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

Primary Purpose

Hepatocellular Carcinoma

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
BMS-986183
Nivolumab
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Escalation Monotherapy

Dose Expansion Monotherapy

Dose Escalation Combination Therapy

Dose Expansion Combination Therapy

Arm Description

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
Incidence of Laboratory Test Toxicity Grade Shifting From Baseline

Secondary Outcome Measures

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.
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
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
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.
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
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
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.
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)]
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).
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
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)
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
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
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.
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.
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.
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).
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.
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.
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.
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.

Full Information

First Posted
July 7, 2016
Last Updated
January 7, 2019
Sponsor
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT02828124
Brief Title
A Study of the Safety and Tolerability of BMS-986183 in Patients With Liver Cancer
Official Title
A Phase 1/2 Study of BMS-986183 in Subjects With Advanced Hepatocellular Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Terminated
Why Stopped
Business objectives have changed
Study Start Date
August 23, 2016 (Actual)
Primary Completion Date
January 8, 2018 (Actual)
Study Completion Date
January 8, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation Monotherapy
Arm Type
Experimental
Arm Title
Dose Expansion Monotherapy
Arm Type
Experimental
Arm Title
Dose Escalation Combination Therapy
Arm Type
Experimental
Arm Title
Dose Expansion Combination Therapy
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
BMS-986183
Intervention Description
specified dose on specified days
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558, Opdivo
Intervention Description
specified dose on specified days
Primary Outcome Measure Information:
Title
Incidence of Adverse Events at Its Worst Grade
Description
Evaluated by comparing the incidence of Adverse Events (AEs) among subjects using their assigned treatment for at least one day.
Time Frame
First dose up to approximately 24 months
Title
Incidence of Serious Adverse Events at Its Worst Grade
Description
Evaluated by comparing the incidence of Serious Adverse Events (SAEs) among subjects using their assigned treatment for at least one day.
Time Frame
First dose up to approximately 24 months
Title
Incidence of Adverse Events Leading to Discontinuation
Description
Evaluated by comparing the incidence of Adverse Events leading to discontinuation among subjects using their assigned treatment for at least one day.
Time Frame
First dose up to approximately 24 months
Title
Incidence of Adverse Events Leading to Death
Description
Evaluated by comparing the incidence of Adverse Events leading to death among subjects using their assigned treatment for at least one day.
Time Frame
First dose up to approximately 24 months
Title
Incidence of Laboratory Test Toxicity Grade Shifting From Baseline
Time Frame
First dose up to approximately 24 months
Secondary Outcome Measure Information:
Title
Best Overall Response (BOR)
Description
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.
Time Frame
First dose up to approximately 24 months
Title
Overall Response Rate (ORR)
Description
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
Time Frame
First dose up to approximately 24 months
Title
Duration of Response (DoR)
Description
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
Time Frame
First dose up to approximately 24 months
Title
Progression Free Survival (PFS)
Description
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.
Time Frame
First dose up to approximately 24 months
Title
PFS Rate at Week 't'
Description
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
Time Frame
First dose up to approximately 24 months
Title
Maximum Observed Concentration (Cmax)
Description
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
Time Frame
From first does up to approximately 24 months
Title
Time of Maximum Observed Concentration (Tmax)
Description
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.
Time Frame
First dose up to approximately 24 months
Title
Area Under the Concentration-time Curve From Time 0 to T of the Last Quantifiable Concentration [AUC(0-T)]
Description
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)]
Time Frame
First does up to appromimately 24 months
Title
Area Under the Concentration-time Curve in 1 Dosing Interval [AUC(TAU)]
Description
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).
Time Frame
First dose up to approximately 24 months
Title
Concentration at the End of a Dosing Interval (Ctau)
Description
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
Time Frame
First dose up to approximately 24 months
Title
Trough Observed Concentration, Including Predose Concentrations and Ctau (Ctrough)
Description
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)
Time Frame
First dose up to approximately 24 months
Title
Total Body Clearance (CLT)
Description
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
Time Frame
First dose to approximately 24 months
Title
Apparent Volume of Distribution at Steady-state (Vss)
Description
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
Time Frame
First dose up to approximately 24 months
Title
Volume of Distribution of Terminal Phase (Vz)
Description
(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.
Time Frame
First dose up to approximately 24 months
Title
Accumulation Index; Ratio of Cmax at Steady-state to Cmax After the First Dose (AI_Cmax)
Description
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.
Time Frame
First dose up to approximately 24 months
Title
Accumulation Index; Ratio of Ctau at Steady-state to Ctau After the First Dose (AI_Ctau)
Description
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.
Time Frame
First dose up to approximately 24 months
Title
Accumulation Index; Ratio of AUC(TAU) at Steady-state to AUC(TAU) After the First Dose [AI_AUC(TAU)]
Description
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).
Time Frame
First dose up to approximately 24 months
Title
Average Concentration Over a Dosing Interval Calculated by Dividing AUC(TAU) at Steady State by Tau (Css,Ave)
Description
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.
Time Frame
First dose up to approximately 24 months
Title
Terminal Half-life (T-HALF)
Description
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.
Time Frame
First dose up to approximately 24 months
Title
Changes in QTcF (ΔQTcF) From Baseline
Description
To assess the effect of dosage regimen and exposure [active ADC and unconjugated tubulysin] of BMS-986183 as monotherapy on the QT interval.
Time Frame
Baseline up to approximately 24 months
Title
Incidence of Positive Anti-drug Antibody (ADA)
Description
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.
Time Frame
First dose up to approximately 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
Local Institution
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
05505
Country
Korea, Republic of
Facility Name
Local Institution
City
Singapore
ZIP/Postal Code
169610
Country
Singapore
Facility Name
Local Institution
City
Taipei
ZIP/Postal Code
10048
Country
Taiwan

12. IPD Sharing Statement

Links:
URL
http://bms.com/studyconnect/Pages/home.aspx
Description
BMS Clinical Trial Patient Recruiting

Learn more about this trial

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

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