A Dose Escalation and Combination Immunotherapy Study to Evaluate BMS-986226 Alone or in Combination With Nivolumab or Ipilimumab in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to investigate BMS-986226 administered alone or in combination with nivolumab or ipilimumab.

Official Title
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A Phase 1/2 Dose Escalation and Combination Cohort Study to Evaluate the Safety and Tolerability, Pharmacokinetics, and Efficacy of BMS-986226 Alone or in Combination With Nivolumab or Ipilimumab in Patients With Advanced Solid Tumors

Conditions
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Cancer, Tumors, Neoplasm, Malignancy

Intervention / Treatment
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* Drug: BMS-986226
* Biological: Nivolumab
* Biological: Ipilimumab
* Biological: Tetanus Vaccine


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: Advanced solid tumors Histological or cytological confirmation of a malignancy that is advanced (metastatic and/or unresectable) with measureable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or PCWG3 (prostate only). At least 1 lesion accessible for biopsy in addition to the target lesion Participants must have received, and then progressed or been intolerant to, at least 1 standard treatment regimen Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Exclusion Criteria: Participants with active central nervous system (CNS) metastases, untreated CNS metastases, or with the CNS as the only site of disease are excluded (controlled brain metastases will be allowed to enroll) Participants with carcinomatous meningitis Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast Active, known, or suspected autoimmune disease Uncontrolled or significant cardiovascular disease Participants with known allergies to egg products, neomycin and tetanus toxoid. Prior adverse reaction to tetanus toxoid- containing vaccines. Other protocol defined inclusion/exclusion criteria could 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BMS-986226<br>administered intravenously | Drug: BMS-986226<br>* specified dose on specified days<br>Biological: Tetanus Vaccine<br>* specified dose on specified days<br>|
| Experimental: BMS-986226 and Nivolumab<br>administered intravenously | Drug: BMS-986226<br>* specified dose on specified days<br>Biological: Nivolumab<br>* specified dose on specified days<br>* Other names: Opdivo;Biological: Tetanus Vaccine<br>* specified dose on specified days<br>|
| Experimental: BMS-986226 and Ipilimumab<br>administered intravenously | Drug: BMS-986226<br>* specified dose on specified days<br>Biological: Ipilimumab<br>* specified dose on specified days<br>* Other names: Yervoy;Biological: Tetanus Vaccine<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 Adverse Events (AEs) | 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 treatment and that does not necessarily have a causal relationship with this treatment. | From first dose up to 100 days post last dose, up to approximately 31 months | 
| The Number of Participants Experiencing Serious Adverse Events (SAEs) | Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization. | From first dose up to 100 days post last dose, up to approximately 31 months | 
| The Number of Participants Experiencing Adverse Events (AEs) Meeting Dose Limiting Toxicity (DLT) Criteria | 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 treatment and that does not necessarily have a causal relationship with this treatment. Dose limiting toxicity (DLT) is defined based on the incidence, intensity, and duration of AEs for which no clear alternative cause is identified. The DLT period will be 28 days (4 weeks) in the Preliminary Safety Cohorts. Any toxicities that occur beyond the 4-week DLT period will also be considered in dose-level decisions. For the purpose of participant management, any AE that meets DLT criteria, regardless of the cycle in which it occurs, will lead to discontinuation of study treatment. AEs will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. | From first dose up to 100 days post last dose, up to approximately 31 months | 
| The Number of Participants Experiencing Adverse Events Leading to Discontinuation | 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 treatment and that does not necessarily have a causal relationship with this treatment. | From first dose up to 100 days post last dose, up to approximately 31 months | 
| The Number of Participants Experiencing Adverse Events Resulting in Death | 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 treatment and that does not necessarily have a causal relationship with this treatment. | From first dose up to 100 days post last dose, up to approximately 31 months | 
| The Number of Participants Experiencing Clinical Laboratory Abnormalities | The number of participants experiencing abnormal laboratory results of Grade 3 or higher. Laboratory values will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 with Grade 3=severe and Grade 4=life threatening. | From first dose up to 30 days post last dose (approximately 28 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) as assessed by investigator per RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must also have reduction in the short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. BOR for a participant is defined as the best response designation recorded between the date of first dose (or date of randomization) and the date of first objectively documented progression per RECIST 1.1 or the date of subsequent therapy, whichever occurs first. | From first dose up to documented disease progression, up to 48 months | 
| Median Duration of Response (DOR) | DOR for a participant with confirmed response is defined as the time from the date of first response CR or PR to the date of first objectively documented tumor progression as determined using RECIST v1.1 or death due to any cause, whichever occurs first. Participant who remain alive and have not progressed will be censored on the date of their last tumor assessment. Participants who started subsequent anticancer therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anticancer therapy. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must also have reduction in the short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | From first dose up to the date of the first objectively documented tumor progression or death, whichever occurs first (up to approximately 24 months) | 
| Progression Free Survival (PFS) Rate at 24 Weeks | The PFSR is defined as the Kaplan Meier estimate of percentage of treated participants remaining progression free and surviving at the prespecified timepoint of 24 weeks since the first dosing date. Progressive Disease (PD) is defined as at least a 20% increase in the sum of the 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. (Note: The appearance of 1 or more new lesions is also considered progression.) | At 24 weeks | 
| Number of Participants With Anti-Drug Antibodies (ADA) for BMS-986226 | ADA for BMS-986226 is defined as the number of participants found to have seroconverted or boosted their pre-existing ADA during the study period. Baseline ADA positive is defined as ADA is detected in the last sample before initiation of treatment. ADA positive is defined as 1) an ADA detected (positive seroconversion) sample in a participant for whom ADA is not detected at baseline, or (2) an ADA detected sample with ADA titer to be at least 4-fold or greater (≥) than baseline positive titer. | Predose on cycles 1-6, post dose on C1D15, and 30, 60, and 100 days post last dose (up to approximately 31 months) | 
| Changes From Baseline in Cell Surface ICOS Expression on T Cells | Summary measures of changes in Median of Fluorescence of ICOS (MFI) from baseline to the last evaluable time point in cell surface Inducible Costimulator (ICOS) expression on T cells. Baseline = last non missing value prior or on to the first dosing. MFI is a unit for median fluorescence intensity. This unit allows for measurement of relative expression of cell surface markers by a flow cytometer. For the ICOS expression assay, whole blood samples collected from patients on study were incubated with fluorescently labeled antibodies that specifically bind to ICOS. Samples were then analyzed for changes in MFI by flow cytometry. An increase in MFI between patient samples corresponds to an increase in cell surface ICOS expression on target cell subsets. | From baseline up to pre-dose and 4 hours post dose on C1D1 and pre-dose and 4 hours post dose on C2D1 (approximately 31 months) | 
| Changes From Baseline in ICOS Ligand+ B Cells | Summary measures of changes in Median of Fluorescence of ICOS (MFI) from baseline to the last evaluable time point in ICOS ligand+ B cells in the tumor and peripheral blood. Baseline = last non missing value prior or on to the first dosing. MFI is a unit for median fluorescence intensity. This unit allows for measurement of relative expression of cell surface markers by a flow cytometer. For the ICOS expression assay, whole blood samples collected from patients on study were incubated with fluorescently labeled antibodies that specifically bind to ICOS. Samples were then analyzed for changes in MFI by flow cytometry. An increase in MFI between patient samples corresponds to an increase in cell surface ICOS expression on target cell subsets. | From baseline up to pre-dose and 4 hours post dose on C1D1, 72 hours post dose on C1D4, and pre-dose on C2D1 (approximately 31 months) | 
| Maximum Observed Plasma Concentration (Cmax) | Cmax is the maximum serum concentration that a drug achieves after the drug has been administered and before the administration of a second dose. | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1, and C3D1 (approximately 31 months) | 
| Effective Elimination Half-Life (T-HALFeff) | Effective elimination half-life that explains the degree of accumulation observed | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C2D1 and C3D1 (approximately 31 months) | 
| Trough Observed Serum Concentrations (Ctrough) | Trough observed serum concentrations (Ctrough) is defined as the concentration reached by a drug immediately before the next dose is administered | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C2D1 and C3D1. Pre-dose and 0.5 post dose on C4D1. Pre-dose on C5D1 and C6D1. Pre-dose and 0.5 hours post dose on C7D1. (approximately 31 months) | 
| Time of Maximum Observed Serum Concentration (Tmax) | Tmax is defined as the amount of time that a drug is present at the maximum concentration in serum | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1, and C3D1 (approximately 31 months) | 
| Area Under Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration [AUC (0-T)] | AUC(0-t) (partial AUC) is defined as the area under the concentration-time curve from dosing (time 0) to time t. AUC(0-t) may be computed for one or more values of t, with specific values of t determined after observing the data. | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1, and C3D1 (approximately 31 months) | 
| Area Under the Concentration-Time Curve in 1 Dosing Interval [AUC (TAU)] | AUC (TAU) is defined as the area under the plasma concentration-time curve from time zero to the end of the dosing interval | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1, and C3D1 (approximately 31 months) | 
| Total Body Clearance (CLT) | CLT is defined as the elimination of the drug from the body | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1, and C3D1 (approximately 31 months) | 
| Average Concentration Over a Dosing Interval (Css-avg) | Css-avg is defined as the average concentration over a dosing interval (AUC[TAU]/tau) Note: Coefficient of variation is reported in lieu of geometric coefficient of variation | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1, and C3D1 (approximately 31 months) | 
| Accumulation Index - Area Under Curve (AI-AUC) | Accumulation Index is defined as the extent of drug accumulation and determined by the ratio of plasma concentration at plateau over plasma concentration after the first dose. The area under curve is defined as the area under the plot of plasma concentration of a drug versus time after dosage which reflects the extent of exposure to a drug and its clearance rate from the body. | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1, and C3D1 (approximately 31 months) | 
| Accumulation Index - Cmax (AI-Cmax) | Accumulation Index is defined as the extent of drug accumulation and determined by the ratio of plasma concentration at plateau over plasma concentration after the first dose. Cmax is the maximum serum concentration that a drug achieves after the drug has been administered and before the administration of a second dose. | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1 and C3D1. Pre-dose and 0.5 post dose on C4D1. (Approximately 31 months) | 
| Accumulation Index - Concentrations at the End of Dosing Interval (AI-CTAU) | Accumulation Index is defined as the extent of drug accumulation and determined by the ratio of plasma concentration at plateau over plasma concentration after the first dose. | Pre-dose, 0.5, 4, 24, 72, 168, 336, 504 hours post dose on C1D1, C2D1 and C3D1. Pre-dose and 0.5 post dose on C4D1. (Approximately 31 months) |