Study of BMS-986158 in Subjects With Select Advanced Cancers

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS-986158 in subjects with select advanced cancers

Official Title
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A Phase I/IIa Trial With BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, as Monotherapy or in Combination With Nivolumab in Subjects With Selected Advanced Solid Tumors or Hematologic Malignancies

Conditions
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Advanced Tumors

Intervention / Treatment
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* Drug: BMS-986158
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have select advanced cancers with specific genetic profiles Must have received appropriate standard of care At least one measurable lesion at baseline Expected to have life expectancy of at least 3 months Eastern Cooperative Oncology Group (ECOG) of 0 to 1 Exclusion Criteria: Concomitant second malignancies Uncontrolled or significant cardiovascular disease Inadequate bone marrow function Chronic gastrointestinal illness Prior treatment with Bromodomain and Extra-Terminal (BET) inhibitor Other protocol defined inclusion/exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 12 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: Monotherapy Treatment<br>Patients treated at various doses and schedules | Drug: BMS-986158<br>* Specified dose on specified days<br>|
| Experimental: Combination Therapy<br>Patients treated at selected doses and schdules | Drug: BMS-986158<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 |
| --- | --- | --- |
| Number of Participants Experiencing Adverse Events | Number of participants experiencing different types of events, including Adverse Events (AEs), Serious Adverse Events (SAEs), AEs leading to discontinuation and deaths. Events are classified based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | From first dose to 30 days following last dose (up to approximately 29 months) | 
| Number of Participants With Abnormal Hepatic Test Values | Number of participants experiencing abnormal hepatic function, as measured by different parameters. ALT = Alanine aminotransferase AST = Aspartate aminotransferase ULN = Upper Limit of Normal | From first dose to 30 days following last dose (up to approximately 29 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) | BOR, as assessed by the investigator, is defined as the best response designation, recorded between the dates of first dose and the date of first objectively documented progression (per RECIST v1.1 for solid tumors, Lugano 2014 criteria for hematologic malignancies or PCWG3 for prostate cancer) or the date of subsequent therapy, whichever occurs first. | From first dose to date of first documented progression or subsequent therapy (up to approximately 28 months) | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants who achieved a best overall response of Complete Response (CR) or Partial Response (PR) | From first dose to date of first documented progression or subsequent therapy (up to approximately 28 months) | 
| Duration of Response (DOR) | DOR is defined as the time between the date of first response and the date of the first objectively documented disease progression (as determined by RECIST v1.1 for solid tumors, Lugano 2014 criteria for hematologic malignancies, or PCWG3 (including PSA assessments) for prostate cancer [CRPC or NEPC]), or death due to any cause, whichever occurs first. | From date of first response to date of first objectively documented disease progression or death (up to approximately 42 weeks) | 
| Progression Free Survival (PFS) | PFS is defined as the time from the first dose of study medication to the date of the first objective documentation of tumor progression or death due to any cause. | From first dose to date of first objectively documented disease progression or death (up to approximately 28 months) | 
| Progression Free Survival Rate (PFSR) | PFSR is defined as the percentage of participants who remain progression free and surviving at the specified timepoints (12 weeks, 24 weeks, and 48 weeks). Reported values are estimates derived from Kaplan-Meier analyses | From first dose to 12 weeks, to 24 weeks, and to 48 weeks after first dose | 
| Maximum Observed Plasma Concentration (Cmax) - Single Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485 | From drug administration in Cycle 1 Day 1 to 168 hours post drug administration | 
| Time of Maximum Observed Plasma Concentration (Tmax) - Single Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485 | From drug administration in Cycle 1 Day 1 to 168 hours post drug administration | 
| Area Under the Plasma Concentration-Time Curve in One Dosing Interval (AUC(0-24)) - Single Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485 | From drug administration in Cycle 1 Day 1 to 168 hours post drug administration | 
| Apparent Terminal Phase Half-Life (T-HALF) - Single Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485 | From drug administration in Cycle 1 Day 1 to 168 hours post drug administration | 
| Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) - Single Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485 | From drug administration in Cycle 1 Day 1 to 168 hours post drug administration | 
| Apparent Total Body Clearance (CLT/F) - Single Dose Administration | Values are reported only for the parent BMS-986158 | From drug administration in Cycle 1 Day 1 to 168 hours post drug administration | 
| Apparent Volume of Distribution of Terminal Phase (Vz/F) - Single Dose Administration | Values are reported only for the parent BMS-986158 | From drug administration in Cycle 1 Day 1 to 168 hours post drug administration | 
| Maximum Observed Plasma Concentration (Cmax) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. Values are also reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Time to Maximum Observed Plasma Concentration (Tmax) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. Values are also reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC(0-T)) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. Values are also reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Area Under the Plasma Concentration-Time Curve in One Dosing Interval (AUC(0-24)) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. Values are also reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Minimum Observed Concentration Within a Dosing Interval (Cmin) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. Values are reported only for the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Concentration at the End of Dosing Interval (C24) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. Values are also reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Trough Observed Plasma Concentration (Ctrough) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. Values are also reported separately for the first and last collection | From Cycle (C)2 Day (D)2 to C2D5 (Schedule A) or from C2D14 to C4D8 (Schedule B) or from C2D7 to C8D8 (Schedule C) | 
| Accumulation Index (AI) - Multiple Dose Administration | AI is defined as the ratio of an exposure measure at steady-state to that after the first dose. Reported exposure measures include Cmax, C24 and AUC24. Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. | Cycle 2 Day 5 (Schedule A) or Cycle 2 Day 14 (Schedule B) or Cycle 2 Day 7 (Schedule C) | 
| Effective Elimination Half-Life (Effective T-HALF) - Multiple Dose Administration | Values are reported separately for the parent BMS-986158 and its metabolite BMT-161485. | Cycle 2 Day 5 (Schedule A) or Cycle 2 Day 14 (Schedule B) or Cycle 2 Day 7 (Schedule C) | 
| Ratio of Metabolite (BMT-161485) Maximum Observed Plasma Concentration (Cmax) to Parent (BMS-986158) Cmax - Multiple Dose Administration | Values are reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Ratio of Metabolite (BMT-161485) Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC(0-T)) to Parent (BMS-986158) AUC(0-T) - Multiple Dose Administration | Values are reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Ratio of Metabolite (BMT-161485) Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) to Parent (BMS-986158) AUC(INF) - Multiple Dose Administration |  | Cycle 1 Day 1 | 
| Ratio of Metabolite (BMT-161485) Area Under the Plasma Concentration-Time Curve in One Dosing Interval (AUC(0-24)) to Parent (BMS-986158) AUC(0-24) - Multiple Dose Administration | Values are reported separately for Cycle 1 Day 1 and the latest collection timepoint available (Cycle 2 Day 5 for Schedule A, Cycle 2 day 14 for Schedule B, Cycle 2 Day 7 for Schedule C) | From Cycle 1 Day 1 to Cycle 2 Day 5 (Schedule A) or to Cycle 2 Day 14 (Schedule B) or to Cycle 2 Day 7 (Schedule C) | 
| Change From Baseline in Electrocardiogram Parameter QTcF | QT Interval corrected for Fridericia's Formula. Change from baseline is calculated from pre-dose at the indicated timepoints. | From Cycle 1 Day 1 to last dosing day in Cycle 2 (C2D8 for Schedule A, C2D14 for Schedule B, C2D7 for Schedule C). |