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 (CheckMate040)

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 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).

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Ipilimumab; Drug: Sorafenib; Biological: Nivolumab; Drug: Cabozantinib

Detailed Description

Study Classification: Pharmacokinetics/Pharmacodynamics

• Study Type: Interventional
• Enrollment (Actual): 657
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B4H 2Y9
      • Local Institution - 0065
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution - 0039
  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • Local Institution - 0022
• France
  • Angers, France, 49933
    • Local Institution - 0061
  • Créteil, France, 94010
    • Local Institution - 0064
  • Marseille, France, 13273
    • Local Institution - 0062
  • Marseille, France, 13385
    • Local Institution - 0059
  • Paris, France, 75651
    • Local Institution - 0042
  • Reims, France, 51092
    • Local Institution - 0060
  • Vandœuvre-lès-Nancy, France, 54500
    • Local Institution - 0058
• Germany
  • Essen, Germany, 45147
    • Local Institution - 0030
  • Frankfurt, Germany, 60590
    • Local Institution - 0028
  • Hanover, Germany, 30625
    • Local Institution - 0029
  • Heidelberg, Germany, 69120
    • Local Institution - 0031
• Hong Kong
  • Hong Kong, Hong Kong
    • Local Institution - 0005
  • Hong Kong, Hong Kong
    • Local Institution - 0006
• Italy
  • Bologna, Italy, 40138
    • Local Institution - 0032
  • Florence, Italy, 50134
    • Local Institution - 0056
  • Meldola (FC), Italy, 47014
    • Local Institution - 0063
  • Milan, Italy, 20141
    • Local Institution - 0055
  • Napoli, Italy, 80131
    • Local Institution - 0034
  • Padua, Italy, Padova
    • Local Institution - 0035
  • Rozzano, Italy, 20089
    • Local Institution - 0040
• Japan
  • Saga, Japan, 8408571
    • Local Institution - 0051
  • Chiba
    • Kashiwa-shi, Chiba, Japan, 2778577
      • Local Institution - 0036
  • Fukuoka
    • Kurume-shi, Fukuoka, Japan, 8300011
      • Local Institution - 0038
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 2320024
      • Local Institution - 0049
  • Kyoto
    • Kyoto, Kyoto, Japan, 6028566
      • Local Institution - 0050
  • Osaka
    • Ōsaka-sayama, Osaka, Japan, 5898511
      • Local Institution - 0037
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Local Institution - 0070
• Singapore
  • Singapore, Singapore, 119074
    • Local Institution - 0017
  • Singapore, Singapore, 168583
    • Local Institution - 0009
  • Singapore, Singapore, 308433
    • Local Institution - 0007
• South Korea
  • Seoul, South Korea, 02841
    • Local Institution - 0066
  • Seoul, South Korea, 03080
    • Local Institution - 0021
  • Seoul, South Korea, 05505
    • Local Institution - 0026
  • Seoul, South Korea, 06351
    • Local Institution - 0016
• Spain
  • Barcelona, Spain, 08036
    • Local Institution - 0019
  • Madrid, Spain, 28050
    • Local Institution - 0018
  • Madrid, Spain, 28009
    • Local Institution - 0020
  • Pamplona, Spain, 31008
    • Local Institution - 0003
• Taiwan
  • Taipei, Taiwan, 100
    • Local Institution - 0027
  • Taipei, Taiwan, 112
    • Local Institution - 0024
  • Taoyuan District, Taiwan, 333
    • Local Institution - 0023
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Local Institution - 0010
  • Greater London
    • London, Greater London, United Kingdom, SE19RT
      • Local Institution - 0011
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • Local Institution - 0014
  • Lanarkshire
    • Glasgow, Lanarkshire, United Kingdom, G12 0YN
      • Local Institution - 0012
  • Merseyside
    • Metropolitan Borough of Wirral, Merseyside, United Kingdom, CH63 4JY
      • Local Institution - 0015
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Local Institution - 0013
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Local Institution - 0008
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Local Institution - 0048
  • Florida
    • Pensacola, Florida, United States, 32504
      • Local Institution - 0053
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Local Institution - 0047
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Local Institution - 0025
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5331
      • Local Institution - 0002
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Local Institution - 0054
    • Paterson, New Jersey, United States, 07503
      • Local Institution - 0067
  • Oregon
    • Portland, Oregon, United States, 97213
      • Local Institution - 0001
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

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

Inclusion Criteria:

• 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

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non-infected: Nivolumab; Nivolumab intravenous solution on specific days	Biological: Nivolumab; Other Names: BMS-936558
Experimental: HCV-infected: Nivolumab; Nivolumab intravenous solution on specific days	Biological: Nivolumab; Other Names: BMS-936558
Experimental: HBV-infected: Nivolumab; Nivolumab intravenous solution on specific days	Biological: Nivolumab; Other Names: BMS-936558
Experimental: Nivolumab; Nivolumab intravenous solution on specific days	Biological: Nivolumab; Other Names: BMS-936558
Active Comparator: Sorafenib; Sorafenib tablets on specific days	Drug: Sorafenib
Experimental: Nivolumab plus Ipilimumab Combination; Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days	Drug: Ipilimumab; Biological: Nivolumab; Other Names: BMS-936558
Experimental: Child-Pugh B; Nivolumab intravenous solution on specific days	Biological: Nivolumab; Other Names: BMS-936558
Experimental: Nivolumab plus Cabozantinib Combination; Nivolumab intravenous solution + cabozantinib oral tablets on specific days	Drug: Cabozantinib
Experimental: Nivolumab plus Ipilimumab plus Cabozantinib; Nivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days	Drug: Cabozantinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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	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).	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).	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	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).	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).	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.	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).	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).	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).	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.	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.	At 6, 12, 24, 48 and 60 months
Maximum Observed Serum Concentration (Cmax)	Cmax is the maximum observed serum concentration.	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).	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.	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.	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.	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)	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	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.	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	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)

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

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2012
• Primary Completion (Actual): November 12, 2024
• Study Completion (Actual): November 12, 2024

Study Registration Dates

• First Submitted: August 3, 2012
• First Submitted That Met QC Criteria: August 3, 2012
• First Posted (Estimated): August 7, 2012

Study Record Updates

• Last Update Posted (Estimated): December 24, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Benzene Derivatives; Urea; Acids, Heterocyclic; Phenylurea Compounds; Niacinamide; Nicotinic Acids; Sorafenib; Nivolumab; Ipilimumab; cabozantinib
• Other Study ID Numbers: CA209-040; 2012-001514-42 (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