Clinical trial NCT01658878: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
Collaborators: name: Ono Pharmaceutical Co. Ltd
First posted: 2012-08-07
Enrollment: 659
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: 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
timeFrame: 100 days after last dose
measure: 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
timeFrame: 100 days after last dose
measure: Objective response rate (ORR) for Expansion phase of nivolumab
timeFrame: Approximately 6 months minimum follow-up
measure: ORR for Nivolumab vs Sorafenib Cohort
timeFrame: Approximately 6 months minimum follow-up
measure: 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
timeFrame: 100 days after last dose
measure: 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
timeFrame: 100 days after last dose
measure: ORR for Nivolumab plus Ipilimumab Combination Cohort
timeFrame: Approximately 6 months minimum follow-up
measure: ORR for Child-Pugh B Cohort
timeFrame: Approximately 6 months minimum follow-up
measure: 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
timeFrame: 100 days after last dose
measure: 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
timeFrame: 100 days after last dose
measure: ORR for Nivolumab plus Ipilimumab plus Cabozantinib Combination Cohort
timeFrame: Approximately 6 months minimum follow-up
Secondary outcomes:
measure: Complete response (CR) Rate
timeFrame: Approximately 6 months minimum follow-up
measure: Disease control rate (DCR)
timeFrame: Approximately 6 months minimum follow-up
measure: Duration of response (DOR)
timeFrame: Approximately 9 years
measure: Time to response (TTR)
timeFrame: Approximately 6 months
measure: Time to progression (TTP)
timeFrame: Approximately 9 years
measure: TTP Rate
timeFrame: Approximately 9 years
measure: Progression free survival (PFS)
timeFrame: Approximately 9 years
measure: Overall survival (OS)
timeFrame: 100 days after last dose
measure: Overall survival rate (OSR)
timeFrame: 100 days after last dose
measure: PD-L1 expression
timeFrame: Approximately 6 months
measure: Maximum observed serum concentration (Cmax) of nivolumab
timeFrame: Approximately 6 months
measure: Time of maximum observed serum concentration (Tmax) of nivolumab
timeFrame: Approximately 6 months
measure: Area under the serum concentration time curve in the dosing interval AUC(TAU) of nivolumab
timeFrame: Approximately 6 months
measure: Serum concentration achieved at the end of dosing interval (trough concentration) (Ctrough) of nivolumab
timeFrame: Approximately 6 months
measure: Serum concentration achieved at the end of the infusion (Ceoinf) of nivolumab
timeFrame: Approximately 6 months
measure: Cmax at Cycle 3/ Cmax at Cycle 1 (AI_Cmax) of nivolumab
timeFrame: Approximately 6 months
measure: AUC(TAU) at Cycle 3/ AUC(TAU) at Cycle 1 (AI_AUC) of nivolumab
timeFrame: Approximately 6 months
measure: Effective T-Half of nivolumab
timeFrame: Approximately 6 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Local Institution - 0008
state: California
city: Washington
country: United States
facility: Local Institution - 0048
state: District of Columbia
city: Pensacola
country: United States
facility: Local Institution - 0053
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 0047
state: Georgia
city: Boston
country: United States
facility: Local Institution - 0025
state: Massachusetts
city: Ann Arbor
country: United States
facility: Local Institution - 0002
state: Michigan
city: Hackensack
country: United States
facility: Local Institution - 0054
state: New Jersey
city: Paterson
country: United States
facility: Local Institution - 0067
state: New Jersey
city: Portland
country: United States
facility: Local Institution - 0001
state: Oregon
city: Houston
country: United States
facility: The University Of Texas MD Anderson Cancer Center
state: Texas
city: Halifax
country: Canada
facility: Local Institution - 0065
state: Nova Scotia
city: Toronto
country: Canada
facility: Local Institution - 0039
state: Ontario
city: Montréal
country: Canada
facility: Local Institution - 0022
state: Quebec
city: Angers
country: France
facility: Local Institution - 0061
city: Creteil Cedex
country: France
facility: Local Institution - 0064
city: Marseille Cedex 5
country: France
facility: Local Institution - 0059
city: Marseille Cedex 9
country: France
facility: Local Institution - 0062
city: Paris Cedex 13
country: France
facility: Local Institution - 0042
city: Reims Cedex
country: France
facility: Local Institution - 0060
city: Vandoeuvre les Nancy
country: France
facility: Local Institution - 0058
city: Essen
country: Germany
facility: Local Institution - 0030
city: Frankfurt
country: Germany
facility: Local Institution - 0028
city: Hannover
country: Germany
facility: Local Institution - 0029
city: Heidelberg
country: Germany
facility: Local Institution - 0031
city: Hong Kong
country: Hong Kong
facility: Local Institution - 0005
city: Hong Kong
country: Hong Kong
facility: Local Institution - 0006
city: Bologna
country: Italy
facility: Local Institution - 0032
city: Firenze
country: Italy
facility: Local Institution - 0056
city: Meldola (FC)
country: Italy
facility: Local Institution - 0063
city: Milano
country: Italy
facility: Local Institution - 0055
city: Napoli
country: Italy
facility: Local Institution - 0034
city: Padova
country: Italy
facility: Local Institution - 0035
city: Rozzano
country: Italy
facility: Local Institution - 0040
city: Kashiwa-shi
country: Japan
facility: Local Institution - 0036
state: Chiba
city: Kurume-shi
country: Japan
facility: Local Institution - 0038
state: Fukuoka
city: Yokohama
country: Japan
facility: Local Institution - 0049
state: Kanagawa
city: Kyoto-shi
country: Japan
facility: Local Institution - 0050
state: Kyoto
city: Osaka-Sayama
country: Japan
facility: Local Institution - 0037
state: Osaka
city: Saga
country: Japan
facility: Local Institution - 0051
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0066
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0021
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0026
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0016
city: San Juan
country: Puerto Rico
facility: Local Institution - 0070
city: Singapore
country: Singapore
facility: Local Institution - 0017
city: Singapore
country: Singapore
facility: Local Institution - 0009
city: Singapore
country: Singapore
facility: Local Institution - 0007
city: Barcelona
country: Spain
facility: Local Institution - 0019
city: Madrid
country: Spain
facility: Local Institution - 0020
city: Madrid
country: Spain
facility: Local Institution - 0018
city: Pamplona
country: Spain
facility: Local Institution - 0003
city: Taipei
country: Taiwan
facility: Local Institution - 0027
city: Taipei
country: Taiwan
facility: Local Institution - 0024
city: Taoyuan
country: Taiwan
facility: Local Institution - 0023
city: London
country: United Kingdom
facility: Local Institution - 0011
state: Greater London
city: Manchester
country: United Kingdom
facility: Local Institution - 0014
state: Greater Manchester
city: Glasgow
country: United Kingdom
facility: Local Institution - 0012
state: Lanarkshire
city: Wirral
country: United Kingdom
facility: Local Institution - 0015
state: Merseyside
city: Birmingham
country: United Kingdom
facility: Local Institution - 0013
state: West Midlands
city: London
country: United Kingdom
facility: Local Institution - 0010
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.