An Investigational Immuno-therapy Study of BMS-986205 Given in Combination With Nivolumab and in Combination With Both Nivolumab and Ipilimumab in 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 safety and effectiveness of experimental medication BMS-986205 when combined with Nivolumab and in combination with both Nivolumab and Ipilimumab in patients with cancers that are advanced or have spread. Pharmacokinetics and pharmacodynamics of BMS-986205 when combined with Nivolumab and in combination with Nivolumab and Ipilimumab in this patient population will also be assessed.

Official Title
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A Phase 1/2a Study of BMS-986205 Administered in Combination With Nivolumab (Anti-PD-1 Monoclonal Antibody) and in Combination With Both Nivolumab and Ipilimumab (Anti-CTLA-4 Monoclonal Antibody) in Advanced Malignant Tumors

Conditions
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Advanced Cancer, Melanoma, Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: BMS-986205
* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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For more information regarding Bristol-Myers Squibb (BMS) Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: During dose escalation, subjects with advanced solid tumors that have progressed following at least one standard regimen During cohort expansion, subjects with advanced cancer that either have received at least one prior therapy or are treatment naive, depending on the specified tumor type Subjects must have measurable disease Subject must consent to provide previously collected tumor tissue and a tumor biopsy during screening. At least 4 weeks since any previous treatment for cancer Must be able to swallow pills or capsules Eastern Cooperative Oncology Group(ECOG) Performance Status 0-1 Exclusion Criteria: Active or chronic autoimmune diseases Uncontrolled or significant cardiovascular disease History of any chronic Hepatitis, active Hepatitis B or C, human immunodeficiency virus (HIV), or acquired immune deficiency syndrome (AIDS) Chronic hepatitis: Positive test for Hepatitis B virus surface antigen or Hepatitis C antibody (except for subjects with hepatocellular carcinoma) Active central nervous system (CNS) metastases and CNS metastases as the only sites of disease Active infection Other protocol defined inclusion/exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Combination Therapy (Dose Escalation)<br>BMS 986205 + Nivolumab specified dose at specified intervals. | Drug: BMS-986205<br> <br> Drug: Nivolumab<br> <br> * Other names: ANTI-PD1;|
| Experimental: Combination Therapy (Dose Expansion)<br>BMS 986205 + Nivolumab specified dose at specified intervals. | Drug: BMS-986205<br> <br> Drug: Nivolumab<br> <br> * Other names: ANTI-PD1;|
| Experimental: Combination Therapy 2 (Dose Expansion)<br>BMS 986205 + both Nivolumab and ipilimumab specified dose at specified intervals | Drug: BMS-986205<br> <br> Drug: Nivolumab<br> <br> * Other names: ANTI-PD1;Drug: Ipilimumab<br> <br> * Other names: ANTI-CTLA-4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With AEs, SAEs, AEs Leading to Discontinuation and Deaths | Number of participants with adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation and deaths. | From first dose to 100 days after last dose (up to 15 months) | 
| Number of Treated Participant With Laboratory Abnormalities - Thyroid | The number of treated participants who experienced a laboratory abnormality of the thyroid during the course of the study. Free T3 (FT3) Free T4 (FT4) Thyroid stimulating hormone (TSH) Lower Limit of Normal (LLN) Upper limit of normal (ULN) Results reported in International System of Units (SI) | From first dose to 100 days after last dose (up to 15 months) | 
| Number of Treated Participant With Laboratory Abnormalities - Liver | The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Results reported in International System of Units (SI) | From first dose to 100 days after last dose (up to 15 months) | 
| Number of Participants With a Best Overall Response (BOR) - Parts 2 and 3 | Best overall response (BOR) is defined as the best response designation over the study as a whole. Complete response (CR) or partial response (PR) determinations included in the BOR assessment must be confirmed by a second scan performed no less than 4 weeks after the criteria for response are first met. For those participants who have surgical resection, only pre-surgical tumor assessments will be considered in the determination of BOR. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Progressive Disease. (PD): At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. Appearance of 1 or more new lesions is also considered progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | From first dose to the last tumor assessment prior to subsequent therapy (up to a maximum of 185 weeks) | 
| Percentage of Participants With an Objective Response Rate (ORR)- Parts 2 and 3 | Objective response rate (ORR) is defined as the percentage of all treated participants whose BOR is either a complete response (CR) or partial response (PR). Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. | From first dose to the last tumor assessment prior to subsequent therapy (up to a maximum of 185 weeks) | 
| Median Duration of Response (DoR) - Parts 2 and 3 | Duration of response (DoR) was computed for all treated subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) and is defined as the time between the date of first response and the date of disease progression or death, whichever occurs first. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. | From first dose to the date of disease progression, death, or until participants withdraw from the study, whichever occurs first (up to a maximum of 185 weeks) | 
| Progression Free Survival Rate (PFSR) at 24 Weeks - Parts 2 and 3 | Progression free survival rate (PFSR) is defined as the percentage of participants who remain progression free and surviving at 24 weeks. Reported values are estimates derived from Kaplan-Meier analyses. | At 24 weeks after first dose | 
| Progression Free Survival Rate (PFSR) at 1 Year - Parts 2 and 3 | Progression free survival rate (PFSR) is defined as the percentage of participants who remain progression free and surviving at 1 year. Reported values are estimates derived from Kaplan-Meier analyses. | At 1 year | 
| Progression Free Survival Rate (PFSR) at 2 Years - Parts 2 and 3 | Progression free survival rate (PFSR) is defined as the percentage of participants who remain progression free and surviving at 2 years. Reported values are estimates derived from Kaplan-Meier analyses. | At 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Serum Kynurenine | Pharmacodynamics assessed by change from baseline in serum kynurenine. Changes in kynurenine expression were evaluated in serum samples from participants treated using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Kynurenine is an important metabolite of the IDO-1 Enzyme. Change in Kynurenine levels from baseline is an important indicator of BMS-986205 (IDO1 inhibitor) pharmacodynamic activity. | At baseline (cycle 1, day 1) and at cycle 1, day 15 [cycle 1 = up to 4 weeks] | 
| Percent Change From Baseline in Serum Kynurenine | Pharmacodynamics assessed by change from baseline in serum kynurenine. Changes in kynurenine expression were evaluated in serum samples from participants treated using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Kynurenine is an important metabolite of the IDO-1 Enzyme. Change in Kynurenine levels from baseline is an important indicator of BMS-986205 (IDO1 inhibitor) pharmacodynamic activity. | At baseline (cycle 1, day 1) and at cycle 1, day 15 [cycle 1 = up to 4 weeks] | 
| Number of Participants With a Best Overall Response (BOR) - Part 1 and Clinical Pharmacology Substudies | Best overall response (BOR) is defined as the best response designation over the study as a whole. Complete response (CR) or partial response (PR) determinations included in the BOR assessment must be confirmed by a second scan performed no less than 4 weeks after the criteria for response are first met. For those participants who have surgical resection, only pre-surgical tumor assessments will be considered in the determination of BOR. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Progressive Disease. (PD): At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. Appearance of 1 or more new lesions is also considered progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | From first dose to the last tumor assessment prior to subsequent therapy (up to a maximum of 185 weeks) | 
| Percentage of Participants With an Objective Response Rate (ORR) - Part 1 and Clinical Pharmacology Substudies | Objective response rate (ORR) is defined as the percentage of all treated participants whose BOR is either a complete response (CR) or partial response (PR). Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. CR+PR confidence interval based on the Clopper and Pearson method. | From first dose to the last tumor assessment prior to subsequent therapy (up to a maximum of 185 weeks) | 
| Median Duration of Response (DoR) - Part 1 and Clinical Pharmacology Substudies | Duration of response (DoR) was computed for all treated subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) and is defined as the time between the date of first response and the date of disease progression or death, whichever occurs first. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. | From first dose to the last tumor assessment prior to subsequent therapy (up to a maximum of 185 weeks) | 
| Progression Free Survival Rate (PFSR) at 24 Weeks - Part 1 and Clinical Pharmacology Substudies | Progression free survival rate (PFSR) is defined as the percentage of participants who remain progression free and surviving at 24 weeks. Reported values are estimates derived from Kaplan-Meier analyses. | At 24 weeks after first dose | 
| Progression Free Survival Rate (PFSR) at 1 Year - Part 1 and Clinical Pharmacology Substudies | Progression free survival rate (PFSR) is defined as the percentage of participants who remain progression free and surviving at 1 year. Reported values are estimates derived from Kaplan-Meier analyses. | At 1 year | 
| Progression Free Survival Rate (PFSR) at 2 Years - Part 1 and Clinical Pharmacology Substudies | Progression free survival rate (PFSR) is defined as the percentage of participants who remain progression free and surviving at 2 years. Reported values are estimates derived from Kaplan-Meier analyses. | At 2 years | 
| Number of Participants With a Positive Anti-Drug Antibody (ADA) Test | A participant with at least one ADA-positive sample relative to baseline after initiation of treatment with nivolumab or ipilimumab. ADA-Positive after initiation of treatment was defined as (1) an ADA detected (positive seroconversion) sample in a subject 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. | From first dose to last dose (up to approximately 48 weeks) | 
| Cmax | Cmax is defined as the maximum observed plasma concentration. Pharmacokinetic parameters measured here are for BMS-986205. | At cycle 0 day 1 and day 14 [cycle 0= up to 2 weeks] | 
| Tmax | Tmax is defined as the time of maximum observed plasma concentration. Pharmacokinetic parameters measured here are for BMS-986205. | At cycle 0 day 1 and day 14 [cycle 0= up to 2 weeks] | 
| AUC(TAU) | AUC(TAU) is defined as the area under the concentration-time curve in 1 dosing interval. Pharmacokinetic parameters measured here are for BMS-986205. | Cycle 0 Day 1 (0, 1, 2, 3, 4, 6, 8, 24 hours post-dose), Cycle 0 Day 14 (0, 1, 2, 3, 4, 6, 8, 24 hours post-dose) | 
| Ctrough | Ctrough is defined as the trough observed plasma concentration at the end of the dosing interval. | At cycles 0 [up to 2 weeks] and at cycles 3, 5, 7, 10, 11, 13, 15 [each cycle is up to 4 weeks] | 
| CLT/F | CLT/F is defined as the apparent total body clearance. Pharmacokinetic parameters measured here are for BMS-986205. | At Cycle 0 Day 14 [cycle 0 = up to 2 weeks] | 
| Accumulation Index (AI) - AUC(TAU) | Accumulation index (AI) of AUC(TAU) is calculated based on the ratio of AUC(TAU) at steady state to after the first dose. Pharmacokinetic parameters measured here are for BMS-986205. | Cycle 0 Day 1 (0, 1, 2, 3, 4, 6, 8, 24 hours post-dose), Cycle 0 Day 14 (0, 1, 2, 3, 4, 6, 8, 24 hours post-dose) | 
| Accumulation Index (AI) - Cmax | Accumulation index (AI) of Cmax is calculated based on the ratio of Cmax at steady state to after the first dose. Pharmacokinetic parameters measured here are for BMS-986205. | At Cycle 0 Day 14 [cycle 0 = up to 2 weeks] |