An Investigational Immuno-Therapy Study of Experimental Medication BMS-986178 by Itself or in Combination With Nivolumab and/or Ipilimumab in Participants With Solid Cancers That Are Advanced or Have Spread

Study Overview
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Brief Summary
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The purpose of the study is to determine the safety and tumor-shrinking ability of experimental medication BMS-986178, when given by itself or in combination with Nivolumab and/or Ipilimumab, in participants with solid cancers that are advanced or have spread.

Official Title
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A Phase 1/2a Study of BMS-986178 Administered Alone or in Combination With Nivolumab and/or Ipilimumab in Subjects With Advanced Solid Tumors

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: BMS-986178
* Drug: Nivolumab
* Drug: Ipilimumab
* Biological: Tetanus vaccine
* Biological: DPV-001 vaccine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: For Part 9 (only arm open for enrollment): Stage IV metastatic or unresectable triple negative breast cancer (TNBC) with zero or one prior systemic therapies in the advanced metastatic setting Participants with < 12 months from receipt of last curative-intent chemotherapy are allowed; curative chemotherapy will be considered first-line therapy Prior receipt of chemotherapy in the (neo)adjuvant setting is acceptable, as long as completed greater than 6 months from start of treatment Tumor biopsy samples (mandatory pre- and on-treatment biopsies) are required for all participants enrolled Must have histologic or cytologic confirmation of a malignancy that is advanced (metastatic, recurrent, refractory, and/or unresectable) with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 Men and women must agree to follow specific methods of contraception, if applicable Exclusion Criteria: Must be immunotherapy treatment naïve, including no prior therapy with T cell immune checkpoint blocker (anti-PDL1, anti-PD1). Prior receipt of intralymphatic cytokine therapy (IRX-2) is acceptable (Part 9 only) Other active malignancy requiring concurrent intervention Prior therapy with any agent specifically targeting T-cell co-stimulation pathways such as anti-OX40 antibody, anti-CD137, anti- glucocorticoid-induced TNFR-related gene (anti-GITR) antibody, and anti-CD27 Known or underlying medical or psychiatric condition and/or social reason that, in the opinion of the investigator or Sponsor, could make the administration of study drug hazardous to the participant or could adversely affect the ability of the participant to comply with or tolerate the study Other protocol-defined inclusion/exclusion criteria apply

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>BMS-986178 at specified doses at specified intervals Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>|
| Experimental: Part 2: Dose Escalation and Expansion<br>BMS-986178 in combination with Nivolumab at specified doses at specified intervals Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;|
| Experimental: Part 3: Dose Escalation and Expansion<br>BMS-986178 in combination with Ipilimumab at specified doses at specified intervals Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Part 4: Dose Schedule and Exploration<br>BMS-986178/Nivolumab at specified doses at specified intervals Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;|
| Experimental: Part 5: Dose Schedule and Exploration<br>BMS-986178/Ipilimumab at specified doses at specified intervals Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Part 6: Dose Safety and Expansion<br>BMS-986178/Ipilimumab/Nivolumab at specified doses at specified intervals Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Drug: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Part 7: Dose Safety and Expansion<br>BMS-986178/Ipilimumab/Nivolumab at specified doses at specified intervals Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Drug: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Part 8: Dose Exploration<br>BMS-986178/Nivolumab with tetanus vaccine at specified doses and interval Enrollment is closed for this arm | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Biological: Tetanus vaccine<br>* Specified dose on specified days<br>|
| Experimental: Part 9: Dose Exploration<br>BMS-986178/Nivolumab/DPV-001 vaccine/cyclophosphamide (cohort 1) at specified doses at specified intervals OR Nivolumab/DPV-001 vaccine/cyclophosphamide (cohort 2) at specified doses at specified intervals Enrollment is open for this arm [Tumor type triple negative breast cancer (TNBC)] | Drug: BMS-986178<br>* Specified dose on specified days<br>Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Biological: DPV-001 vaccine<br>* DPV-001 (UbiLT3 and UbiLT6): Specified dose on specified days<br>Drug: Cyclophosphamide<br>* Specified dose on specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) | The number of participants experiencing dose-limiting toxicities (DLTs) to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. DLTs are defined based on the incidence, severity, and duration of adverse events (AEs) for which no clear alternative cause is identified. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. | From first dose to 28 days after first dose | 
| The Number of Participants Experiencing Adverse Events (AEs) | The number of participants experiencing adverse events (AEs) to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. | From first dose to 100 days after last dose (up to approximately 2.5 years) | 
| The Number of Participants Experiencing Serious Adverse Events (SAEs) | The number of participants experiencing serious adverse events (SAEs) to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. A SAE is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or is an important medical event. | From first dose to 100 days after last dose (up to approximately 2.5 years) | 
| The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation | The number of participants experiencing adverse events (AEs) leading to discontinuation of study drug to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. | From first dose to 100 days after last dose (up to approximately 2.5 years) | 
| The Number of Participant Deaths | The number of deaths in each arm to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. | From first dose to study completion (up to approximately 4 years 5 months) | 
| The Number of Participants With Clinical Laboratory Test Abnormalities (Hematology) | The number of participants with clinical laboratory test abnormalities to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. Results will be categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life Threatening Grade 5 = Death Related to AE Baseline is defined as the last non-missing measurement prior to the first dosing date and time | From baseline to 100 days after last dose (up to approximately 2.5 years) | 
| The Number of Participants With Clinical Laboratory Test Abnormalities (LIVER AND KIDNEY FUNCTION) | The number of participants with clinical laboratory test abnormalities to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. Results will be categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life Threatening Grade 5 = Death Related to AE Baseline is defined as the last non-missing measurement prior to the first dosing date and time | From baseline to 100 days after last dose (up to approximately 2.5 years) | 
| The Number of Participants With Clinical Laboratory Test Abnormalities (OTHER CHEMISTRY TESTING ) | The number of participants with clinical laboratory test abnormalities to assess the overall safety and tolerability of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab in participants with advanced solid tumors. Results will be categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life Threatening Grade 5 = Death Related to AE Baseline is defined as the last non-missing measurement prior to the first dosing date and time | From baseline to 100 days after last dose (up to approximately 2.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The total number of participants whose best overall response (BOR) is either a complete response (CR) or partial response (PR) based on assessment of tumor response using RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Overall Response (OR) = CR + PR Baseline is defined as the last non-missing measurement prior to the first dosing date and time. | From baseline up to approximately 2.5 years | 
| Duration of Response (DOR) | The time between the date of first response and the subsequent date of disease progression or death (death after re-treatment will not be considered), whichever occurs first in participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is assessed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Baseline is defined as the last non-missing measurement prior to the first dosing date and time. Due to high percentage of censored response, median estimate may be misleading | From baseline up to approximately 2.5 years | 
| Progression Free Survival (PFS) Rate at 24 Weeks | The percentage of treated participants remaining progression free and surviving at 24 weeks since the first dosing date. | 24 weeks after first dose | 
| Cmax: Maximum Observed Serum Concentration | The maximum observed serum concentration was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| Tmax: Time of Maximum Observed Serum Concentration | The time of maximum observed serum concentration was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| AUC(0-t): Area Under the Serum Concentration-time Curve From Time 0 to Time t | The area under the serum concentration-time curve from time 0 to time t was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| AUC(TAU): Area Under the Serum Concentration-time Curve in 1 Dosing Interval | The area under the serum concentration-time curve in 1 dosing interval was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| Ctau: Observed Serum Concentration at the End of a Dosing Interval When Intensive Samples Are Collected | The observed serum concentration at the end of a dosing interval when intensive samples are collected was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| CLT: Total Body Clearance | The total body clearance was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| Css-avg: Average Concentration Over a Dosing Interval (AUC(TAU)/Tau) | The average concentration over a dosing interval (AUC(TAU)/tau) was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| AI: Accumulation Index. Ratio of an Exposure Measure at Steady State (Cmax) | The ratio of an exposure measure at steady state to that after the first dose was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| AI: Accumulation Index. Ratio of an Exposure Measure at Steady State (AUC) | The ratio of an exposure measure at steady state to that after the first dose was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| AI: Accumulation Index. Ratio of an Exposure Measure at Steady State (Ctau) | The ratio of an exposure measure at steady state to that after the first dose was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| T-HALFeff: Effective Elimination Half-life That Explains the Degree of Accumulation Observed for a Specific Exposure Measure (Exposure Measure Includes AUC(TAU), Cmax) | The effective elimination half-life that explains the degree of accumulation observed for a specific exposure measure was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab | Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) | 
| Ctrough: Trough Observed Plasma Concentration | Trough observed plasma concentration (this includes predose concentrations and Ctau concentrations) was measured after dosing to assess the pharmacokinetics of BMS-986178 administered alone or in combination with Nivolumab and/or Ipilimumab. Note: The geometric CV was not calculated. Arithmetic % CV is reported instead. | Cycle 1-17 timepoints can include (Pre-dose, 336, 504, 672 hours post dose) | 
| Frequency of Positive Anti-Drug Antibodies (ADA) to BMS-986178 | The number of participants with positive anti-drug antibodies (ADA) is assessed to characterize the immunogenicity of BMS-986178 administered alone or in combination with nivolumab and/or ipilimumab. ADA Positive: A participant with at least one ADA-positive sample relative to baseline (ADA negative at baseline or ADA titer to be at least 4-fold or greater (>=) than baseline positive titer) at any time after initiation of treatment. | Cycle 1-6 timepoints can include (Pre-dose, 696 hours post dose) | 
| Frequency of Positive Anti-Drug Antibodies (ADA) to Nivolumab | The number of participants with positive anti-drug antibodies (ADA) is assessed to characterize the immunogenicity of Nivolumab administered with BMS-986178 ADA Positive: A participant with at least one ADA-positive sample relative to baseline (ADA negative at baseline or ADA titer to be at least 4-fold or greater (>=) than baseline positive titer) at any time after initiation of treatment. | Cycle 1-6 timepoints can include (Pre-dose, 336, 696 hours post dose) | 
| Frequency of Positive Anti-Drug Antibodies (ADA) to Ipilimumab. | The number of participants with positive anti-drug antibodies (ADA) is assessed to characterize the immunogenicity of Ipilimumab administered with BMS-986178 ADA Positive: A participant with at least one ADA-positive sample relative to baseline (ADA negative at baseline or ADA titer to be at least 4-fold or greater (>=) than baseline positive titer) at any time after initiation of treatment. | Cycle 1-6 timepoints can include (Pre-dose, 696 hours post dose) | 
| The Number of Participants Showing a Change in Soluble OX40 and Peripheral OX40 Receptor Occupancy Pharmacodynamic Biomarkers in Part 8 | The Number of Participants Showing a Change in Soluble OX40 and Peripheral OX40 Receptor Occupancy Pharmacodynamic Biomarkers in Part 8. A threshold of 80% receptor occupancy following treatment was applied. | Cycle 1-6 timepoints can include (Pre-dose, 24, 168, 336, 672, 1848 hours post dose) | 
| Tumor Pharmacodynamics of BMS-986178 in Combination With Nivolumab or Nivolumab Monotherapy in Part 8 | Tumor pharmacodynamics of BMS-986178 in combination with nivolumab or nivolumab monotherapy | Screening, cycle 1-2 timepoints can include (Pre-dose, 336, 1848 hours post dose) | 
| The Number of Participants With Sustained T Cell Expansion With DPV-001 in Combination With Nivolumab or Nivolumab Monotherapy in Part 9 | The number of participants with Sustained T Cell Expansion with DPV-001 in Combination with Nivolumab or Nivolumab Monotherapy was assessed to show a change in pharmacodynamics biomarkers | Cycle 1-6 timepoints can include (Pre-dose, 24, 168, 336, 672, 1848 hours post dose) |