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)

• ClinicalTrials.gov Identifier: NCT01658878
• Recruitment Status: Active, not recruiting
• First Posted: August 7, 2012
• Last Update Posted: December 14, 2023
• Sponsor: Bristol-Myers Squibb
• Collaborator: Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: August 3, 2012
• First Posted Date: August 7, 2012
• Last Update Posted Date: December 14, 2023
• Actual Study Start Date: October 30, 2012
• Estimated Primary Completion Date: June 28, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 12, 2017)

• 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 [ Time Frame: 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 [ Time Frame: 100 days after last dose ]
• Objective response rate (ORR) for Expansion phase of nivolumab [ Time Frame: Approximately 6 months minimum follow-up ]
• ORR for Nivolumab vs Sorafenib Cohort [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 100 days after last dose ]
• ORR for Nivolumab plus Ipilimumab Combination Cohort [ Time Frame: Approximately 6 months minimum follow-up ]
• ORR for Child-Pugh B Cohort [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 100 days after last dose ]
• ORR for Nivolumab plus Ipilimumab plus Cabozantinib Combination Cohort [ Time Frame: Approximately 6 months minimum follow-up ]

Original Primary Outcome Measures (submitted: August 3, 2012)

• Incidence of worst adverse events [ Time Frame: Up to 100 days after the last dose of BMS-936558 ]
  All non-serious adverse events will be collected from Day 1 until 100 days after the subject's last dose of BMS-936558
• Incidence of clinical laboratory test abnormalities including hematology and serum chemistry abnormalities [ Time Frame: Up to Week 214 ]

Current Secondary Outcome Measures (submitted: March 22, 2017)

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

Original Secondary Outcome Measures (submitted: August 3, 2012)

• Objective response rate and disease control rate [ Time Frame: Up to Week 214 ]
• Frequency of subjects with increase in anti-drug antibodies (ADA) levels [ Time Frame: Up to Week 214 ]
• Geometric means and coefficients of variation for the pharmacokinetic parameter of serum concentration achieved at the end of the dosing interval (trough concentration, Cmin) [ Time Frame: Up to Week 214 ]
• Geometric means and coefficients of variation for the pharmacokinetic parameter of maximum observed serum concentration (Cmax) [ Time Frame: Up to Week 214 ]
• Geometric means and coefficients of variation for the pharmacokinetic parameter of serum concentration achieved at the end of the infusion (Ceoinf) [ Time Frame: Up to Week 214 ]
• Geometric means and coefficients of variation for the pharmacokinetic parameter of area under the concentration-time curve from time zero to the time of the last quantifiable concentration [AUC(0-T)] [ Time Frame: Up to Week 214 ]
• Geometric means and coefficients of variation for the pharmacokinetic parameter of area under the concentration-time curve in one dosing interval [AUC(TAU)] [ Time Frame: Up to Week 214 ]
• Medians, minimum, and maximum for the pharmacokinetic parameter of time to maximum observed concentration (Tmax) [ Time Frame: Up to Week 214 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

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.

• Detailed Description: Study Classification: Pharmacokinetics/Pharmacodynamics
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hepatocellular Carcinoma

Intervention

• Biological: Nivolumab
  Other Name: BMS-936558
• Drug: Sorafenib
• Drug: Ipilimumab
• Drug: Cabozantinib

Study Arms

• Experimental: Non-infected: Nivolumab
  Nivolumab intravenous solution on specific days
  Intervention: Biological: Nivolumab
• Experimental: HCV-infected: Nivolumab
  Nivolumab intravenous solution on specific days
  Intervention: Biological: Nivolumab
• Experimental: HBV-infected: Nivolumab
  Nivolumab intravenous solution on specific days
  Intervention: Biological: Nivolumab
• Experimental: Nivolumab
  Nivolumab intravenous solution on specific days
  Intervention: Biological: Nivolumab
• Active Comparator: Sorafenib
  Sorafenib tablets on specific days
  Intervention: Drug: Sorafenib
• Experimental: Nivolumab plus Ipilimumab Combination
  Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days
  Interventions:

  • Biological: Nivolumab
  • Drug: Ipilimumab
• Experimental: Child-Pugh B
  Nivolumab intravenous solution on specific days
  Intervention: Biological: Nivolumab
• Experimental: Nivolumab plus Cabozantinib Combination
  Nivolumab intravenous solution + cabozantinib oral tablets on specific days
  Intervention: Drug: Cabozantinib
• Experimental: Nivolumab plus Ipilimumab plus Cabozantinib
  Nivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days
  Intervention: Drug: Cabozantinib

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 14, 2021): 659
• Original Estimated Enrollment (submitted: August 3, 2012): 72
• Estimated Study Completion Date: June 28, 2024
• Estimated Primary Completion Date: June 28, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Puerto Rico, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT01658878
• Other Study ID Numbers: CA209-040; 2012-001514-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Ono Pharmaceutical Co. Ltd

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: December 2023