Nivolumab in Combination With Ipilimumab (Part 1); Nivolumab Plus Ipilimumab in Combination With Chemotherapy (Part 2) as First Line Therapy in Stage IV Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of part 1 of this study is to determine the objective response rate (ORR) in stage IV NSCLC subjects treated with nivolumab in combination with ipilimumab as first line therapy. The purpose of part 2 of this study is to determine the safety and tolerability of nivolumab and ipilimumab combined with a short course of chemotherapy in first line stage IV NSCLC.

Official Title
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A Study of Nivolumab in Combination With Ipilimumab (Part 1); and Nivolumab Plus Ipilimumab in Combination With Chemotherapy (Part 2) as First Line Therapy in Stage IV Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small-Cell Lung Cancer

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab
* Drug: Platinum Doublet Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and Women ≥ 18 years of age Diagnosed with stage IV Non-Small Cell Lung Cancer Diagnosed with recurrent stage IIIB non-small cell lung cancer and failed previous concurrent chemoradiation with no further curative options. Exclusion Criteria: Subjects with untreated CNS metastases are excluded. Subjects with carcinomatous meningitis Subjects with an active, known or suspected autoimmune disease. Subjects with a condition requiring systemic treatment with either corticosteroids ( > 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment. Women who are pregnant, plan to become pregnant, and/or breastfeed during the study. Other protocol defined inclusion/exclusion criteria 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: Nivolumab+Ipilimumab<br>Part 1 Specified Dose on Specified Days | Biological: Nivolumab<br>* Specified Dose on Specified Days<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Specified Dose on Specified Days<br>* Other names: Yervoy;|
| Experimental: Nivolumab+Ipilimumab + 2 cycles Platinum Doublet Chemotherapy<br>Part 2 Specified Dose on Specified Days | Biological: Nivolumab<br>* Specified Dose on Specified Days<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Specified Dose on Specified Days<br>* Other names: Yervoy;Drug: Platinum Doublet Chemotherapy<br> <br> * Other names: Cisplatin + pemetrexed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) by PD-L1 Positive and Negative Levels - Part 1 | Objective response rate (ORR) in PD-L1 positive (PD-L1 ≥1%) and PD-L1 negative (PD-L1 <1%) participants was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on Blinded Independent Central Review (BICR) assessment. | From first dose to database lock (Up to 18 months) | 
| Number of Participants With Dose Limiting Toxicities (DLTs) - Part 2 | Dose limiting toxicities (DLTs) were defined as any of the items listed below. Any Grade 2 drug-related uveitis or eye pain that does not respond to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires systemic treatment. Any Grade 2 drug-related pneumonitis or interstitial lung disease that does not resolve to dose delay and systemic steroids in 14 days. Any Grade 3 non-skin drug-related adverse event with the exception of laboratory abnormalities that cannot be alleviated or controlled by appropriate care within 14 days. Any Grade 4 drug-related adverse event including laboratory abnormalities except Grade 4 leukopenia or neutropenia lasting < 14 days and asymptomatic amylase/lipase elevation. Drug-related hepatic function laboratory abnormalities. | 9 weeks after first dose | 
| Number of Participants With Adverse Events (AEs) - Part 2 | Number of participants with adverse events (AEs) including serious adverse events (SAEs) and deaths graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy. | Deaths are from first dose to database lock (Up to 24 months). AEs and SAEs are from first dose to 30 days post last dose | 
| Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 | Number of participant with specific liver laboratory abnormalities graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy. | From first dose to 30 days post last dose | 
| Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 | Number of participants with specific thyroid laboratory abnormalities graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy. | From first dose to 30 days post last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) - Part 1 | Overall survival (OS) was defined as the time from date of first treatment to the date of death due to any cause. A participant who has not died will be censored at the last known date alive. | From the date of first treatment to the date of death due to any cause (Up to approximately 72 months) | 
| Overall Survival (OS) - Part 2 | Overall survival (OS) was defined as the time from date of first treatment to the date of death due to any cause. A participant who has not died will be censored at the last known date alive. | From the date of first treatment to the date of death due to any cause (Up to approximately 59 months) | 
| Progression Free Survival (PFS) - Part 1 | Progression Free Survival (PFS) was defined as the time between the date of first dose and the first date of documented progression, as determined by blinded independent central review (BICR), or death due to any cause, whichever occurred first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 72 months) | 
| Progression Free Survival (PFS) - Part 2 | Progression Free Survival (PFS) was defined as the time between the date of first dose and the first date of documented progression, as determined by investigator (per RECIST 1.1), or death due to any cause, whichever occurred first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 59 months) | 
| Objective Response Rate (ORR) - Part 1 | Objective response rate (ORR) was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on Blinded Independent Central Review (BICR) assessment. CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR = 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 72 months | 
| Objective Response Rate (ORR) - Part 2 | Objective response rate (ORR) was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on investigator assessment. CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR = 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 59 months | 
| Overall Survival (OS) by PD-L1 Expression Levels - Part 1 | Overall survival (OS) by PD-L1 expression levels was defined as the time from date of first treatment to the date of death due to any cause. A participant who has not died will be censored at the last known date alive. PD-L1 ≥1% = PD-L1 positive (membranous staining in ≥ 1% tumor cells) PD-L1 <1% = PD-L1 negative (membranous staining in <1% tumor cells) | From the date of first treatment to the date of death due to any cause (Up to approximately 72 months) | 
| Progression Free Survival (PFS) by PD-L1 Expression Levels - Part 1 | Progression Free Survival (PFS) by PD-L1 expression levels was defined as the time between the date of first dose and the first date of documented progression, as determined by blinded independent central review (BICR), or death due to any cause, whichever occurred first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PD-L1 ≥1% = PD-L1 positive (membranous staining in ≥ 1% tumor cells) PD-L1 <1% = PD-L1 negative (membranous staining in <1% tumor cells) | From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 72 months) | 
| Objective Response Rate (ORR) by PD-L1 Expression Levels-Part 1 | Objective response rate (ORR) by PD-L1 expression levels was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on Blinded Independent Central Review (BICR) assessment. CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD-L1 ≥1% = PD-L1 positive (membranous staining in ≥ 1% tumor cells) PD-L1 <1% = PD-L1 negative (membranous staining in <1% tumor cells) | From first dose up to approximately 72 months | 
| Overall Survival (OS) by Tumor Mutation Burden (TMB) Levels - Part 1 | Overall survival (OS) by tumor mutational burden (TMB) using DNA derived from tumor specimens was defined as the time from date of first treatment to the date of death due to any cause. A participant who has not died will be censored at the last known date alive. High TMB = ≥ 10 mutations per megabase Low TMB = < 10 mutations per megabase | From the date of first treatment to the date of death due to any cause (Up to approximately 72 months) | 
| Progression Free Survival (PFS) by Tumor Mutation Burden (TMB) Levels - Part 1 | Progression Free Survival (PFS) by tumor mutational burden (TMB) using DNA derived from tumor specimens was defined as the time between the date of first dose and the first date of documented progression, as determined by blinded independent central review (BICR), or death due to any cause, whichever occurred first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. High TMB = ≥ 10 mutations per megabase Low TMB = < 10 mutations per megabase | From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 72 months) | 
| Objective Response Rate (ORR) by Tumor Mutation Burden (TMB) Levels - Part 1 | Objective response rate (ORR) by tumor mutational burden (TMB) using DNA derived from tumor specimens was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on Blinded Independent Central Review (BICR) assessment. CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. High TMB = ≥ 10 mutations per megabase Low TMB = < 10 mutations per megabase | From first dose up to approximately 72 months |