 0033
Singapore, Central Singapore, 168583
Local Institution - 0034
Singapore, 119228
Spain2 sites
Local Institution - 0063
Barcelona, 08035
Local Institution - 0062
Madrid, 28050
About this study
Official title: A Randomized Phase 3 Study of Nivolumab Plus Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin in Subjects With Unresectable Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma
The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin
- Conditions
- Various Advanced Cancer
- Being tested
- Nivolumab, Ipilimumab, Cisplatin, Fluorouracil
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabBiological
Also called BMS-936558 (Nivolumab), Opdivo (Nivolumab)
Specified dose on specified days
IpilimumabBiological
Also called BMS-734016 (Ipilimumab), Yervoy (Ipilimumab)
Specified dose on specified days
CisplatinDrug
Specified dose on specified days
FluorouracilDrug
Specified dose on specified days
| Study group | Role | What they receive |
|---|---|---|
| Nivolumab + Ipilimumab | Experimental | Not described Receives: Biological: Nivolumab; Biological: Ipilimumab |
| Nivolumab + Cisplatin + Fluorouacil | Experimental | Not described Receives: Biological: Nivolumab; Drug: Cisplatin; Drug: Fluorouracil |
| Cisplatin + Fluorouracil | Active comparator | Not described Receives: Drug: Cisplatin; Drug: Fluorouracil |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival (OS) in Participants With Tumor Cell PD-L1
Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
Measured: From the date of randomization to up to the date of death (up to approximately 20 months)
Progression-free Survival (PFS) as Assessed by BICR in Participants With Tumor Cell PD-L1
Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
Measured: From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 9 months)
Secondary outcomes (3)
Overall Survival (OS) in All Randomized Participants
Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
Measured: From the date of randomization to up to the date of death (up to approximately 88 months)
Progression-free Survival (PFS) in All Randomized Participants as Assessed by BICR
Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
Measured: From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 88 months)
Objective Response Rate (ORR) as Assessed by BICR
Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation as determined by BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1) or the date of subsequent anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Complete response is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm.
Measured: From the date of randomization to up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to 88 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 May 2017
- Study start29 Jun 2017
- Primary completion18 Jan 2021
- Study completion13 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Various Advanced CancerStudies of the same condition, open and under way.
- More trials run by Bristol-Myers SquibbThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 970 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bristol-Myers Squibb
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Ono Pharmaceutical Co., Ltd.
- Responsible party
- Sponsor
- Investigators
- Bristol-Myers Squibb, Study director, Bristol-Myers Squibb
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03143153
- Sponsor's protocol ID
- CA209-648
- Other IDs
- 2016-001514-20, 2016
- Acronym
- CheckMate 648
- Status last verified
- Feb 2026
- First submitted
- 4 May 2017
- Last updated
- 17 Feb 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Expanded access
- Available
Publications
Zhang Y, Li C, Du K, Pengkhun N, Huang Z, Gong M, Li Y, Liu X, Li L, Wang D, Wang C, Chen F, Li J. Comparative analysis of immune checkpoint inhibitors in first-line treatment of esophageal squamous cell carcinoma: a network meta-analysis. Immunotherapy. 2023 Jul;15(10):737-750. doi: 10.2217/imt-2022-0236. Epub 2023 May 4.
PubMed 37139963Kato K, Doki Y, Ogata T, Motoyama S, Kawakami H, Ueno M, Kojima T, Shirakawa Y, Okada M, Ishihara R, Kubota Y, Amaya-Chanaga C, Chen T, Matsumura Y, Kitagawa Y. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus. 2023 Apr;20(2):291-301. doi: 10.1007/s10388-022-00970-1. Epub 2022 Nov 19.
PubMed 36401133Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. doi: 10.1056/NEJMoa2111380.
PubMed 35108470