Phase I Ascending Multiple-Dose Study of BMS-986115 in Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety and effectiveness of daily doses of BMS-986115 in subjects with advanced solid tumors

Official Title
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Phase I Ascending Multiple-Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BMS-986115 in Subjects With Advanced Solid Tumors

Conditions
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Various Advanced Cancer

Intervention / Treatment
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* Drug: BMS-986115


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 with a histologically or cytologically confirmed diagnosis of solid tumors, advanced or metastatic, refractory to or relapsed from standard therapies or for which there is no known effective treatment Life expectancy of at least 3 months Eastern Cooperative Oncology Group (ECOG) performance status score 0-1 Prior anti-cancer treatments are permitted (i.e., chemotherapy, radiotherapy, hormonal, or immunotherapy) At least 4 weeks must have elapsed from last dose of prior anti-cancer therapy and the initiation of study therapy Exclusion Criteria: Subjects with known or suspected brain metastases, primary brain tumors, or brain as the only site of disease Evidence of uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral or anti-fungal therapy ≤ 7 days prior to administration of study medication Current or recent (within 3 months of study drug administration) gastrointestinal disease such as chronic or intermittent diarrhea, or disorders that increase the risk of diarrhea, such as inflammatory bowel disease. Non-chronic conditions (e.g. infectious diarrhea) that are completely resolved for at least 2 weeks prior to starting study treatment are not exclusionary Any major surgery or gastrointestinal disease that would interfere with administration of oral medications Conditions requiring chronic systemic glucocorticoid use, such as autoimmune disease or severe asthma, excluding inhalation steroids for maintenance. Uncontrolled or significant cardiovascular disease History of medically significant thromboembolic events or bleeding diathesis within the past 6 months Inadequate bone marrow function (Absolute neutrophil count (ANC) < 1,500 cells/mm3; Platelet count < 100,000 cells/mm3; Hemoglobin < 9.0 g/dL) Inadequate hepatic function (Total bilirubin > 1.5 times the institutional upper limit of normal (ULN) (except known Gilbert's syndrome); Alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 times the institutional ULN. ALT or AST up to 3 times the institutional ULN permitted if total bilirubin is normal Uncontrolled (≥ Grade 2) hypertriglyceridemia (fasting triglycerides > 300 mg/dL (3.42 mmol/L)) Inadequate renal function (Blood creatinine > 1.5 times the institutional ULN) Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or Human Immunodeficiency Virus (HIV) -1, -2 antibody

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: Arm A: Dose Escalation (BMS-986115)<br>Continuous daily dosing until disease progression or unacceptable toxicity | Drug: BMS-986115<br> <br> * Other names: BMS-986115 (Notch Inhibitor);|
| Experimental: Arm A: Dose Expansion (BMS-986115)<br>Continuous daily dosing until disease progression or unacceptable toxicity | Drug: BMS-986115<br> <br> * Other names: BMS-986115 (Notch Inhibitor);|
| Experimental: Arm B: Dose Escalation (BMS-986115)<br>Twice weekly dosing until disease progression or unacceptable toxicity | Drug: BMS-986115<br> <br> * Other names: BMS-986115 (Notch Inhibitor);|
| Experimental: Arm B: Dose Expansion (BMS-986115)<br>Twice weekly dosing until disease progression or unacceptable toxicity | Drug: BMS-986115<br> <br> * Other names: BMS-986115 (Notch Inhibitor);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of multiple daily doses of BMS-986115 | Measured by the frequency of adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, Grade 3 or 4 AEs, deaths, laboratory abnormalities and clinically relevant electrocardiogram (ECG) changes from baseline | Up to 30 days after the last dose of study medication (approximately 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Time of maximum observed plasma concentration (Tmax) of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Trough observed plasma concentration (Ctrough) of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration [AUC(0-T)] of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Terminal plasma half-life (T-HALF) of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Apparent total body clearance (CLT/F) of BMS-986115 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Apparent volume of distribution at steady-state (Vz/F) of BMS-986115 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| AUC Accumulation Index; ratio of AUC(TAU) at steady state to AUC(TAU) after the first dose (AI_AUC) of BMS-986115 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Ratio of metabolite AUC(INF) to parent AUC(INF) after single dose and ratio of metabolite AUC(TAU) to parent AUC(TAU) at steady state, corrected for molecular weight (MR_AUC) of BMS-986115 and its active metabolite BMT-100948 |  | 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) | 
| Pharmacodynamics (PD) changes in the expression of Notch pathway-related genes, including but not limited to Hes1 and Deltex1, as determined by standard molecular methods |  | 16 timepoints up to Cycle 2 Day 16 (approximately 20 days) | 
| Preliminary anti-tumor activity of BMS-986115 as measured by response evaluation criteria in solid tumors (RECIST) | Assessed by: Tumor Response based on the Investigator's assessment using RECIST v1.1 [categorized as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD)] Best Overall Response (BOR), defined as the best tumor response recorded between the data of first dose and the last on-study tumor assessment (prior to any subsequent cancer therapy) Overall Response Rate, defined as the proportion of subjects with BOR responses of CR or PR Disease Control Rate, defined as the proportion of subjects with BOR responses of CR, PR or SD Progression-Free Survival (or PFS), defined as time from first dose to either progressive disease, initiation of subsequent off-study therapy, or death | Screening (within 30 days prior to Day 1), Every 8 weeks, End of Treatment or 30-Day follow-up visits (approximately 18 months) |