A Study of BMS-986253 in Combination With Nivolumab or Nivolumab Plus Ipilimumab in Advanced Cancers

• BMS-986253 (Drug): Specified dose on specified days
• Nivolumab (Biological), also known as BMS-936558, Opdivo: Specified dose on specified days
• Ipilimumab (Biological), also known as BMS-734016, YERVOY: Specified dose on specified days
• Placebo (Other): Specified dose on specified days

Primary outcomes

• Number of Participants Experiencing Adverse Events (AEs) - Part 1 [From first dose up to 100 days after last dose (up to 65 months)]: An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Number of Participants Experiencing Serious Adverse Events (SAEs) - Part 1 [From first dose up to 100 days after last dose (up to 65 months)]: A serious adverse event is defined as 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, is an important medical event. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Number of Participants Experiencing Dose Limiting Toxicities (DLTs) - Part 1 [From first dose up to 100 days after last dose (up to 65 months)]: Dose-Limiting Toxicities (DLTs) are effects of a treatment that are serious enough to prevent an increase in dose of that treatment, as advised by the Dose Review Team. DLTs will be defined based on the incidence, intensity, and duration of AEs that are possibly related to study treatment. DLTs will include gastrointestinal, hepatic, hematologic, dermatologic, and other AEs. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation - Part 1 [From first dose up to 100 days after last dose (up to 65 months)]: Number of participants with any grade adverse events (AEs) leading to discontinuation of study treatment. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Number of Participants Who Died - Part 1 [From first dose up to 100 days after last dose (up to 65 months)]: The number of participants who died due to any cause are summarized. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Most Frequently Reported Grade 3 and Grade 4 Laboratory Test Results - Part 1 [From first dose up to 30 days after last dose (up to 63 months)]: Laboratory results were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Laboratory tests are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Objective Response Rate (ORR) - Part 2 [From the date of the first dose to the date of first objectively documented progression per RECIST v1.1 or the date of subsequent therapy, whichever occurred first (up to approximately 22 months)]: Objective Response Rate per blinded independent central review (BICR) is the percentage of participants who have a confirmed complete or partial best overall response (BOR) among participants who have measurable disease at baseline. Complete Response (CR) is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to =< 10 mm. Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Baseline was defined as evaluations or events that occur before the date and time of the first dose of study treatment or evaluations on the same date and time of the first dose of study treatment were also considered as baseline evaluations. This endpoint was prespecified in the protocol to include only participants in Part 2.

Secondary outcomes

• Objective Response Rate (ORR) - Part 1 [From the date of the first dose to the date of first objectively documented progression per RECIST v1.1 or the date of subsequent therapy, whichever occurred first (up to approximately 74 months)]: Objective Response Rate per investigator is the percentage of participants who have a confirmed complete or partial best overall response (BOR) among participants who have measurable disease at baseline. Complete Response (CR) is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to =< 10 mm. Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Baseline was defined as evaluations or events that occur before the date and time of the first dose of study treatment or evaluations on the same date and time of the first dose of study treatment were also considered as baseline evaluations. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Duration of Response (DOR) - Part 1 [From the date of the first dose to the date of first objectively documented progression per RECIST v1.1 or the date of subsequent therapy, whichever occurred first (up to approximately 74 months)]: DOR for a participant with a best overall response (BOR) of CR or PR is defined as the date of first response up to the date of the first objectively documented tumor progression by the investigator per RECIST v1.1 or death, whichever occurs first. Analysis computed using Kaplan-Meier method. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to =< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. This endpoint was prespecified in the protocol to include only participants in Part 1.
• Maximum Concentration (Cmax) - Part 1 [Cycle 1 Day 1]: Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days)
• AUC(0-T)-Area Under Curve From Time Zero up to Last Quantifiable Concentration - Part 1 [0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Cycle 1 Day 1]: AUC (0-T) represents the observed exposure to a drug (area under the concentration curve) from first exposure until the last quantifiable concentration. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days)
• AUC(TAU)-Area Under Curve in 1 Dosing Interval - Part 1 [Cycle 1 Day 1]: Area under the concentration-time curve in 1 dosing interval. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days)
• Observed Serum Concentration at the End of a Dosing Interval (Ctau) - Part 1 [Cycle 1 Day 1]: BMS-986253 observed serum concentration at the end of a dosing interval (Ctau). Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except Cycles 1 and 2 (1 cycle=42 days) in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group
• Total Body Clearance (CLT) - Part 1 [Cycle 1 Day 1]: Clearance is the rate of elimination of BMS-986253 from the blood calculated as the rate of elimination divided by serum concentration. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days)
• Average Serum Concentration Over a Dosing Interval (Css-avg) - Part 1 [Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]: BMS-986253 Average concentration over a dosing interval (\\\[AUC(TAU)/tau\\\] (Css-avg) at steady state. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days) Note: C2D1, C3D1, C4D1 were partial samplings only as pre-specified in the protocol and did not include a sampling for each arm.
• AUC Accumulation Index (AI_AUC) - Part 1 [Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1]: AUC Accumulation Index is defined as the ratio of AUC(TAU) at steady state to AUC(TAU) after the first dose. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days) Note: C2D1, C3D1, C4D1 were partial samplings only as pre-specified in the protocol and did not include a sampling for each arm.
• Cmax Accumulation Index (AI_Cmax) - Part 1 [Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1]: BMS-986253 Cmax accumulation index (AI_Cmax). Ratio of an exposure measure at steady state to that after the first dose. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days) Note: C2D1, C3D1, C4D1 were partial samplings only as pre-specified in the protocol and did not include a sampling for each arm.
• Ctau Accumulation Index (AI_Ctau) - Part 1 [Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1]: Ctau is the observed serum concentration at the end of a dosing interval. Ctau accumulation index (AI_Ctau) is the ratio of an exposure measure at steady state to that after the first dose. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. Ctau was reported on non-compartmental analysis day, which is on Cycle 1 Day1, Cycle 2 Day 1, Cycle 3 Day 1, or Cycle 4 Day 1 based on data available. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days) Note: C2D1, C3D1, C4D1 were partial samplings only as pre-specified in the protocol and did not include a sampling for each arm.
• Effective Elimination (T-HALFeff) - Part 1 [Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1]: BMS-986253 effective elimination (T-HALFeff) that explains the degree of accumulation observed for a specific exposure measure. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days) Note: C2D1, C3D1, C4D1 were partial samplings only as pre-specified in the protocol and did not include a sampling for each arm.
• Time to Maximum Concentration (Tmax) - Part 1 [Cycle 1 Day 1]: Tmax is defined as the time it takes for a drug to reach the maximum concentration (Cmax) after administration of a drug. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days)
• Serum Trough Concentration (Ctrough) - Part 1 [C1D15, C1D29, C2D1, C2D9, C2D15, C3D1, C4D1, C4D15, C5D1, C7D1, C9D1, C10D1, C14D1, C20D1, and C26D1]: A serum trough concentration (Ctrough) is the concentration reached by a drug immediately before the next dose is administered. Serum trough concentrations (Ctrough) of BMS-986253 will be summarized with descriptive statistics by treatment and visit. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days) Note: The timepoints listed were partial samplings only as pre-specified in the protocol and did not include a sampling for each arm.
• Number of Participants With Anti-Drug Antibodies (ADA) - Part 1 [C1D1, C1D2, C1D8, C1D15, C1D22, C2D1, C2D2, C2D8, C2D15, C3D1, C4D1, C4D2, C4D8, C4D15, C4D22, C5D1, C9D1, C14D1, C20D1, C26D1, C32D1, C38D1, 30-day follow-up, 100-day follow-up]: Blood samples were evaluated for development of Anti-Drug Antibody (ADA) by a validated electrochemiluminescent (ECL) immunoassay. Baseline is defined as first dose. ADA-positive subject: A subject with at least one ADA positive-sample relative to baseline at any time after initiation of treatment. Persistent Positive (PP): ADA-positive sample at 2 or more consecutive time points, where the first and last ADA-positive samples are at least 16 weeks apart Not PP-Last Sample Positive: Not persistent positive with ADA-positive sample at the last sampling time point Other Positive: Not persistent positive but some ADA-positive samples with the last sample being negative Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected ADA-negative subject: A subject with no ADA-positive sample after the initiation of treatment. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days)
• Change From Baseline in Interleukin 8 (IL-8)- Part 1 [C1D2, C1D8, C1D15, C1D22, C1D29, C1D36, C2D1, C2D2, C2D8, C2D15, C2D22, C2D29, C3D1, C3D2, C3D8, C4D1, C4D2, C4D8, C4D15, C4D22, C5D1, C7D1, C8D1, C9D1, C10D1, C11D1, C14D1, C16D1, C17D1, C20D1, C23D1, C26D1, at last dose, and 100 days post last dose]: Change from baseline in IL-8 measured in pg/mL. Baseline is defined as first dose. 1 cycle=28 days for all Arms/Groups except in "Part 1: 3600Q2W + Nivo + Ipi" Arm/Group (1 cycle=42 days) Note: Some timepoints were partial samplings only as pre-specified in the protocol and did not include a sampling for each arm.
• Progression Free Survival (PFS) - Part 2 [From the date of the first dose to the date of first objectively documented progression per RECIST v1.1 or the date of subsequent therapy, whichever occurred first (up to approximately 22 months)]: Progression free survival (PFS) is defined for all randomized participants as the date from randomization to the date of the documentation of disease progression by BICR or death due to any cause, whichever is earlier. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. This endpoint was prespecified in the protocol to include only participants in Part 2.
• Number of Participants Experiencing Adverse Events (AEs) - Part 2 [From first dose up to 100 days after last dose (up to 25 months)]: An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal. This endpoint was prespecified in the protocol to include only participants in Part 2.
• Number of Participants Experiencing Serious Adverse Events (SAEs) - Part 2 [From first dose up to 100 days after last dose (up to 25 months)]: A serious adverse event is defined as 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, is an important medical event.
• Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation - Part 2 [From first dose up to 100 days after last dose (up to 25 months)]: Number of participants with any grade adverse events (AEs) leading to discontinuation of study treatment. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
• Number of Participants Who Died - Part 2 [From first dose up to 100 days after last dose (up to 25 months)]: The number of participants who died due to any cause are summarized.
• Most Frequently Reported Grade 3 and Grade 4 Laboratory Test Results - Part 2 [From first dose up to 30 days after last dose (up to 23 months)]: Laboratory results were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Laboratory tests are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal. This endpoint was prespecified in the protocol to include only participants in Part 2.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologic or cytologic confirmation of a solid tumor that is advanced (metastatic, recurrent and/or unresectable) with measurable disease per RECIST v1.1
* At least 1 lesion accessible for biopsy
* Eastern Cooperative Oncology Group Performance Status of 0 or 1

Exclusion Criteria:

* Participants with CNS metastases as the only site of active disease (Participants with controlled brain metastases; however, will be allowed to enroll)
* Participants with active, known or suspected autoimmune disease
* Participants with conditions requiring systemic treatment with either corticosteroids (> 10mg prednisone equivalents) or other immunosuppressive medications within 14 days of study treatment administration
* Participants with a known history of testing positive for Human Immunodeficiency Virus (HIV) or known Acquired Immunodeficiency Syndrome (AIDS)
* Cytotoxic agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer therapy and initiation of study therapy

Other protocol defined inclusion/exclusion criteria could apply

• Results publication: Cai S, Wei X, Li Q, Jiang Z, Li L. Smart materials in pharmacological drug development: Neutrophils and its constituents for drug delivery and consequent antitumor effects. Mol Immunol. 2025 Jul;183:18-32. doi: 10.1016/j.molimm.2025.04.010. Epub 2025 May 2. PMID 40318595

• Study Protocol and Statistical Analysis Plan (PDF, 2024-05-17)

• Bristol-Myers Squibb, Study director, Bristol-Myers Squibb

NIH grants: 2023