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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02737475
Recruitment Status : Completed
First Posted : April 14, 2016
Results First Posted : January 25, 2022
Last Update Posted : January 25, 2022
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: BMS-986178 Drug: Nivolumab Drug: Ipilimumab Biological: Tetanus vaccine Biological: DPV-001 vaccine Drug: Cyclophosphamide Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 166 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2a Study of BMS-986178 Administered Alone or in Combination With Nivolumab and/or Ipilimumab in Subjects With Advanced Solid Tumors
Actual Study Start Date : June 17, 2016
Actual Primary Completion Date : November 2, 2020
Actual Study Completion Date : November 2, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part 1: Dose Escalation
  • BMS-986178 at specified doses at specified intervals
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Experimental: Part 2: Dose Escalation and Expansion
  • BMS-986178 in combination with Nivolumab at specified doses at specified intervals
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Drug: Nivolumab
Specified dose on specified days
Other Names:
  • BMS-936558
  • Opdivo

Experimental: Part 3: Dose Escalation and Expansion
  • BMS-986178 in combination with Ipilimumab at specified doses at specified intervals
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Drug: Ipilimumab
Specified dose on specified days
Other Names:
  • BMS-734016
  • Yervoy

Experimental: Part 4: Dose Schedule and Exploration
  • BMS-986178/Nivolumab at specified doses at specified intervals
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Drug: Nivolumab
Specified dose on specified days
Other Names:
  • BMS-936558
  • Opdivo

Experimental: Part 5: Dose Schedule and Exploration
  • BMS-986178/Ipilimumab at specified doses at specified intervals
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Drug: Ipilimumab
Specified dose on specified days
Other Names:
  • BMS-734016
  • Yervoy

Experimental: Part 6: Dose Safety and Expansion
  • BMS-986178/Ipilimumab/Nivolumab at specified doses at specified intervals
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Drug: Nivolumab
Specified dose on specified days
Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab
Specified dose on specified days
Other Names:
  • BMS-734016
  • Yervoy

Experimental: Part 7: Dose Safety and Expansion
  • BMS-986178/Ipilimumab/Nivolumab at specified doses at specified intervals
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Drug: Nivolumab
Specified dose on specified days
Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab
Specified dose on specified days
Other Names:
  • BMS-734016
  • Yervoy

Experimental: Part 8: Dose Exploration
  • BMS-986178/Nivolumab with tetanus vaccine at specified doses and interval
  • Enrollment is closed for this arm
Drug: BMS-986178
Specified dose on specified days

Drug: Nivolumab
Specified dose on specified days
Other Names:
  • BMS-936558
  • Opdivo

Biological: Tetanus vaccine
Specified dose on specified days

Experimental: Part 9: Dose Exploration
  • 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
Specified dose on specified days

Drug: Nivolumab
Specified dose on specified days
Other Names:
  • BMS-936558
  • Opdivo

Biological: DPV-001 vaccine
DPV-001 (UbiLT3 and UbiLT6): Specified dose on specified days

Drug: Cyclophosphamide
Specified dose on specified days




Primary Outcome Measures :
  1. The Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) [ Time Frame: From first dose to 28 days after first dose ]

    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.


  2. The Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: From first dose to 100 days after last dose (up to approximately 2.5 years) ]

    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.


  3. The Number of Participants Experiencing Serious Adverse Events (SAEs) [ Time Frame: From first dose to 100 days after last dose (up to approximately 2.5 years) ]

    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.


  4. The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation [ Time Frame: 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 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.

  5. The Number of Participant Deaths [ Time Frame: From first dose to study completion (up to approximately 4 years 5 months) ]
    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.

  6. The Number of Participants With Clinical Laboratory Test Abnormalities (Hematology) [ Time Frame: From baseline to 100 days after last dose (up to approximately 2.5 years) ]

    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


  7. The Number of Participants With Clinical Laboratory Test Abnormalities (LIVER AND KIDNEY FUNCTION) [ Time Frame: From baseline to 100 days after last dose (up to approximately 2.5 years) ]

    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


  8. The Number of Participants With Clinical Laboratory Test Abnormalities (OTHER CHEMISTRY TESTING ) [ Time Frame: From baseline to 100 days after last dose (up to approximately 2.5 years) ]

    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



Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: From baseline up to approximately 2.5 years ]

    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.


  2. Duration of Response (DOR) [ Time Frame: From baseline up to approximately 2.5 years ]

    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


  3. Progression Free Survival (PFS) Rate at 24 Weeks [ Time Frame: 24 weeks after first dose ]
    The percentage of treated participants remaining progression free and surviving at 24 weeks since the first dosing date.

  4. Cmax: Maximum Observed Serum Concentration [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  5. Tmax: Time of Maximum Observed Serum Concentration [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]
    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

  6. AUC(0-t): Area Under the Serum Concentration-time Curve From Time 0 to Time t [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  7. AUC(TAU): Area Under the Serum Concentration-time Curve in 1 Dosing Interval [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  8. Ctau: Observed Serum Concentration at the End of a Dosing Interval When Intensive Samples Are Collected [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  9. CLT: Total Body Clearance [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  10. Css-avg: Average Concentration Over a Dosing Interval (AUC(TAU)/Tau) [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  11. AI: Accumulation Index. Ratio of an Exposure Measure at Steady State (Cmax) [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  12. AI: Accumulation Index. Ratio of an Exposure Measure at Steady State (AUC) [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  13. AI: Accumulation Index. Ratio of an Exposure Measure at Steady State (Ctau) [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]

    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.


  14. T-HALFeff: Effective Elimination Half-life That Explains the Degree of Accumulation Observed for a Specific Exposure Measure (Exposure Measure Includes AUC(TAU), Cmax) [ Time Frame: Cycle 1-9 timepoints can include (Pre-dose, 0.30, 4, 24, 72, 168, 336, 696 hours post dose) ]
    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

  15. Ctrough: Trough Observed Plasma Concentration [ Time Frame: Cycle 1-17 timepoints can include (Pre-dose, 336, 504, 672 hours post dose) ]

    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.


  16. Frequency of Positive Anti-Drug Antibodies (ADA) to BMS-986178 [ Time Frame: Cycle 1-6 timepoints can include (Pre-dose, 696 hours post dose) ]
    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.

  17. Frequency of Positive Anti-Drug Antibodies (ADA) to Nivolumab [ Time Frame: Cycle 1-6 timepoints can include (Pre-dose, 336, 696 hours post dose) ]
    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.

  18. Frequency of Positive Anti-Drug Antibodies (ADA) to Ipilimumab. [ Time Frame: Cycle 1-6 timepoints can include (Pre-dose, 696 hours post dose) ]
    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.

  19. The Number of Participants Showing a Change in Soluble OX40 and Peripheral OX40 Receptor Occupancy Pharmacodynamic Biomarkers in Part 8 [ Time Frame: Cycle 1-6 timepoints can include (Pre-dose, 24, 168, 336, 672, 1848 hours post dose) ]
    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.

  20. Tumor Pharmacodynamics of BMS-986178 in Combination With Nivolumab or Nivolumab Monotherapy in Part 8 [ Time Frame: Screening, cycle 1-2 timepoints can include (Pre-dose, 336, 1848 hours post dose) ]
    Tumor pharmacodynamics of BMS-986178 in combination with nivolumab or nivolumab monotherapy

  21. The Number of Participants With Sustained T Cell Expansion With DPV-001 in Combination With Nivolumab or Nivolumab Monotherapy in Part 9 [ Time Frame: Cycle 1-6 timepoints can include (Pre-dose, 24, 168, 336, 672, 1848 hours post dose) ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02737475


Locations
Show Show 22 study locations
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
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Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  Study Documents (Full-Text)

Documents provided by Bristol-Myers Squibb:
Study Protocol  [PDF] February 8, 2019
Statistical Analysis Plan  [PDF] September 3, 2021

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT02737475    
Other Study ID Numbers: CA012-004
2015-004816-39 ( EudraCT Number )
First Posted: April 14, 2016    Key Record Dates
Results First Posted: January 25, 2022
Last Update Posted: January 25, 2022
Last Verified: December 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Cyclophosphamide
Nivolumab
Ipilimumab
Vaccines
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors