Hepatocellular CarcinomaPhase 1/2CheckMate040NCT01658878

An Immuno-therapy Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab or Nivolumab in Combination With Other Agents in Patients With Advanced Liver Cancer

A Phase 1/2 study testing Nivolumab, Sorafenib and Ipilimumab in people with Hepatocellular Carcinoma, run by Bristol-Myers Squibb at 60 sites in 13 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The first part of the study is the Dose Escalation Phase designed to establish the safety of nivolumab at different dose levels for each of the three cohorts (uninfected hepatocellular carcinoma (HCC) subjects, hepatitis C virus (HCV)-infected HCC subjects, and hepatitis B virus (HBV)-infected subjects). Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Hepatocellular Carcinoma
What is being tested?: Nivolumab, Sorafenib and Ipilimumab
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 657 participants
Where: 60 sitesin 13 countries
Study dates: 30 Oct 2012to 12 Nov 2024
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

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

Subjects of 18 years or older (men and women) with histologically confirmed advanced hepatocellular carcinoma, not eligible for surgical and/or locoregional therapies; or progressive disease after surgical and /or locoregional therapies
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
Dose Escalation Phase: Child-Pugh score of 7 points or less. Cohort 5: Child-Pugh Class B (B7-B8). For all other cohorts Child-Pugh score of 6 points or less

Who cannot join

History of autoimmune disease
Any prior or current clinically significant ascites
Any history of hepatic encephalopathy

Trial locations and contacts

60 sites in 13 countries.

Country

City, postcode or hospital

60 sites in 13 countries

United States10 sites

Local Institution - 0002
Ann Arbor, Michigan, 48109-5331
Local Institution - 0047
Atlanta, Georgia, 30322
Local Institution - 0025
Boston, Massachusetts, 02114
Local Institution - 0054
Hackensack, New Jersey, 07601
The University Of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Local Institution - 0008
Los Angeles, California, 90033
Local Institution - 0067
Paterson, New Jersey, 07503
Local Institution - 0053
Pensacola, Florida, 32504
Local Institution - 0001
Portland, Oregon, 97213
Local Institution - 0048
Washington D.C., District of Columbia, 20007

Other trials in United States

France7 sites

Local Institution - 0061
Angers, 49933
Local Institution - 0064
Créteil, 94010
Local Institution - 0062
Marseille, 13273
Local Institution - 0059
Marseille, 13385
Local Institution - 0042
Paris, 75651
Local Institution - 0060
Reims, 51092
Local Institution - 0058
Vandœuvre-lès-Nancy, 54500

Other trials in France

Italy7 sites

Local Institution - 0032
Bologna, 40138
Local Institution - 0056
Florence, 50134
Local Institution - 0063
Meldola (FC), 47014
Local Institution - 0055
Milan, 20141
Local Institution - 0034
Naples, 80131
Local Institution - 0035
Padova, Padova
Local Institution - 0040
Rozzano, 20089

Other trials in Italy

Japan6 sites

Local Institution - 0036
Kashiwa-shi, Chiba, 2778577
Local Institution - 0038
Kurume-shi, Fukuoka, 8300011
Local Institution - 0050
Kyoto, Kyoto, 6028566
Local Institution - 0037
Ōsaka-sayama, Osaka, 5898511
Local Institution - 0051
Saga, 8408571
Local Institution - 0049
Yokohama, Kanagawa, 2320024

Other trials in Japan

United Kingdom6 sites

Local Institution - 0013
Birmingham, West Midlands, B15 2TH
Local Institution - 0012
Glasgow, Lanarkshire, G12 0YN
Local Institution - 0011
London, Greater London, SE19RT
Local Institution - 0010
London, NW3 2QG
Local Institution - 0014
Manchester, Greater Manchester, M20 4BX
Local Institution - 0015
Metropolitan Borough of Wirral, Merseyside, CH63 4JY

Other trials in United Kingdom

Germany4 sites

Local Institution - 0030
Essen, 45147
Local Institution - 0028
Frankfurt, 60590
Local Institution - 0029
Hanover, 30625
Local Institution - 0031
Heidelberg, 69120

Other trials in Germany

South Korea4 sites

Local Institution - 0066
Seoul, 02841
Local Institution - 0021
Seoul, 03080
Local Institution - 0026
Seoul, 05505
Local Institution - 0016
Seoul, 06351

Other trials in South Korea

Spain4 sites

Local Institution - 0019
Barcelona, 08036
Local Institution - 0020
Madrid, 28009
Local Institution - 0018
Madrid, 28050
Local Institution - 0003
Pamplona, 31008

Other trials in Spain

Canada3 sites

Local Institution - 0065
Halifax, Nova Scotia, B4H 2Y9
Local Institution - 0022
Montreal, Quebec, H2X 3E4
Local Institution - 0039
Toronto, Ontario, M5G 2M9

Other trials in Canada

Singapore3 sites

Local Institution - 0017
Singapore, 119074
Local Institution - 0009
Singapore, 168583
Local Institution - 0007
Singapore, 308433

Other trials in Singapore

Taiwan3 sites

Local Institution - 0027
Taipei, 100
Local Institution - 0024
Taipei, 112
Local Institution - 0023
Taoyuan, 333

Other trials in Taiwan

Hong Kong2 sites

Local Institution - 0005
Hong Kong, 0
Local Institution - 0006
Hong Kong

Other trials in Hong Kong

Puerto Rico1 site

Local Institution - 0070
San Juan, 00927

Other trials in Puerto Rico

About this study

Official title: A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab in Combination With Ipilimumab in Advanced Hepatocellular Carcinoma Subjects With or Without Chronic Viral Hepatitis; and a Randomized, Open-label Study of Nivolumab vs Sorafenib in Advanced Hepatocellular Carcinoma Subjects Who Are Naive to Systemic Therapy

The second part of the study is the Expansion Phase designed to generate additional clinical data at specified doses for each of the 3 cohorts. A third cohort has been added in this study to compare the efficacy of nivolumab and sorafenib in the treatment of Advanced HCC. A fourth cohort will generate data on the safety and efficacy of the combination nivolumab plus ipilimumab in the treatment of Advanced HCC. In the fifth cohort, additional clinical data will be generated for Child-Pugh B subjects. A Cabozantinib Combination Cohort has been added to evaluate the safety and tolerability of nivolumab in combination with cabozantinib and nivolumab with ipilimumab in combination with cabozantinib.

Read the detailed description

Study Classification: Pharmacokinetics/Pharmacodynamics

Conditions: Hepatocellular Carcinoma
Being tested: Nivolumab, Sorafenib, Ipilimumab, Cabozantinib
Medical subject headings: Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

NivolumabBiological
Also called BMS-936558
SorafenibDrug
IpilimumabDrug
CabozantinibDrug

Study groups in NCT01658878
Study group	Role	What they receive
Non-infected: Nivolumab	Experimental	Nivolumab intravenous solution on specific days Receives: Biological: Nivolumab
HCV-infected: Nivolumab	Experimental	Nivolumab intravenous solution on specific days Receives: Biological: Nivolumab
HBV-infected: Nivolumab	Experimental	Nivolumab intravenous solution on specific days Receives: Biological: Nivolumab
Nivolumab	Experimental	Nivolumab intravenous solution on specific days Receives: Biological: Nivolumab
Sorafenib	Active comparator	Sorafenib tablets on specific days Receives: Drug: Sorafenib
Nivolumab plus Ipilimumab Combination	Experimental	Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days Receives: Biological: Nivolumab; Drug: Ipilimumab
Child-Pugh B	Experimental	Nivolumab intravenous solution on specific days Receives: Biological: Nivolumab
Nivolumab plus Cabozantinib Combination	Experimental	Nivolumab intravenous solution + cabozantinib oral tablets on specific days Receives: Drug: Cabozantinib
Nivolumab plus Ipilimumab plus Cabozantinib	Experimental	Nivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days Receives: Drug: Cabozantinib

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With Adverse Events (AEs)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measured: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants With Serious Adverse Events (SAEs)
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, and requires inpatient hospitalization or causes prolongation of existing hospitalization.
Measured: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants With Adverse Events Leading to Discontinuation
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measured: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants Who Died
Number of participants who died during the study.
Measured: From first dose of study medication until study closure (Up to approximately 144 months)
Number of Participants With Laboratory Abnormalities in Specific Liver Tests
Participants with abnormalities in liver function tests related to potential drug-induced liver injury. Blood samples were collected and analyzed for liver function parameters, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Abnormalities were assessed relative to the upper limit of normal (ULN) for each parameter.
Abbreviations: ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; ULN = Upper Limit of Normal.
Measured: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests
Number of participants with thyroid-related laboratory abnormalities during the study. Blood samples were collected and analyzed for thyroid function markers (FT3, FT4). Abnormalities were assessed against LLN and ULN for each parameter.
Abbreviations: FT3 = Free T3; FT4 = Free T4; LLN = Lower Limit of Normal; ULN = Upper Limit of Normal; TSH = Thyroid Stimulating Hormone
Measured: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 2
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Objective Response Rate (ORR) by Investigator for Cohorts 3, 4, 5, and 6
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)

Secondary outcomes (19)

Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 1
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Number of Participants With Complete Response (CR) Assessed by Blinded Independent Central Review (BICR)
The number of participants whose best overall response (BOR) is CR in the population of interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
Measured: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to approximately 144 months after first dose
Disease Control Rate (DCR) Assessed by Blinded Independent Central Review (BICR)
The percentage of participants whose best overall response (BOR) is CR, PR or SD in the population of interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Failure to meet criteria for complete or partial response, in the absence of progressive disease. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Duration of Response (DOR) Assessed by Blinded Independent Central Review (BICR)
DOR is defined as the time from the first documented objective response (either complete or partial response) until the date of disease progression or death from any cause, whichever occurs first.
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: From first documented response to first documented progression or death, whichever occurs first (Up to approximately 144 months)
Time to Response (TTR) Assessed by Blinded Independent Central Review (BICR)
Time to Response (TTR) defined as the time from randomization to the date of the first confirmed CR or PR for Cohort 3, 4 and 6, and from the first dosing date of study medication to the date of the first confirmed CR or PR for cohort 1, 2 and 5.
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Measured: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of attainment of complete response (CR) or partial response (PR) (up to approximately 144 months)
Time to Progression (TTP) Assessed by Blinded Independent Central Review (BICR)
Time to Progression (TTP) is defined from the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of the first objectively documented disease progression. Participants who have not progressed as assessed by radiography will be censored at the last tumor assessment date prior to subsequent anti-cancer therapy. Participants who have no on-study tumor assessments were censored at the date of randomization.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Time to Progression (TTP) Rate Assessed by Blinded Independent Central Review (BICR)
TTP rate is defined as the percentage of participants without disease progression at select time points (milestones) during the study.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: At 6 and 12 months
Progression Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR)
PFS is defined as the time from randomization date or first dosing date of study medication to the date of the first objectively documented tumor progression or death due to any cause. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Measured: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to documented disease progression or death, whichever occurs first (up to approximately 144 months)
Overall Survival (OS)
OS is defined as the time from randomization date or first dosing date of study medication to the date of death (due to any cause). Participants who were alive were censored at the last known alive dates.
Measured: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of death or date last known alive (up to approximately 144 months)
Overall Survival (OS) Rate
OS rate is defined as the percentage of participants who are still alive at certain time points during the study.
Measured: At 6, 12, 24, 48 and 60 months
Maximum Observed Serum Concentration (Cmax)
Cmax is the maximum observed serum concentration.
Measured: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Time of Maximum Observed Serum Concentration (Tmax)
Tmax is the time taken to reach the maximum observed serum concentration (Cmax).
Measured: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Area Under the Serum Concentration Time Curve in the Dosing Interval [AUC(TAU)]
AUC (TAU) is the area measured under the concentration-time curve taken over the dosing interval.
Measured: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Serum Concentration Achieved at the End of Dosing Interval (Trough Concentration) (Ctrough)
Ctrough is the lowest observed serum concentration.
Measured: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Serum Concentration Achieved at the End of the Infusion (Ceoinf)
Serum Concentration Achieved at the End of the Infusion (Ceoinf) refers to the amount of drug present in the blood (serum) immediately after the completion of an infusion. It represents the concentration measured at the exact time the infusion ends, before any significant elimination or distribution occurs.
Measured: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Ratio of an Exposure Measure at Steady State to That After the First Dose (Exposure Measure Includes Cmax) (AI_Cmax)
AI_Cmax is ratio of an exposure measure at steady state to that after the first dose (exposure measure includes Cmax)
Measured: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Accumulation Index Ratio of AUC at Steady State to That After the First Dose (AI_AUC)
AI_AUC is accumulation index ratio of AUC at steady state to that after the first dose
Measured: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Effective T-Half (T-HALF)
Effective half-life is defined as the time it takes for the amount of a drug in the body to decrease by half.
Measured: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Number of Participants With Anti-drug Antibodies (ADA)
Baseline ADA Positive: Participant with baseline ADA-positive sample ADA Positive: Participant with at least one ADA-positive sample relative to baseline Persistent Positive (PP): ADA-positive sample at 2 or more consecutive timepoints Not PP-Last Sample Positive: Not persistent but with ADA-positive sample at the last sampling timepoint Other Positive: Not persistent but some ADA-positive samples with the last sample being negative ADA Negative: Participant with no ADA-positive sample after initiation of treatment
Measured: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

30 Oct 201212 Nov 2024

First posted7 Aug 2012 (estimated)
Study start30 Oct 2012
Primary completion12 Nov 2024
Study completion12 Nov 2024

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 (8)Papers the sponsor has linked to this study.
Other trials for Hepatocellular CarcinomaStudies 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 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 657 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01658878
Sponsor's protocol ID: CA209-040
Other IDs: 2012-001514-42
Acronym: CheckMate040
Status last verified: Dec 2025
First submitted: 3 Aug 2012
Last updated: 24 Dec 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

Zhou X, Cao J, Topatana W, Xie T, Chen T, Hu J, Li S, Juengpanic S, Lu Z, Zhang B, Wang K, Feng X, Shen J, Chen M. Evaluation of PD-L1 as a biomarker for immunotherapy for hepatocellular carcinoma: systematic review and meta-analysis. Immunotherapy. 2023 Apr;15(5):353-365. doi: 10.2217/imt-2022-0168. Epub 2023 Feb 27.
PubMed 36852452
Yau T, Zagonel V, Santoro A, Acosta-Rivera M, Choo SP, Matilla A, He AR, Cubillo Gracian A, El-Khoueiry AB, Sangro B, Eldawy TE, Bruix J, Frassineti GL, Vaccaro GM, Tschaika M, Scheffold C, Koopmans P, Neely J, Piscaglia F. Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. J Clin Oncol. 2023 Mar 20;41(9):1747-1757. doi: 10.1200/JCO.22.00972. Epub 2022 Dec 13.
PubMed 36512738
Sove RJ, Verma BK, Wang H, Ho WJ, Yarchoan M, Popel AS. Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model. J Immunother Cancer. 2022 Nov;10(11):e005414. doi: 10.1136/jitc-2022-005414.
PubMed 36323435
Kudo M, Matilla A, Santoro A, Melero I, Gracian AC, Acosta-Rivera M, Choo SP, El-Khoueiry AB, Kuromatsu R, El-Rayes B, Numata K, Itoh Y, Di Costanzo F, Crysler O, Reig M, Shen Y, Neely J, Tschaika M, Wisniewski T, Sangro B. CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol. 2021 Sep;75(3):600-609. doi: 10.1016/j.jhep.2021.04.047. Epub 2021 May 26.
PubMed 34051329
Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020 Nov 1;6(11):e204564. doi: 10.1001/jamaoncol.2020.4564. Epub 2020 Nov 12.
PubMed 33001135
Sangro B, Melero I, Wadhawan S, Finn RS, Abou-Alfa GK, Cheng AL, Yau T, Furuse J, Park JW, Boyd Z, Tang HT, Shen Y, Tschaika M, Neely J, El-Khoueiry A. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol. 2020 Dec;73(6):1460-1469. doi: 10.1016/j.jhep.2020.07.026. Epub 2020 Jul 22.
PubMed 32710922
Yau T, Hsu C, Kim TY, Choo SP, Kang YK, Hou MM, Numata K, Yeo W, Chopra A, Ikeda M, Kuromatsu R, Moriguchi M, Chao Y, Zhao H, Anderson J, Cruz CD, Kudo M. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis. J Hepatol. 2019 Sep;71(3):543-552. doi: 10.1016/j.jhep.2019.05.014. Epub 2019 Jun 7.
PubMed 31176752
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.
PubMed 28434648

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RecruitingPhase 2/3
A Study of VRT106, Combined With Camrelizumab, and Apatinib for Advanced HCC
HCC
Not yet recruitingObservational study
A Post Approval Study to Evaluate Safety and Effectiveness of Multicompartmental Dosimetry Planning.
Hepatocellular Carcinoma (HCC)
Active, not recruitingPhase 2
TheraSphere With Durvalumab and Tremelimumab for HCC
Hepatocellular Carcinoma
RecruitingPhase 1
A DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Glutamine Antagonist DRP-104, Nivolumab, and Ipilimumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC)
Liver Cancer (Fibrolamellar Hepatocellular Cancer (FLC))
RecruitingPhase 2
DB-1311 in Combination With BNT327 or DB-1305 in Advanced/Metastatic Solid Tumors
Solid Tumors

All Hepatocellular Carcinoma trials

Study at a glance

From the registry record, last updated by the sponsor on 24 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab in Combination With Ipilimumab in Advanced Hepatocellular Carcinoma Subjects With or Without Chronic Viral Hepatitis; and a Randomized, Open-label Study of Nivolumab vs Sorafenib in Advanced Hepatocellular Carcinoma Subjects Who Are Naive to Systemic Therapy
ClinicalTrials.gov ID: NCT01658878
Acronym / sponsor ID: CheckMate040 / CA209-040
Conditions: Hepatocellular Carcinoma
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 657 participants (actual)
Lead sponsor: Bristol-Myers SquibbIndustry (pharma, biotech, devices)
Collaborators: Ono Pharmaceutical Co., Ltd.
Study start: 30 Oct 2012 (actual)
Primary completion: 12 Nov 2024 (actual)
Study completion: 12 Nov 2024 (actual)
First posted: 7 Aug 2012 (estimated)
Results: Posted 24 Dec 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study Classification: Pharmacokinetics/Pharmacodynamics

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 9

Arm	Type	Receives
Non-infected: Nivolumab	Experimental	Biological: NivolumabNivolumab intravenous solution on specific days
HCV-infected: Nivolumab	Experimental	Biological: NivolumabNivolumab intravenous solution on specific days
HBV-infected: Nivolumab	Experimental	Biological: NivolumabNivolumab intravenous solution on specific days
Nivolumab	Experimental	Biological: NivolumabNivolumab intravenous solution on specific days
Sorafenib	Active comparator	Drug: SorafenibSorafenib tablets on specific days
Nivolumab plus Ipilimumab Combination	Experimental	Biological: Nivolumab, Drug: IpilimumabNivolumab intravenous solution + Ipilimumab intravenous solution on specific days
Child-Pugh B	Experimental	Biological: NivolumabNivolumab intravenous solution on specific days
Nivolumab plus Cabozantinib Combination	Experimental	Drug: CabozantinibNivolumab intravenous solution + cabozantinib oral tablets on specific days
Nivolumab plus Ipilimumab plus Cabozantinib	Experimental	Drug: CabozantinibNivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Subjects of 18 years or older (men and women) with histologically confirmed advanced hepatocellular carcinoma, not eligible for surgical and/or locoregional therapies; or progressive disease after surgical and /or locoregional therapies
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
Dose Escalation Phase: Child-Pugh score of 7 points or less. Cohort 5: Child-Pugh Class B (B7-B8). For all other cohorts Child-Pugh score of 6 points or less

Key exclusion criteria (3 listed)

History of autoimmune disease
Any prior or current clinically significant ascites
Any history of hepatic encephalopathy

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
NivolumabAlso: BMS-936558	Biological	Child-Pugh B, HBV-infected: Nivolumab, HCV-infected: Nivolumab, Nivolumab, Nivolumab plus Ipilimumab Combination, Non-infected: Nivolumab
Sorafenib	Drug	Sorafenib
Ipilimumab	Drug	Nivolumab plus Ipilimumab Combination
Cabozantinib	Drug	Nivolumab plus Cabozantinib Combination, Nivolumab plus Ipilimumab plus Cabozantinib

Primary outcome

Number of Participants With Adverse Events (AEs)
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Number of Participants With Serious Adverse Events (SAEs)
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, and requires inpatient hospitalization or causes prolongation of existing hospitalization.
Number of Participants With Adverse Events Leading to Discontinuation
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Number of Participants Who Died
Time frame: From first dose of study medication until study closure (Up to approximately 144 months)
Number of participants who died during the study.
Number of Participants With Laboratory Abnormalities in Specific Liver Tests
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Participants with abnormalities in liver function tests related to potential drug-induced liver injury. Blood samples were collected and analyzed for liver function parameters, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Abnormalities were assessed relative to the upper limit of normal (ULN) for each parameter. Abbreviations: ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; ULN = Upper Limit of Normal.
Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of participants with thyroid-related laboratory abnormalities during the study. Blood samples were collected and analyzed for thyroid function markers (FT3, FT4). Abnormalities were assessed against LLN and ULN for each parameter. Abbreviations: FT3 = Free T3; FT4 = Free T4; LLN = Lower Limit of Normal; ULN = Upper Limit of Normal; TSH = Thyroid Stimulating Hormone
Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 2
Time frame: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Objective Response Rate (ORR) by Investigator for Cohorts 3, 4, 5, and 6
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).

19 secondary outcomes

Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 1
Time frame: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Number of Participants With Complete Response (CR) Assessed by Blinded Independent Central Review (BICR)
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to approximately 144 months after first dose
Disease Control Rate (DCR) Assessed by Blinded Independent Central Review (BICR)
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Duration of Response (DOR) Assessed by Blinded Independent Central Review (BICR)
Time frame: From first documented response to first documented progression or death, whichever occurs first (Up to approximately 144 months)
Time to Response (TTR) Assessed by Blinded Independent Central Review (BICR)
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of attainment of complete response (CR) or partial response (PR) (up to approximately 144 months)
Time to Progression (TTP) Assessed by Blinded Independent Central Review (BICR)
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Time to Progression (TTP) Rate Assessed by Blinded Independent Central Review (BICR)
Time frame: At 6 and 12 months
Progression Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR)
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to documented disease progression or death, whichever occurs first (up to approximately 144 months)
Overall Survival (OS)
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of death or date last known alive (up to approximately 144 months)
Overall Survival (OS) Rate
Time frame: At 6, 12, 24, 48 and 60 months
Maximum Observed Serum Concentration (Cmax)
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Time of Maximum Observed Serum Concentration (Tmax)
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Area Under the Serum Concentration Time Curve in the Dosing Interval [AUC(TAU)]
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Serum Concentration Achieved at the End of Dosing Interval (Trough Concentration) (Ctrough)
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Serum Concentration Achieved at the End of the Infusion (Ceoinf)
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Ratio of an Exposure Measure at Steady State to That After the First Dose (Exposure Measure Includes Cmax) (AI_Cmax)
Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Accumulation Index Ratio of AUC at Steady State to That After the First Dose (AI_AUC)
Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Effective T-Half (T-HALF)
Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Number of Participants With Anti-drug Antibodies (ADA)
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)

Results and safety

Results posted to the registry on 24 Dec 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Cohort 1 Uninfected HCC: Treatment 1	1	1
Cohort 1 Uninfected HCC: Treatment 2	3	3
Cohort 1 Uninfected HCC: Treatment 3	3	3
Cohort 1 Uninfected HCC: Treatment 4	3	3
Cohort 1 Uninfected HCC: Treatment 5	13	13
Cohort 1 HCV Infected: Treatment 6	3	3
Cohort 1 HCV Infected: Treatment 7	4	4
Cohort 1 HCV Infected: Treatment 8	3	3
Cohort 1 HBV Infected: Treatment 9	5	5
Cohort 1 HBV Infected: Treatment 10	3	3
Cohort 1 HBV Infected: Treatment 11	3	3
Cohort 1 HBV Infected: Treatment 12	4	4
Cohort 2 Uninfected Sorafenib Naive/Intolerant: Treatment 1	56	56
Cohort 2 Uninfected Sorafenib Progressors: Treatment 2	57	57
Cohort 2 HCV Infected: Treatment 3	50	50
Cohort 2 HBV Infected: Treatment 4	51	51
Cohort 3: Treatment 1	61	60
Cohort 3: Treatment 2	66	62
Cohort 4: Treatment 1	50	49
Cohort 4: Treatment 2	49	49
Cohort 4: Treatment 3	49	48
Cohort 5: Treatment 1	49	49
Cohort 6: Treatment 1	36	36
Cohort 6: Treatment 2	35	35

Primary outcome: Number of Participants With Adverse Events (AEs)

Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months). Count of participants. Unit: Participants

Measure	Cohort 1 Uninfected HCC: Treatment 1 n = 1	Cohort 1 Uninfected HCC: Treatment 2 n = 3	Cohort 1 Uninfected HCC: Treatment 3 n = 3	Cohort 1 Uninfected HCC: Treatment 4 n = 3	Cohort 1 Uninfected HCC: Treatment 5 n = 13	Cohort 1 HCV Infected: Treatment 6 n = 3	Cohort 1 HCV Infected: Treatment 7 n = 4	Cohort 1 HCV Infected: Treatment 8 n = 3	Cohort 1 HBV Infected: Treatment 9 n = 5	Cohort 1 HBV Infected: Treatment 10 n = 3	Cohort 1 HBV Infected: Treatment 11 n = 3	Cohort 1 HBV Infected: Treatment 12 n = 4	Cohort 2 Uninfected Sorafenib Naive/Intolerant: Treatment 1 n = 56	Cohort 2 Uninfected Sorafenib Progressors: Treatment 2 n = 57	Cohort 2 HCV Infected: Treatment 3 n = 50	Cohort 2 HBV Infected: Treatment 4 n = 51	Cohort 3: Treatment 1 n = 60	Cohort 3: Treatment 2 n = 62	Cohort 4: Treatment 1 n = 49	Cohort 4: Treatment 2 n = 49	Cohort 4: Treatment 3 n = 48	Cohort 5: Treatment 1 n = 49	Cohort 6: Treatment 1 n = 36	Cohort 6: Treatment 2 n = 35
Value	1	3	3	3	13	3	4	3	5	3	3	4	56	56	50	51	58	59	48	47	48	47	36	35

Population analysed: All treated participants

Primary outcome: Number of Participants With Serious Adverse Events (SAEs)

Measure	Cohort 1 Uninfected HCC: Treatment 1 n = 1	Cohort 1 Uninfected HCC: Treatment 2 n = 3	Cohort 1 Uninfected HCC: Treatment 3 n = 3	Cohort 1 Uninfected HCC: Treatment 4 n = 3	Cohort 1 Uninfected HCC: Treatment 5 n = 13	Cohort 1 HCV Infected: Treatment 6 n = 3	Cohort 1 HCV Infected: Treatment 7 n = 4	Cohort 1 HCV Infected: Treatment 8 n = 3	Cohort 1 HBV Infected: Treatment 9 n = 5	Cohort 1 HBV Infected: Treatment 10 n = 3	Cohort 1 HBV Infected: Treatment 11 n = 3	Cohort 1 HBV Infected: Treatment 12 n = 4	Cohort 2 Uninfected Sorafenib Naive/Intolerant: Treatment 1 n = 56	Cohort 2 Uninfected Sorafenib Progressors: Treatment 2 n = 57	Cohort 2 HCV Infected: Treatment 3 n = 50	Cohort 2 HBV Infected: Treatment 4 n = 51	Cohort 3: Treatment 1 n = 60	Cohort 3: Treatment 2 n = 62	Cohort 4: Treatment 1 n = 49	Cohort 4: Treatment 2 n = 49	Cohort 4: Treatment 3 n = 48	Cohort 5: Treatment 1 n = 49	Cohort 6: Treatment 1 n = 36	Cohort 6: Treatment 2 n = 35
Value	0	1	2	0

Primary outcome: Number of Participants With Adverse Events Leading to Discontinuation

Measure	Cohort 1 Uninfected HCC: Treatment 1 n = 1	Cohort 1 Uninfected HCC: Treatment 2 n = 3	Cohort 1 Uninfected HCC: Treatment 3 n = 3	Cohort 1 Uninfected HCC: Treatment 4 n = 3	Cohort 1 Uninfected HCC: Treatment 5 n = 13	Cohort 1 HCV Infected: Treatment 6 n = 3	Cohort 1 HCV Infected: Treatment 7 n = 4	Cohort 1 HCV Infected: Treatment 8 n = 3	Cohort 1 HBV Infected: Treatment 9 n = 5	Cohort 1 HBV Infected: Treatment 10 n = 3	Cohort 1 HBV Infected: Treatment 11 n = 3	Cohort 1 HBV Infected: Treatment 12 n = 4	Cohort 2 Uninfected Sorafenib Naive/Intolerant: Treatment 1 n = 56	Cohort 2 Uninfected Sorafenib Progressors: Treatment 2 n = 57	Cohort 2 HCV Infected: Treatment 3 n = 50	Cohort 2 HBV Infected: Treatment 4 n = 51	Cohort 3: Treatment 1 n = 60	Cohort 3: Treatment 2 n = 62	Cohort 4: Treatment 1 n = 49	Cohort 4: Treatment 2 n = 49	Cohort 4: Treatment 3 n = 48	Cohort 5: Treatment 1 n = 49	Cohort 6: Treatment 1 n = 36	Cohort 6: Treatment 2 n = 35
Value	0	0	0

Primary outcome: Number of Participants Who Died

Time frame: From first dose of study medication until study closure (Up to approximately 144 months). Count of participants. Unit: Participants

Measure	Cohort 1 Uninfected HCC: Treatment 1 n = 1	Cohort 1 Uninfected HCC: Treatment 2 n = 3	Cohort 1 Uninfected HCC: Treatment 3 n = 3	Cohort 1 Uninfected HCC: Treatment 4 n = 3	Cohort 1 Uninfected HCC: Treatment 5 n = 13	Cohort 1 HCV Infected: Treatment 6 n = 3	Cohort 1 HCV Infected: Treatment 7 n = 4	Cohort 1 HCV Infected: Treatment 8 n = 3	Cohort 1 HBV Infected: Treatment 9 n = 5	Cohort 1 HBV Infected: Treatment 10 n = 3	Cohort 1 HBV Infected: Treatment 11 n = 3	Cohort 1 HBV Infected: Treatment 12 n = 4	Cohort 2 Uninfected Sorafenib Naive/Intolerant: Treatment 1 n = 56	Cohort 2 Uninfected Sorafenib Progressors: Treatment 2 n = 57	Cohort 2 HCV Infected: Treatment 3 n = 50	Cohort 2 HBV Infected: Treatment 4 n = 51	Cohort 3: Treatment 1 n = 60	Cohort 3: Treatment 2 n = 62	Cohort 4: Treatment 1 n = 49	Cohort 4: Treatment 2 n = 49	Cohort 4: Treatment 3 n = 48	Cohort 5: Treatment 1 n = 49	Cohort 6: Treatment 1 n = 36	Cohort 6: Treatment 2 n = 35
Value	1	3	2	2	13	1	4	3	5	3

19 secondary outcomes are reported in the full results.

Adverse events

Time frame: Participants were assessed for All-Cause Mortality from the date of their randomization (Cohorts 3, 4, and 6) or first dose (Cohorts 1, 2, and 5) until study completion (assessed up to approximately 144 months). SAEs and Other AEs were assessed from first dose of study medication through 100 days following last dose of study treatment (Assessed for approximately 04 months up to a max of approximately 106 months).. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Cohort 1 Uninfected HCC: Treatment 1	0 of 1 (0%)	1 of 1 (100%)	1 of 1
Cohort 1 Uninfected HCC: Treatment 2	1 of 3 (33.3%)	3 of 3 (100%)	3 of 3
Cohort 1 Uninfected HCC: Treatment 3	2 of 3 (66.7%)	3 of 3 (100%)	2 of 3
Cohort 1 Uninfected HCC: Treatment 4	0 of 3 (0%)	3 of 3 (100%)	2 of 3
Cohort 1 Uninfected HCC: Treatment 5	8 of 13 (61.5%)	13 of 13 (100%)	13 of 13
Cohort 1 HCV Infected: Treatment 6	0 of 3 (0%)	3 of 3 (100%)	1 of 3
Cohort 1 HCV Infected: Treatment 7	3 of 4 (75%)	4 of 4 (100%)	4 of 4
Cohort 1 HCV Infected: Treatment 8	1 of 3 (33.3%)	3 of 3 (100%)	3 of 3
Cohort 1 HBV Infected: Treatment 9	5 of 5 (100%)	5 of 5 (100%)	5 of 5
Cohort 1 HBV Infected: Treatment 10	3 of 3 (100%)	3 of 3 (100%)	3 of 3
Cohort 1 HBV Infected: Treatment 11	1 of 3 (33.3%)	3 of 3 (100%)	3 of 3
Cohort 1 HBV Infected: Treatment 12	3 of 4 (75%)	4 of 4 (100%)	4 of 4
Cohort 2: Nivolumab 3 mg/kg	137 of 214 (64%)	210 of 214 (98.1%)	186 of 214
Cohort 3: Treatment 1	35 of 60 (58.3%)	55 of 60 (91.7%)	52 of 61
Cohort 3: Treatment 2	33 of 62 (53.2%)	57 of 62 (91.9%)	53 of 66
Cohort 4: Treatment 1	35 of 49 (71.4%)

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 24 Dec 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 36852452Zhou X, Cao J, Topatana W, Xie T, Chen T, Hu J, Li S, Juengpanic S, Lu Z, Zhang B, Wang K, Feng X, Shen J, Chen M. Evaluation of PD-L1 as a biomarker for immunotherapy for hepatocellular carcinoma: systematic review and meta-analysis. Immunotherapy. 2023 Apr;15(5):353-365. doi: 10.2217/imt-2022-0168. Epub 2023 Feb 27.
Derived from this study: PubMed 36512738Yau T, Zagonel V, Santoro A, Acosta-Rivera M, Choo SP, Matilla A, He AR, Cubillo Gracian A, El-Khoueiry AB, Sangro B, Eldawy TE, Bruix J, Frassineti GL, Vaccaro GM, Tschaika M, Scheffold C, Koopmans P, Neely J, Piscaglia F. Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. J Clin Oncol. 2023 Mar 20;41(9):1747-1757. doi: 10.1200/JCO.22.00972. Epub 2022 Dec 13.
Derived from this study: PubMed 36323435Sove RJ, Verma BK, Wang H, Ho WJ, Yarchoan M, Popel AS. Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model. J Immunother Cancer. 2022 Nov;10(11):e005414. doi: 10.1136/jitc-2022-005414.
Derived from this study: PubMed 34051329Kudo M, Matilla A, Santoro A, Melero I, Gracian AC, Acosta-Rivera M, Choo SP, El-Khoueiry AB, Kuromatsu R, El-Rayes B, Numata K, Itoh Y, Di Costanzo F, Crysler O, Reig M, Shen Y, Neely J, Tschaika M, Wisniewski T, Sangro B. CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol. 2021 Sep;75(3):600-609. doi: 10.1016/j.jhep.2021.04.047. Epub 2021 May 26.
Derived from this study: PubMed 33001135Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020 Nov 1;6(11):e204564. doi: 10.1001/jamaoncol.2020.4564. Epub 2020 Nov 12.
Derived from this study: PubMed 32710922Sangro B, Melero I, Wadhawan S, Finn RS, Abou-Alfa GK, Cheng AL, Yau T, Furuse J, Park JW, Boyd Z, Tang HT, Shen Y, Tschaika M, Neely J, El-Khoueiry A. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol. 2020 Dec;73(6):1460-1469. doi: 10.1016/j.jhep.2020.07.026. Epub 2020 Jul 22.
Derived from this study: PubMed 31176752Yau T, Hsu C, Kim TY, Choo SP, Kang YK, Hou MM, Numata K, Yeo W, Chopra A, Ikeda M, Kuromatsu R, Moriguchi M, Chao Y, Zhao H, Anderson J, Cruz CD, Kudo M. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis. J Hepatol. 2019 Sep;71(3):543-552. doi: 10.1016/j.jhep.2019.05.014. Epub 2019 Jun 7.
Derived from this study: PubMed 28434648El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.
BMS Clinical Trial InformationLink provided by the sponsor.
BMS Clinical Trial Patient RecruitingLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Bristol-Myers Squibb study director

Bristol-Myers Squibb

60 sites in 13 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Nivolumab, Sorafenib and Ipilimumab in people with Hepatocellular Carcinoma, run by Bristol-Myers Squibb at 60 sites in 13 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 60 sites in United States, France, Italy, Japan, United Kingdom and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Dec 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Adverse Events (AEs) (time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01658878, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Dec 2025.