Hepatocellular Carcinoma
Conditions
Brief summary
The purpose of this study is to evaluate the safety and tolerability of BMS-986183 in patients with liver cancer.
Interventions
BIOLOGICALBMS-986183
specified dose on specified days
BIOLOGICALNivolumab
specified dose on specified days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events at Its Worst Grade | First dose up to approximately 24 months | 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 | First dose up to approximately 24 months | 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 | First dose up to approximately 24 months | 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 | First dose up to approximately 24 months | 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 | First dose up to approximately 24 months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) | From first does up to approximately 24 months | 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) | First dose up to approximately 24 months | 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)] | First does up to appromimately 24 months | 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)] | First dose up to approximately 24 months | 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) | First dose up to approximately 24 months | 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) | First dose up to approximately 24 months | 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) | First dose to approximately 24 months | 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) | First dose up to approximately 24 months | 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 |
| Best Overall Response (BOR) | First dose up to approximately 24 months | 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. |
| Accumulation Index; Ratio of Cmax at Steady-state to Cmax After the First Dose (AI_Cmax) | First dose up to approximately 24 months | 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) | First dose up to approximately 24 months | 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)] | First dose up to approximately 24 months | 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) | First dose up to approximately 24 months | 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) | First dose up to approximately 24 months | 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 | Baseline up to approximately 24 months | 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) | First dose up to approximately 24 months | 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. |
| Volume of Distribution of Terminal Phase (Vz) | First dose up to approximately 24 months | (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. |
| Overall Response Rate (ORR) | First dose up to approximately 24 months | 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) | First dose up to approximately 24 months | 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) | First dose up to approximately 24 months | 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' | First dose up to approximately 24 months | 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 |
Countries
Canada, Singapore, South Korea, Taiwan
Participant flow
Recruitment details
There were 10 subjects were treated in this study. All 10 subjects were enrolled in BMS-986183 escalation (Part 1)
Participants by arm
| Arm | Count |
|---|---|
| BMS-986183 3 mg Dose escalation in combination with Nivolumab | 1 |
| BMS-986183 9 mg Dose escalation in combination with Nivolumab | 2 |
| BMS-986183 18 mg Dose escalation in combination with Nivolumab | 1 |
| BMS-986183 36 mg Dose escalation in combination with Nivolumab | 6 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | AE Unrelated to Study Drug | 0 | 0 | 0 | 1 |
| Overall Study | Disease Progression | 1 | 2 | 1 | 4 |
| Overall Study | Subject Withdrew Consent | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | BMS-986183 3 mg | BMS-986183 9 mg | BMS-986183 18 mg | BMS-986183 36 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56.0 Years | 67.5 Years STANDARD_DEVIATION 4.9 | 57.0 Years | 49.5 Years STANDARD_DEVIATION 8.6 | 54.5 Years STANDARD_DEVIATION 10 |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 2 / 2 | 0 / 1 | 5 / 6 |
| other Total, other adverse events | 1 / 1 | 2 / 2 | 1 / 1 | 5 / 6 |
| serious Total, serious adverse events | 0 / 1 | 1 / 2 | 1 / 1 | 2 / 6 |
Outcome results
Primary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Primary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Primary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Primary
Incidence of Laboratory Test Toxicity Grade Shifting From Baseline
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Primary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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).
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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)\]
Time frame: First does up to appromimately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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).
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: Baseline up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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 frame: From first does up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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
Time frame: First dose to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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)
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.
Secondary
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.
Time frame: First dose up to approximately 24 months
Population: The study was terminated and data is not reported for privacy reasons.