A Study of the Safety and Tolerability of BMS-986183 in Patients With Liver Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of BMS-986183 in patients with liver cancer.

Official Title
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A Phase 1/2 Study of BMS-986183 in Subjects With Advanced Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: BMS-986183
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Must have advanced liver cancer that cannot be treated with surgery or other local methods Liver cancer is confirmed by a microscopic examination of tissue Liver disease is classified as 'A' by a standard method called Child-Pugh score Daily living abilities are classified as '0 or 1' by a standard method from the Eastern Cooperative Oncology Group (ECOG) Women must use contraception Exclusion Criteria: Prior liver transplant Increase in blood pressure in some of the veins entering the liver Cancer that has spread to the brain or the layers of tissue that cover the brain or spinal cord Infection with both hepatitis B and C, both hepatitis D and B, infection with HIV, or other infections Disease of the heart or blood vessels around the heart Active cancers within the last 2 years No more than 2 prior systemic treatments or other investigational agents except PD-1/PD-L1 or Ipilimumab (Part 2) Currently on anti-platelet or anti-coagulation therapy Radiotherapy within 4 weeks of treatment Any major allergies Other protocol defined inclusion/exclusion criteria could apply

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: Dose Escalation Monotherapy<br> | Biological: BMS-986183<br>* specified dose on specified days<br>|
| Experimental: Dose Expansion Monotherapy<br> | Biological: BMS-986183<br>* specified dose on specified days<br>|
| Experimental: Dose Escalation Combination Therapy<br> | Biological: BMS-986183<br>* specified dose on specified days<br>Biological: Nivolumab<br>* specified dose on specified days<br>* Other names: Opdivo;|
| Experimental: Dose Expansion Combination Therapy<br> | Biological: BMS-986183<br>* specified dose on specified days<br>Biological: Nivolumab<br>* specified dose on specified days<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events at Its Worst Grade | Evaluated by comparing the incidence of Adverse Events (AEs) among subjects using their assigned treatment for at least one day. | First dose up to approximately 24 months | 
| Incidence of Serious Adverse Events at Its Worst Grade | Evaluated by comparing the incidence of Serious Adverse Events (SAEs) among subjects using their assigned treatment for at least one day. | First dose up to approximately 24 months | 
| Incidence of Adverse Events Leading to Discontinuation | Evaluated by comparing the incidence of Adverse Events leading to discontinuation among subjects using their assigned treatment for at least one day. | First dose up to approximately 24 months | 
| Incidence of Adverse Events Leading to Death | Evaluated by comparing the incidence of Adverse Events leading to death among subjects using their assigned treatment for at least one day. | First dose up to approximately 24 months | 
| Incidence of Laboratory Test Toxicity Grade Shifting From Baseline |  | First dose up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) | Defined as BOR designation over the study as a whole, recorded between the dates of first dose until the last tumor assessment prior to subsequent therapy. CR or PR determinations included in the BOR assessment must be confirmed by a second scan performed no less than 4 weeks after the criteria for response are first met. | First dose up to approximately 24 months | 
| Overall Response Rate (ORR) | Defined as the total number of subjects whose BOR is either a CR or PR divided by the total number of subjects in the population of interest | First dose up to approximately 24 months | 
| Duration of Response (DoR) | Defined as the time between the date of first response and the subsequent date of objectively documented disease progression or death, whichever occurs first. For those subjects who remain alive and have not progressed or received subsequent therapy, DoR will be censored on the date of last tumor assessment | First dose up to approximately 24 months | 
| Progression Free Survival (PFS) | Defined as the time from the first dose of study drug to the date of the first objective documentation of tumor progression or death due to any cause. Subjects who did not progress nor died will be censored on the date of their last tumor assessment. Subjects who did not have any on-study tumor assessments will be censored on the date of the first dose of study drug. | First dose up to approximately 24 months | 
| PFS Rate at Week 't' | Defined as the proportion of subjects who remain progression free and surviving at 't' weeks (t=12, 24, 36, etc). The proportion will be calculated by the product-limit method (Kaplan-Meier [K-M] estimate) which takes into account censored data | First dose up to approximately 24 months | 
| Maximum Observed Concentration (Cmax) | To characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by Cmax | From first does up to approximately 24 months | 
| Time of Maximum Observed Concentration (Tmax) | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by Tmax. | First dose up to approximately 24 months | 
| Area Under the Concentration-time Curve From Time 0 to T of the Last Quantifiable Concentration [AUC(0-T)] | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by AUC(0-T)] | First does up to appromimately 24 months | 
| Area Under the Concentration-time Curve in 1 Dosing Interval [AUC(TAU)] | To characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by AUC(TAU). | First dose up to approximately 24 months | 
| Concentration at the End of a Dosing Interval (Ctau) | To characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by | First dose up to approximately 24 months | 
| Trough Observed Concentration, Including Predose Concentrations and Ctau (Ctrough) | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by (Ctrough) | First dose up to approximately 24 months | 
| Total Body Clearance (CLT) | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by CLT | First dose to approximately 24 months | 
| Apparent Volume of Distribution at Steady-state (Vss) | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by Vss | First dose up to approximately 24 months | 
| Volume of Distribution of Terminal Phase (Vz) | (to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by Vz. | First dose up to approximately 24 months | 
| Accumulation Index; Ratio of Cmax at Steady-state to Cmax After the First Dose (AI_Cmax) | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by AI_Cmax. | First dose up to approximately 24 months | 
| Accumulation Index; Ratio of Ctau at Steady-state to Ctau After the First Dose (AI_Ctau) | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by AI_Ctau. | First dose up to approximately 24 months | 
| Accumulation Index; Ratio of AUC(TAU) at Steady-state to AUC(TAU) After the First Dose [AI_AUC(TAU)] | To characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by AI_AUC(TAU). | First dose up to approximately 24 months | 
| Average Concentration Over a Dosing Interval Calculated by Dividing AUC(TAU) at Steady State by Tau (Css,Ave) | To characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by Css,avg. | First dose up to approximately 24 months | 
| Terminal Half-life (T-HALF) | to characterize the PK of the total antibody [unconjugated antibody + antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites], active ADC [antibody conjugated to tubulysin], and unconjugated tubulysin) of BMS-986183 as monotherapy and in combination with nivolumab will be measured by T-HALF. | First dose up to approximately 24 months | 
| Changes in QTcF (ΔQTcF) From Baseline | To assess the effect of dosage regimen and exposure [active ADC and unconjugated tubulysin] of BMS-986183 as monotherapy on the QT interval. | Baseline up to approximately 24 months | 
| Incidence of Positive Anti-drug Antibody (ADA) | The immunogenicity of BMS-986183 (as monotherapy and in combination with nivolumab) will be measured by assessment of the presence or absence of specific ADA to BMS-986183. The incidence of positive ADA will be calculated. | First dose up to approximately 24 months |