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
- Conditions
- Hepatocellular Carcinoma
- Interventions
- Registration Number
- NCT01658878
- Lead Sponsor
- Bristol-Myers Squibb
- 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 659
- 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
- History of autoimmune disease
- Any prior or current clinically significant ascites
- Any history of hepatic encephalopathy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description HCV-infected: Nivolumab Nivolumab Nivolumab intravenous solution on specific days HBV-infected: Nivolumab Nivolumab Nivolumab intravenous solution on specific days Nivolumab plus Cabozantinib Combination Cabozantinib Nivolumab intravenous solution + cabozantinib oral tablets on specific days Non-infected: Nivolumab Nivolumab Nivolumab intravenous solution on specific days Sorafenib Sorafenib Sorafenib tablets on specific days Nivolumab plus Ipilimumab Combination Nivolumab Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days Nivolumab plus Ipilimumab plus Cabozantinib Cabozantinib Nivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days Nivolumab plus Ipilimumab Combination Ipilimumab Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days Nivolumab Nivolumab Nivolumab intravenous solution on specific days Child-Pugh B Nivolumab Nivolumab intravenous solution on specific days
- Primary Outcome Measures
Name Time Method ORR for Nivolumab vs Sorafenib Cohort Approximately 6 months minimum follow-up ORR for Nivolumab plus Ipilimumab Combination Cohort Approximately 6 months minimum follow-up 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 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 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 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 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 ORR for Nivolumab plus Ipilimumab plus Cabozantinib Combination Cohort Approximately 6 months minimum follow-up
- Secondary Outcome Measures
Name Time Method Complete response (CR) Rate Approximately 6 months minimum follow-up The proportion of subjects whose best overall response (BOR) is CR in the population of interest
Time to response (TTR) 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.
Progression free survival (PFS) 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
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 Duration of response (DOR) 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.
TTP Rate Approximately 9 years It is defined as the K-M estimated proportion of subjects without progression at select milestones.
PD-L1 expression 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 Disease control rate (DCR) 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
Overall survival (OS) 100 days after last dose It is defined as the time from date of randomization to the date of death
Overall survival rate (OSR) 100 days after last dose It is defined as the K-M estimated proportion of subjects surviving at select milestones.
Time of maximum observed serum concentration (Tmax) of nivolumab Approximately 6 months Maximum observed serum concentration (Cmax) of nivolumab Approximately 6 months Area under the serum concentration time curve in the dosing interval AUC(TAU) of nivolumab Approximately 6 months Time to progression (TTP) Approximately 9 years It is defined from the date randomization to the date of the first objectively documented disease progression.
Effective T-Half of nivolumab Approximately 6 months
Trial Locations
- Locations (60)
Local Institution - 0002
🇺🇸Ann Arbor, Michigan, United States
Local Institution - 0008
🇺🇸Los Angeles, California, United States
Local Institution - 0048
🇺🇸Washington, District of Columbia, United States
Local Institution - 0053
🇺🇸Pensacola, Florida, United States
Local Institution - 0047
🇺🇸Atlanta, Georgia, United States
Local Institution - 0025
🇺🇸Boston, Massachusetts, United States
Local Institution - 0054
🇺🇸Hackensack, New Jersey, United States
Local Institution - 0067
🇺🇸Paterson, New Jersey, United States
Local Institution - 0001
🇺🇸Portland, Oregon, United States
Local Institution - 0014
🇬🇧Manchester, Greater Manchester, United Kingdom
Local Institution - 0011
🇬🇧London, Greater London, United Kingdom
Local Institution - 0012
🇬🇧Glasgow, Lanarkshire, United Kingdom
Local Institution - 0015
🇬🇧Wirral, Merseyside, United Kingdom
Local Institution - 0013
🇬🇧Birmingham, West Midlands, United Kingdom
Local Institution - 0010
🇬🇧London, United Kingdom
Local Institution - 0026
🇰🇷Seoul, Korea, Republic of
Local Institution - 0016
🇰🇷Seoul, Korea, Republic of
Local Institution - 0070
🇵🇷San Juan, Puerto Rico
Local Institution - 0017
🇸🇬Singapore, Singapore
Local Institution - 0009
🇸🇬Singapore, Singapore
Local Institution - 0007
🇸🇬Singapore, Singapore
Local Institution - 0019
🇪🇸Barcelona, Spain
Local Institution - 0020
🇪🇸Madrid, Spain
Local Institution - 0018
🇪🇸Madrid, Spain
Local Institution - 0003
🇪🇸Pamplona, Spain
Local Institution - 0027
🇨🇳Taipei, Taiwan
Local Institution - 0024
🇨🇳Taipei, Taiwan
Local Institution - 0023
🇨🇳Taoyuan, Taiwan
The University Of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Local Institution - 0065
🇨🇦Halifax, Nova Scotia, Canada
Local Institution - 0039
🇨🇦Toronto, Ontario, Canada
Local Institution - 0022
🇨🇦Montréal, Quebec, Canada
Local Institution - 0061
🇫🇷Angers, France
Local Institution - 0064
🇫🇷Creteil Cedex, France
Local Institution - 0059
🇫🇷Marseille Cedex 5, France
Local Institution - 0062
🇫🇷Marseille Cedex 9, France
Local Institution - 0042
🇫🇷Paris Cedex 13, France
Local Institution - 0060
🇫🇷Reims Cedex, France
Local Institution - 0058
🇫🇷Vandoeuvre les Nancy, France
Local Institution - 0030
🇩🇪Essen, Germany
Local Institution - 0028
🇩🇪Frankfurt, Germany
Local Institution - 0029
🇩🇪Hannover, Germany
Local Institution - 0031
🇩🇪Heidelberg, Germany
Local Institution - 0005
🇭🇰Hong Kong, Hong Kong
Local Institution - 0006
🇭🇰Hong Kong, Hong Kong
Local Institution - 0032
🇮🇹Bologna, Italy
Local Institution - 0056
🇮🇹Firenze, Italy
Local Institution - 0063
🇮🇹Meldola (FC), Italy
Local Institution - 0055
🇮🇹Milano, Italy
Local Institution - 0034
🇮🇹Napoli, Italy
Local Institution - 0035
🇮🇹Padova, Italy
Local Institution - 0040
🇮🇹Rozzano, Italy
Local Institution - 0036
🇯🇵Kashiwa-shi, Chiba, Japan
Local Institution - 0038
🇯🇵Kurume-shi, Fukuoka, Japan
Local Institution - 0049
🇯🇵Yokohama, Kanagawa, Japan
Local Institution - 0050
🇯🇵Kyoto-shi, Kyoto, Japan
Local Institution - 0037
🇯🇵Osaka-Sayama, Osaka, Japan
Local Institution - 0051
🇯🇵Saga, Japan
Local Institution - 0066
🇰🇷Seoul, Korea, Republic of
Local Institution - 0021
🇰🇷Seoul, Korea, Republic of