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

Study Overview
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Brief Summary
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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
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Study Classification: Pharmacokinetics/Pharmacodynamics

Official Title
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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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: Nivolumab
* Drug: Sorafenib
* Drug: Ipilimumab
* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-infected: Nivolumab<br>Nivolumab intravenous solution on specific days | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: HCV-infected: Nivolumab<br>Nivolumab intravenous solution on specific days | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: HBV-infected: Nivolumab<br>Nivolumab intravenous solution on specific days | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: Nivolumab<br>Nivolumab intravenous solution on specific days | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Active Comparator: Sorafenib<br>Sorafenib tablets on specific days | Drug: Sorafenib<br> <br> |
| Experimental: Nivolumab plus Ipilimumab Combination<br>Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Drug: Ipilimumab<br> <br> |
| Experimental: Child-Pugh B<br>Nivolumab intravenous solution on specific days | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: Nivolumab plus Cabozantinib Combination<br>Nivolumab intravenous solution + cabozantinib oral tablets on specific days | Drug: Cabozantinib<br> <br> |
| Experimental: Nivolumab plus Ipilimumab plus Cabozantinib<br>Nivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days | Drug: Cabozantinib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |