A Study of an Anti-KIR Antibody Lirilumab in Combination With an Anti-PD1 Antibody Nivolumab and Nivolumab Plus an Anti-CTLA-4 Ipilimumab Antibody in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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To assess the safety and tolerability and preliminary anti-tumor activity of lirilumab (BMS-986015) given in combination with nivolumab (BMS-936558) and to identify dose limiting toxicities (DLTs) and the maximally tolerated dose (MTD) of the combination. In addition, to assess the combinations of lirilumab and nivolumab or lirilumab and nivolumab plus ipilimumab (BMS-734016) in subjects with advanced (metastatic and/or unresectable) refractory solid tumors.

Official Title
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A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab (Anti-PD-1) or Lirilumab Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors

Conditions
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CANCER,NOS

Intervention / Treatment
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* Drug: Lirilumab
* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: During dose escalation, subjects with advanced solid tumors (except for primary CNS metastases) that have progressed following at least one standard regimen During cohort expansion, subjects with various solid tumors that have received at least one and no more than 5 prior treatment regimens Subjects must have measurable disease Subject must consent to provide previously collected tumor tissue Women and men ≥18 years of age with performance status of 0 or 1 At least 4 weeks since any previous treatment for cancer Exclusion Criteria: Active or chronic autoimmune diseases Uncontrolled or significant cardiovascular disease Chronic hepatitis (except for subjects with hepatocellular carcinoma) Active infection Active Central nervous system (CNS) metastases Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome((HIV/AIDS) Positive test for Hepatitis B virus surface antigen or Hepatitis C antibody (except for subjects with hepatocellular carcinoma) 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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>Dose Escalation and Initial Signal Detection in Multiple Solid Tumors - Nivolumab with Lirilumab | Drug: Lirilumab<br>* Specified dose on specified days.<br>* Other names: ANTI-KIR (Killer-cell Immunoglobulin-like Receptors);Drug: Nivolumab<br>* Specified dose on specified days.<br>* Other names: ANTI-PD1;|
| Experimental: Part 2 and 3: Cohort Expansion<br>In platinum-refractory recurrent or metastatic SCCHN - Nivolumab with or without Lirilumab | Drug: Lirilumab<br>* Specified dose on specified days.<br>* Other names: ANTI-KIR (Killer-cell Immunoglobulin-like Receptors);Drug: Nivolumab<br>* Specified dose on specified days.<br>* Other names: ANTI-PD1;|
| Experimental: Part 4: Cohort Expansion<br>Additional Signal Detection in Solid Tumors - Nivolumab with Lirilumab (Study Part 4 Removed; No Subjects Enrolled) | Drug: Lirilumab<br>* Specified dose on specified days.<br>* Other names: ANTI-KIR (Killer-cell Immunoglobulin-like Receptors);Drug: Nivolumab<br>* Specified dose on specified days.<br>* Other names: ANTI-PD1;|
| Experimental: Part 5 and 6<br>Safety Lead-In and Additional Signal Detection in Solid Tumors -- Nivolumab Plus Ipilimumab with Lirilumab (Study Part 6 Removed; No Subjects Enrolled) | Drug: Lirilumab<br>* Specified dose on specified days.<br>* Other names: ANTI-KIR (Killer-cell Immunoglobulin-like Receptors);Drug: Nivolumab<br>* Specified dose on specified days.<br>* Other names: ANTI-PD1;Drug: Ipilimumab<br>* Specified dose on specified days.<br>* Other names: Anti-CTLA4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) - Parts 1, 2 and 5 | 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 an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Number of Participants With Serious Adverse Events (SAEs) - Parts 1, 2 and 5 | A Serious Adverse Event (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, or is an important medical event. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Number of Participants With Adverse Events (AEs) Leading to Discontinuation - Parts 1, 2 and 5 | Number of participants that experienced an AE leading to discontinuation. An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| The Number of Participant Deaths in the Study - Parts 1, 2 and 5 | The number of participants who died. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Number of Participants With Clinical Laboratory Test Abnormalities - Parts 1, 2 and 5 | Number of participants that experienced a clinical laboratory test abnormality, including hematology and serum chemistry, and thyroid panel abnormalities. Abnormalities considered are those Grade 3-4 events with a >= 1 grade increase from baseline. Laboratory tests are graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 3 is severe, and Grade 4 is life threatening. Baseline is defined as the last non-missing measurement prior to the first dosing date and time. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Objective Response Rate (ORR) | Objective Response Rate (ORR) is defined as the percent of participants whose best overall response (BOR) is either a complete response (CR) or partial response (PR). BOR for a participant was derived using investigator-provided tumor measurements per RECIST v1.1. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From first dose up to approximately 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) - Part 3 | Disease Control Rate (DCR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD). CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. All participants will be monitored by radiographic assessment every 8 weeks from first dose to Week 48, and every 12 weeks thereafter until PD or treatment discontinuation. | From first dose up to approximately 2.5 years | 
| Median Duration of Response (mDOR) - Parts 3 and 5 | DOR 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 were censored on the date of their last evaluable tumor assessment. Participants who started subsequent anticancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to initiation of the subsequent anticancer therapy. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From first dose to the date of the first documented tumor progression as determined or death due to any cause, whichever occurs first. (Up to approximately 2.5 years) | 
| Median Time to Response (mTTR) - Part 3 | TTR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR). CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From date of first dose of study medication to the date of the first documented objective response (up to approximately 2.5 years) | 
| The Number of Participants With >=50% or >=80% Tumor Reduction - Parts 3 and 5 | Depth of response is defined as the target tumor burden percent change from baseline at nadir for each participant as measured by the number of participants with >= 50% and >= 80% tumor reduction. Tumor assessments are performed every 8 weeks from first dose date for 48 weeks, and then every 12 weeks thereafter until progressive disease (PD) or treatment discontinuation, whichever occurs earlier. | From first dose until progressive disease (PD) or treatment discontinuation, whichever occurs earlier. (Up to approximately 2.5 years) | 
| Overall Survival (OS) - Part 3 | Overall Survival (OS) is defined as the time from date of first dose of study medication to the date of death for any cause. A participant who has not died will be censored at last known date alive. OS for a participant who initiated new cancer treatment, will also be censored at the date of the new treatment initiation. Estimated by Kaplan-Meier Method. | From date of first dose of study medication to the date of death for any cause. (Up to approximately 2.5 years) | 
| Progression Free Survival (PFS) - Part 3 | PFS is defined as the time from the first dosing date to the date of first objectively documented disease progression or death due to any cause, whichever occurs first. Participants who died without a reported prior progression was considered to have progressed on the date of their death. Participants alive with no progression were censored on the last evaluable tumor assessment date. Participants who started subsequent therapy with no prior progression were censored at the last evaluable tumor assessment prior to initiation of the subsequent therapy. Participants with no post-baseline tumor assessment and alive were censored on the date of first dose. Progression is defined as At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Clinical deterioration in the absence of radiographic evidence is not considered progression. | From first dose to the date of first objectively documented disease progression or death due to any cause, whichever occurs first. (Up to approximately 2.5 years) | 
| Progression Free Survival Rate (PFSR) at 6 Months - Part 3 | Percentage of treated participants remaining progression free and surviving at 6 months. For those participants who remain alive and have not progressed, PFS will be censored on the date of the last tumor assessment. Progression is defined as At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Clinical deterioration in the absence of radiographic evidence is not considered progression. | At 6 months after first dose | 
| Number of Participants With Adverse Events (AEs) - Part 3 | 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 an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Number of Participants With Serious Adverse Events (SAEs) - Part 3 | A Serious Adverse Event (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, or is an important medical event. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Number of Participants With Adverse Events (AEs) Leading to Discontinuation - Part 3 | Number of participants that experienced an AE leading to discontinuation. An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| The Number of Participant Deaths in the Study - Part 3 | The number of participants who died. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Number of Participants With Clinical Laboratory Test Abnormalities - Part 3 | Number of participants that experienced a clinical laboratory test abnormality, including hematology and serum chemistry, and thyroid panel abnormalities. Abnormalities considered are those Grade 3-4 events with a >= 1 grade increase from baseline. Laboratory tests are graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 3 is severe, and Grade 4 is life threatening. Baseline is defined as the last non-missing measurement prior to the first dosing date and time. | From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years) | 
| Number of Participants With Anti-Drug Antibodies (ADA) - Parts 1, 2 and 5 | Number of participants observed as ADA positive at baseline, ADA positive (post-baseline), and ADA negative (post-baseline). Baseline is defined as the last sample before initiation of treatment Baseline ADA Positive Participant: A participant with baseline ADA positive sample. ADA Positive Participant: Participant with >=1 ADA +ve sample relative to baseline (baseline ADA -ve, or ADA titer >= 9-fold for Lirilumab and >= 4-fold for Nivolumab relative to baseline +ve titer) at any time after first dose during the defined observation time period. ADA Negative Participant: A participant with no ADA positive sample after the initiation of treatment. | From first dose to 100 days after last dose (up to approximately 126 weeks) | 
| The Number of Participants With PD-L1 Status at Pretreatment - Parts 1, 2 and 5 | The number of participants with 1% or 5% PD-L1 expression in the tumor cell membrane. Participants are considered positive if they show >=1% or >= 5% PD-L1 expression in the tumor cell membrane and negative if they show < 1% or < 5%. PD-L1 expression is defined as the percent of tumor cells demonstrating plasma membrane PDL1 staining of any intensity. PD-L1 will be evaluated by immunohistochemistry (IHC). PD-L1 status at pretreatment is considered positive if any pretreatment sample is positive. PDL1= programmed cell death ligand 1 | Pre-dose Day 1 (Cycles 1 ,3 ,5, 7, 9), Pre-dose Day 29 (Cycle 1, 2) | 
| Maximum Observed Plasma Concentration (Cmax) - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval [AUC(TAU)] - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Time of Maximum Observed Concentration (Tmax) - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. | Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Half-life (T-HALF) - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. | Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Clearance Per Time (CLT) - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Trough Observed Concentration (Cmin, Also Known as CTAU) - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Area Under the Pasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time ([AUC(INF)] - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. AUC(INF) was based on appropriate characterization of the elimination phase of the concentration versus time curve, which was unable to be performed due to limited sampling in this study. | Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| Apparent Volume of Distribution During Terminal Phase (Vz) - Parts 1, 2 and 5 | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. VZ was based on appropriate characterization of the elimination phase of the concentration versus time curve, which was unable to be performed due to limited sampling in this study. | Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29. | 
| End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Liri) | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose and end of infusion on cycle 1 day 1 and cycle 2 day 29. | 
| Ctrough - Parts 1, 2 and 5 (Liri) | Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose on cycle 1 day 29 and Pre-dose and end of infusion on cycle 2 day 29. | 
| End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Nivo) | Pharmacokinetics of nivolumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | Pre-dose and end of infusion on cycle 1 day 1 and cycle 2 day 29. | 
| Ctrough - Parts 1, 2 and 5 (Nivo) | Pharmacokinetics of nivolumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. | 336 hours post dose on cycle 1 day 1 (cycle 1 day 15) and pre-dose and end of infusion on cycle 2 day 29. |