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

NCT01658878 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: CA209-0402012-001514-42
• Study Type: interventional
• Target: 657
• Locations: 13 countries
• Sites: 60

Brief 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). 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.

Conditions

Hepatocellular Carcinoma

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (19)

• Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 1

  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)

  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)

  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)

  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)

  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)

Study Arms (9)

Non-infected: Nivolumab

EXPERIMENTAL

Nivolumab intravenous solution on specific days

Biological: Nivolumab

HCV-infected: Nivolumab

EXPERIMENTAL

Nivolumab intravenous solution on specific days

Biological: Nivolumab

HBV-infected: Nivolumab

EXPERIMENTAL

Nivolumab intravenous solution on specific days

Biological: Nivolumab

Nivolumab

EXPERIMENTAL

Nivolumab intravenous solution on specific days

Biological: Nivolumab

Sorafenib

ACTIVE COMPARATOR

Sorafenib tablets on specific days

Drug: Sorafenib

Nivolumab plus Ipilimumab Combination

EXPERIMENTAL

Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days

Biological: Nivolumab; Drug: Ipilimumab

Child-Pugh B

EXPERIMENTAL

Nivolumab intravenous solution on specific days

Biological: Nivolumab

Nivolumab plus Cabozantinib Combination

EXPERIMENTAL

Nivolumab intravenous solution + cabozantinib oral tablets on specific days

Drug: Cabozantinib

Nivolumab plus Ipilimumab plus Cabozantinib

EXPERIMENTAL

Nivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days

Drug: Cabozantinib

Interventions

Nivolumab BIOLOGICAL

Also known as: BMS-936558

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Bristol-Myers Squibb: lead
• Ono Pharmaceutical Co. Ltd: collaborator

Study Sites (60)

Local Institution - 0008

Los Angeles, California, 90033, United States

Location

Local Institution - 0048

Washington D.C., District of Columbia, 20007, United States

Location

Local Institution - 0053

Pensacola, Florida, 32504, United States

Location

Local Institution - 0047

Atlanta, Georgia, 30322, United States

Location

Local Institution - 0025

Boston, Massachusetts, 02114, United States

Location

Local Institution - 0002

Ann Arbor, Michigan, 48109-5331, United States

Location

Local Institution - 0054

Hackensack, New Jersey, 07601, United States

Location

Local Institution - 0067

Paterson, New Jersey, 07503, United States

Location

Local Institution - 0001

Portland, Oregon, 97213, United States

Location

The University Of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Local Institution - 0065

Halifax, Nova Scotia, B4H 2Y9, Canada

Location

Local Institution - 0039

Toronto, Ontario, M5G 2M9, Canada

Location

Local Institution - 0022

Montreal, Quebec, H2X 3E4, Canada

Location

Local Institution - 0061

Angers, 49933, France

Location

Local Institution - 0064

Créteil, 94010, France

Location

Local Institution - 0062

Marseille, 13273, France

Location

Local Institution - 0059

Marseille, 13385, France

Location

Local Institution - 0042

Paris, 75651, France

Location

Local Institution - 0060

Reims, 51092, France

Location

Local Institution - 0058

Vandœuvre-lès-Nancy, 54500, France

Location

Local Institution - 0030

Essen, 45147, Germany

Location

Local Institution - 0028

Frankfurt, 60590, Germany

Location

Local Institution - 0029

Hanover, 30625, Germany

Location

Local Institution - 0031

Heidelberg, 69120, Germany

Location

Local Institution - 0005

Hong Kong, 0, Hong Kong

Location

Local Institution - 0006

Hong Kong, Hong Kong

Location

Local Institution - 0032

Bologna, 40138, Italy

Location

Local Institution - 0056

Florence, 50134, Italy

Location

Local Institution - 0063

Meldola (FC), 47014, Italy

Location

Local Institution - 0055

Milan, 20141, Italy

Location

Local Institution - 0034

Naples, 80131, Italy

Location

Local Institution - 0035

Padua, Padova, Italy

Location

Local Institution - 0040

Rozzano, 20089, Italy

Location

Local Institution - 0036

Kashiwa-shi, Chiba, 2778577, Japan

Location

Local Institution - 0038

Kurume-shi, Fukuoka, 8300011, Japan

Location

Local Institution - 0049

Yokohama, Kanagawa, 2320024, Japan

Location

Local Institution - 0050

Kyoto, Kyoto, 6028566, Japan

Location

Local Institution - 0037

Ōsaka-sayama, Osaka, 5898511, Japan

Location

Local Institution - 0051

Saga, 8408571, Japan

Location

Local Institution - 0070

San Juan, 00927, Puerto Rico

Location

Local Institution - 0017

Singapore, 119074, Singapore

Location

Local Institution - 0009

Singapore, 168583, Singapore

Location

Local Institution - 0007

Singapore, 308433, Singapore

Location

Local Institution - 0066

Seoul, 02841, South Korea

Location

Local Institution - 0021

Seoul, 03080, South Korea

Location

Local Institution - 0026

Seoul, 05505, South Korea

Location

Local Institution - 0016

Seoul, 06351, South Korea

Location

Local Institution - 0019

Barcelona, 08036, Spain

Location

Local Institution - 0020

Madrid, 28009, Spain

Location

Local Institution - 0018

Madrid, 28050, Spain

Location

Local Institution - 0003

Pamplona, 31008, Spain

Location

Local Institution - 0027

Taipei, 100, Taiwan

Location

Local Institution - 0024

Taipei, 112, Taiwan

Location

Local Institution - 0023

Taoyuan District, 333, Taiwan

Location

Local Institution - 0011

London, Greater London, SE19RT, United Kingdom

Location

Local Institution - 0014

Manchester, Greater Manchester, M20 4BX, United Kingdom

Location

Local Institution - 0012

Glasgow, Lanarkshire, G12 0YN, United Kingdom

Location

Local Institution - 0015

Metropolitan Borough of Wirral, Merseyside, CH63 4JY, United Kingdom

Location

Local Institution - 0013

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Local Institution - 0010

London, NW3 2QG, United Kingdom

Location

Related Publications (8)

• 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.

  PMID: 36852452 DERIVED

• 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.

  PMID: 36512738 DERIVED

• 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.

  PMID: 36323435 DERIVED

• 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.

  PMID: 34051329 DERIVED

• 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.

  PMID: 33001135 DERIVED

• 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.

  PMID: 32710922 DERIVED

• 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.

  PMID: 31176752 DERIVED

• 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.

  PMID: 28434648 DERIVED

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Nivolumab; Sorafenib; Ipilimumab; cabozantinib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 3, 2012
• First Posted: August 7, 2012
• Study Start: October 30, 2012
• Primary Completion: November 12, 2024
• Study Completion: November 12, 2024
• Last Updated: December 24, 2025
• Results First Posted: December 24, 2025

Record last verified: 2025-12

Locations

IT (7); DE (4); PR (1); KR (4); HK (2); ES (4); FR (7); JP (6); TW (3); CA (3); SG (3); GB (6); US (10)