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

• ClinicalTrials.gov Identifier: NCT01986218
• Recruitment Status: Terminated
• First Posted: November 18, 2013
• Last Update Posted: September 15, 2016
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Various Advanced Cancer	Drug: BMS-986115	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Ascending Multiple-Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BMS-986115 in Subjects With Advanced Solid Tumors
• Study Start Date: November 2013
• Actual Primary Completion Date: March 2016
• Actual Study Completion Date: March 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A: Dose Escalation (BMS-986115); Continuous daily dosing until disease progression or unacceptable toxicity	Drug: BMS-986115; Other Name: BMS-986115 (Notch Inhibitor)
Experimental: Arm A: Dose Expansion (BMS-986115); Continuous daily dosing until disease progression or unacceptable toxicity	Drug: BMS-986115; Other Name: BMS-986115 (Notch Inhibitor)
Experimental: Arm B: Dose Escalation (BMS-986115); Twice weekly dosing until disease progression or unacceptable toxicity	Drug: BMS-986115; Other Name: BMS-986115 (Notch Inhibitor)
Experimental: Arm B: Dose Expansion (BMS-986115); Twice weekly dosing until disease progression or unacceptable toxicity	Drug: BMS-986115; Other Name: BMS-986115 (Notch Inhibitor)

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability of multiple daily doses of BMS-986115 [ Time Frame: Up to 30 days after the last dose of study medication (approximately 18 months) ]
   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

Secondary Outcome Measures :

1. Maximum observed plasma concentration (Cmax) of BMS-986115 and its active metabolite BMT-100948 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
2. Time of maximum observed plasma concentration (Tmax) of BMS-986115 and its active metabolite BMT-100948 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
3. Trough observed plasma concentration (Ctrough) of BMS-986115 and its active metabolite BMT-100948 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
4. 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 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
5. 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 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
6. Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-986115 and its active metabolite BMT-100948 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
7. Terminal plasma half-life (T-HALF) of BMS-986115 and its active metabolite BMT-100948 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
8. Apparent total body clearance (CLT/F) of BMS-986115 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
9. Apparent volume of distribution at steady-state (Vz/F) of BMS-986115 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
10. AUC Accumulation Index; ratio of AUC(TAU) at steady state to AUC(TAU) after the first dose (AI_AUC) of BMS-986115 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
11. 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 [ Time Frame: 29 timepoints up to Cycle 3 Day 1 (approximately 32 days) ]
12. 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 [ Time Frame: 16 timepoints up to Cycle 2 Day 16 (approximately 20 days) ]
13. Preliminary anti-tumor activity of BMS-986115 as measured by response evaluation criteria in solid tumors (RECIST) [ Time Frame: Screening (within 30 days prior to Day 1), Every 8 weeks, End of Treatment or 30-Day follow-up visits (approximately 18 months) ]

    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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Usc/Norris Comprehensive Cancer Center

Los Angeles, California, United States, 90033

Australia, Victoria

Local Institution

Parkville, Victoria, Australia, 3050

Canada, British Columbia

Local Institution

Vancouver, British Columbia, Canada, V5Z 4E6

Canada, Ontario

Local Institution

Toronto, Ontario, Canada, M5G 2M9

Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

More Information

Additional Information:

BMS clinical trial educational resource 

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01986218
• Other Study ID Numbers: CA002-001
• First Posted: November 18, 2013
• Last Update Posted: September 15, 2016
• Last Verified: September 2016