Study of Nivolumab (BMS-936558) in Combination With Gemcitabine/Cisplatin, Pemetrexed/Cisplatin, Carboplatin/Paclitaxel, Bevacizumab Maintenance, Erlotinib, Ipilimumab or as Monotherapy in Subjects With Stage IIIB/IV Non-small Cell Lung Cancer (NSCLC) (CheckMate 012)

Study Overview
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Brief Summary
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The study is evaluating the safety and tolerability of Nivolumab (BMS-936558) when combined with three platinum-based doublet chemotherapy regimens (Cisplatin/Gemcitabine; Cisplatin/Pemetrexed; and Carboplatin/Paclitaxel) in subjects with NSCLC. The study is evaluating the safety and tolerability of Nivolumab as maintenance therapy in combination with Bevacizumab/Avastin that will be given after at least 4 cycles of platinum doublet chemotherapy. The study is evaluating the safety and tolerability of Nivolumab in combination with Erlotinib among epidermal growth factor receptor (EGFR) mutation positive non-squamous NSCLC subjects and as monotherapy in subjects with NSCLC. The study is evaluating the safety and tolerability of Nivolumab in combination with Ipilimumab in subjects with squamous and non-squamous NSCLC. The study is evaluating the safety and tolerability of Nivolumab as switch maintenance therapy in subjects with squamous and non-squamous NSCLC. The study is evaluating the safety and tolerability of Nivolumab as monotherapy among subjects with untreated, asymptomatic brain metastases and no evidence of cerebral edema.

Official Title
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A Multi-arm Phase I Safety Study of Nivolumab in Combination With Gemcitabine/Cisplatin, Pemetrexed/Cisplatin, Carboplatin/Paclitaxel, Bevacizumab Maintenance, Erlotinib, Ipilimumab or as Monotherapy in Subjects With Stage IIIB/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
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Pemetrexed
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Bevacizumab
* Drug: Erlotinib
* Biological: 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: Newly diagnosed and confirmed Stage IIIB/IV NSCLC Previously treated NSCLC with asymptomatic brain metastases (eligible for Arm M) See additional details below Men and women aged ≥18 years Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Subject must be chemotherapy naive (except Arm D, K, L and M). Prior use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is acceptable. For Arms D, K, and L, subjects must be non-progressors within 42 days after completion of first-line treatment with ≥4 cycles of Platinum Doublet chemotherapy with or without Bevacizumab. See below for Arm M Either a formalin fixed tissue block or a minimum of 10 slides of tumor sample (archived or fresh) must be available for biomarker evaluation (a local pathologist must review for adequacy of sampling) Life expectancy of at least 3 months Prior radiotherapy must have been completed at least 2 weeks prior to study entry For Arm M: No more than 4 brain metastases Each brain metastases ≤3 cm in size No evidence of cerebral edema Subjects must be free of neurologic symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroids for ≥10 days prior to initiation of study treatment At least 1 measurable target brain lesion >0.5 cm and no larger than 3 cm in diameter and/or 2 measurable brain target lesions >0.3 cm No prior radiation therapy, surgery, or other local therapy for target brain lesions Must have received at least one prior systemic anticancer therapy for NSCLC Exclusion Criteria: Subjects with symptomatic brain metastases, spinal cord compression, or intractable back pain due to a compressive or destructive mass Subjects who require emergent use of systemic steroids, emergent surgery and/or radiotherapy Any active or history of a known autoimmune disease Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric, or colon cancers or cervical cancers/dysplasia, or breast carcinoma in situ) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period History of Grade ≥2 neuropathy Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Nivolumab + Gemcitabine + Cisplatin<br>Nivolumab solution intravenously every 3 weeks until progressive disease (PD) or discontinuation due to toxicity. Administered prior to chemotherapy on Day 1 of each cycle Gemcitabine solution intravenously on Day 1 and Day 8 of every cycle for 4 cycles Cisplatin solution intravenously on Day 1 of each cycle for 4 cycles | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Drug: Gemcitabine<br> <br> Drug: Cisplatin<br> <br> |
| Experimental: Arm B: Nivolumab + Pemetrexed + Cisplatin<br>Nivolumab solution intravenously every 3 weeks until PD or discontinuation due to toxicity. Administered prior to chemotherapy on Day 1 of each cycle Pemetrexed solution intravenously on Day 1 of every cycle for 4 cycles Cisplatin solution intravenously on Day 1 of each cycle for 4 cycles | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Drug: Cisplatin<br> <br> Drug: Pemetrexed<br> <br> |
| Experimental: Arm C: Nivolumab + Paclitaxel + Carboplatin<br>Nivolumab solution intravenously every 3 weeks until PD or discontinuation due to toxicity. Administered prior to chemotherapy on Day 1 of each cycle Paclitaxel solution intravenously on Day 1 of every cycle for 4 cycles Carboplatin area under curve (AUC) 6 solution intravenously on Day 1 of every cycle for 4 cycles | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Drug: Paclitaxel<br> <br> Drug: Carboplatin<br> <br> |
| Experimental: Arm D: Nivolumab + Bevacizumab maintenance<br>Nivolumab solution intravenously every 3 weeks until PD or discontinuation due to toxicity. Administered prior to chemotherapy on Day 1 of each cycle Bevacizumab administered prior to intravenous infusion on Cycle 1 Day 1 followed by intravenous infusion every 3 weeks on Cycle 2 onwards and until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Drug: Bevacizumab<br> <br> |
| Experimental: Arm E: Nivolumab + Erlotinib<br>Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered prior to chemotherapy on Day 1 of each cycle Erlotinib tablet by mouth daily until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Drug: Erlotinib<br> <br> |
| Experimental: Arm F: Nivolumab<br>Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: Arm G: Nivolumab + Ipilimumab<br>In Squamous histology subjects (NSCLC) Nivolumab solution administered intravenously prior to Ipilimumab on Day 1 of each cycle. Combination regimen will be provided for 4 cycles Ipilimumab solution administered intravenously on Day 1 of each cycle, for 4 cycles Followed by Nivolumab administered until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm H: Nivolumab + Ipilimumab<br>In non-squamous histology subjects (NSCLC) Nivolumab solution administered intravenously prior to Ipilimumab on Day 1 of each cycle. Combination regimen will be provided for 4 cycles Ipilimumab solution administered intravenously on Day 1 of each cycle, for 4 cycles Followed by Nivolumab administered every 2 weeks until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm I: Nivolumab + Ipilimumab<br>In squamous histology subjects (NSCLC) Nivolumab solution administered intravenously prior to Ipilimumab on Day 1 of each cycle. Combination regimen will be provided for 4 cycles Ipilimumab solution administered intravenously on Day 1 of each cycle, for 4 cycles Followed by Nivolumab administered every 2 weeks until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm J: Nivolumab + Ipilimumab<br>In non-squamous histology subjects (NSCLC) Nivolumab solution administered intravenously prior to Ipilimumab on Day 1 of each cycle. Combination regimen will be provided for 4 cycles Ipilimumab solution administered intravenously on Day 1 of each cycle, for 4 cycles Followed by Nivolumab administered every 2 weeks until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm K: Nivolumab<br>In squamous histology subjects (NSCLC) Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered as switch maintenance therapy. A cycle is 2 weeks | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: Arm L: Nivolumab<br>In non-squamous histology subjects (NSCLC) Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes as switch maintenance therapy. A cycle is 2 weeks | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: Arm M: Nivolumab<br>NSCLC subjects with untreated, asymptomatic brain metastases and have no evidence of cerebral edema Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered for up to an hour as monotherapy. A cycle is 2 weeks | Biological: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: Arm N: Nivolumab + Ipilimumab<br>In subjects with any histology (NSCLC) Nivolumab solution administered intravenously prior to Ipilimumab on Day 1 of each cycle. Combination regimen will be provided for 4 cycles Ipilimumab solution administered intravenously on Day 1 of each cycle, for 4 cycles Followed by Nivolumab administered every 2 weeks until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm O: Nivolumab + Ipilimumab<br>Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm P: Nivolumab + Ipilimumab<br>Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm Q: Nivolumab + Ipilimumab<br>Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm R: Nivolumab + Ipilimumab<br>Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |
| Experimental: Arm S: Nivolumab + Ipilimumab<br>Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity | Biological: Nivolumab<br> <br> * Other names: BMS-936558;Biological: Ipilimumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Serious Adverse Events (SAE), Adverse Events (AE) Leading to Discontinuation, or Death | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. | From first dose to 30 days after the last dose of study drug (assessed up to July 2016, approximately 55 months) | 
| Number of Participants Who Experienced Selected Adverse Events | The number of participants who experienced an AE of interest due to any cause is presented. Endocrine, Gastrointestinal, Hepatic, Pulmonary, Renal, Skin, and Hypersensitivity/Infusion select AEs were identified that are potentially associated with the use of nivolumab, based on the following 4 guiding principles: AEs that may differ in type, frequency, or severity from AEs caused by non-immunotherapies AEs that may require immunosuppression (eg, corticosteroids) as part of their management AEs whose early recognition and management may mitigate severe toxicity AEs for which multiple event terms may be used to describe a single type of AE, thereby necessitating the pooling of terms for full characterization. | From first dose to 30 days after the last dose of study drug (assessed up to July 2016, approximately 55 months) | 
| Number of Participants With Abnormalities in Selected Hepatic Clinical Laboratory Tests | The number of subjects with selected hepatic laboratory abnormalities is reported. AST= aspartate aminotransferase; ALT= alanine aminotransferase; ULN= upper limit of normal. | From first dose to 30 days following last dose of study drug (assessed up to July 2016, approximately 55 months) | 
| Number of Participants With Abnormalities in Selected Thyroid Clinical Laboratory Tests | The number of subjects with selected thyroid laboratory abnormalities is reported. FT3 and FT4 test abnormalities were considered for a 2-week window after the abnormal TSH test date. TSH= thyroid-stimulating hormone; FT3= Free T3; FT4= Free T4; LLN= lower limit of normal; ULN= upper limit of normal | From first dose to 30 days following last dose of study drug (assessed up to July 2016, approximately 55 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the percentage of all treated participants who achieved a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria as per investigator assessment. This proportion was multiplied by 100 and expressed as a percentage. BOR was defined as the best response designation recorded between the date of randomization and the date of progression, or the date of subsequent anticancer therapy, whichever occurred first. CR or PR determinations included in the BOR assessment were confirmed by a second scan at least 4 weeks after the criteria for responses were first met. For participants without progression or subsequent therapy, all available response designations contributed to the BOR determination. For participants who continued treatment beyond progression, the BOR was determined based on response designations recorded up to the time of the initial progression. | From first dose until date of progression or subsequent anti-cancer therapy (assessed up to July 2016, approximately 55 months) | 
| Progression-Free Survival Rate (PFSR) at Week 24 | Progression-Free Survival (PFS) was defined as the time from the date of first dose of study medication to the date of first disease progression or death, if death occurred within 100 days of the final dose of study drug. Among participants without previous RECIST-defined progression, participants who died beyond 100 days and those who remained alive were censored at the last tumor assessment date (before subsequent therapy). PFSR at week 24 was defined as the proportion of subjects remaining progression free and surviving at 24 weeks. The proportion was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data, and expressed as a percentage. | 24 weeks |