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: Active, not recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Ipilimumab; Drug: Sorafenib; Biological: Nivolumab; Drug: Cabozantinib

Detailed Description

Study Classification: Pharmacokinetics/Pharmacodynamics

• Study Type: Interventional
• Enrollment (Actual): 659
• 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
    • Montréal, Quebec, Canada, H2X 3E4
      • Local Institution - 0022
• France
  • Angers, France, 49933
    • Local Institution - 0061
  • Creteil Cedex, France, 94010
    • Local Institution - 0064
  • Marseille Cedex 5, France, 13385
    • Local Institution - 0059
  • Marseille Cedex 9, France, 13273
    • Local Institution - 0062
  • Paris Cedex 13, France, 75651
    • Local Institution - 0042
  • Reims Cedex, France, 51092
    • Local Institution - 0060
  • Vandoeuvre les Nancy, France, 54500
    • Local Institution - 0058
• Germany
  • Essen, Germany, 45147
    • Local Institution - 0030
  • Frankfurt, Germany, 60590
    • Local Institution - 0028
  • Hannover, 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
  • Firenze, Italy, 50134
    • Local Institution - 0056
  • Meldola (FC), Italy, 47014
    • Local Institution - 0063
  • Milano, Italy, 20141
    • Local Institution - 0055
  • Napoli, Italy, 80131
    • Local Institution - 0034
  • Padova, 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-shi, Kyoto, Japan, 6028566
      • Local Institution - 0050
  • Osaka
    • Osaka-sayama-shi, Osaka, Japan, 5898511
      • Local Institution - 0037
• Korea, Republic of
  • Seoul, Korea, Republic of, 02841
    • Local Institution - 0066
  • Seoul, Korea, Republic of, 03080
    • Local Institution - 0021
  • Seoul, Korea, Republic of, 05505
    • Local Institution - 0026
  • Seoul, Korea, Republic of, 06351
    • Local Institution - 0016
• 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
• 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, 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
    • 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, 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
      • Univ Of Michigan
  • 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, 97225
      • 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	Time Frame
Safety of nivolumab as evaluated by incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities	100 days after last dose
Tolerability of nivolumab as evaluated by incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities	100 days after last dose
Objective response rate (ORR) for Expansion phase of nivolumab	Approximately 6 months minimum follow-up
ORR for Nivolumab vs Sorafenib Cohort	Approximately 6 months minimum follow-up
Safety of nivolumab plus ipilimumab as evaluated by incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities	100 days after last dose
Tolerability of nivolumab plus ipilimumab as evaluated by incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities	100 days after last dose
ORR for Nivolumab plus Ipilimumab Combination Cohort	Approximately 6 months minimum follow-up
ORR for Child-Pugh B Cohort	Approximately 6 months minimum follow-up
Safety of nivolumab plus ipilimumab plus cabozantinib as evaluated by incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities	100 days after last dose
Tolerability of nivolumab plus ipilimumab plus cabozantinib as evaluated by incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities	100 days after last dose
ORR for Nivolumab plus Ipilimumab plus Cabozantinib Combination Cohort	Approximately 6 months minimum follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response (CR) Rate	The proportion of subjects whose best overall response (BOR) is CR in the population of interest	Approximately 6 months minimum follow-up
Disease control rate (DCR)	The proportion of subjects whose BOR is CR, Partial response (PR) or stable disease (SD) in the population of interest	Approximately 6 months minimum follow-up
Duration of response (DOR)	It is defined as time between the date of first radiographic documented objective response and the date of the radiographic disease progression.	Approximately 9 years
Time to response (TTR)	It is defined as the time from randomization to the date of the first confirmed CR or PR for the 1L Nivolumab vs Sorafenib Cohort, and from the first dosing date of any study medication to the date of the first confirmed CR or PR for all other cohorts.	Approximately 6 months
Time to progression (TTP)	It is defined from the date randomization to the date of the first objectively documented disease progression.	Approximately 9 years
TTP Rate	It is defined as the K-M estimated proportion of subjects without progression at select milestones.	Approximately 9 years
Progression free survival (PFS)	PFS is defined as the time from randomization date to the date of the first objectively documented tumor progression or death due to any cause	Approximately 9 years
Overall survival (OS)	It is defined as the time from date of randomization to the date of death	100 days after last dose
Overall survival rate (OSR)	It is defined as the K-M estimated proportion of subjects surviving at select milestones.	100 days after last dose
PD-L1 expression		Approximately 6 months
Maximum observed serum concentration (Cmax) of nivolumab		Approximately 6 months
Time of maximum observed serum concentration (Tmax) of nivolumab		Approximately 6 months
Area under the serum concentration time curve in the dosing interval AUC(TAU) of nivolumab		Approximately 6 months
Serum concentration achieved at the end of dosing interval (trough concentration) (Ctrough) of nivolumab		Approximately 6 months
Serum concentration achieved at the end of the infusion (Ceoinf) of nivolumab		Approximately 6 months
Cmax at Cycle 3/ Cmax at Cycle 1 (AI_Cmax) of nivolumab		Approximately 6 months
AUC(TAU) at Cycle 3/ AUC(TAU) at Cycle 1 (AI_AUC) of nivolumab		Approximately 6 months
Effective T-Half of nivolumab		Approximately 6 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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. Erratum In: J Immunother Cancer. 2023 Jan;11(1):
• 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.
• 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. Erratum In: JAMA Oncol. 2021 Jan 1;7(1):140.
• 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.
• 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. Erratum In: J Hepatol. 2019 Dec;71(6):1278.
• 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.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2012
• Primary Completion (Estimated): June 28, 2024
• Study Completion (Estimated): June 28, 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 14, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Sorafenib; Nivolumab; Ipilimumab
• 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