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

• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of drug related adverse events [ Time Frame: Up to 100 days after the last dose of study drug (approximately 36 weeks) ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of serious adverse events [ Time Frame: Up to 100 days after the last dose of study drug (approximately 36 weeks) ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: At screening (up to 28 days prior to first treatment) ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: Cycle 1 Day 1 ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: Cycle 1 Day 8 ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: Cycle 1 Day 15 ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: Cycle 2 Day 1 ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: Cycle 3 Day 1 ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: Cycle 4 Day 1 ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: Day 1 of every cycle from Cycle 4 until progression (approximately 24 weeks) ] [ Designated as safety issue: Yes ]
• Safety and tolerability of Nivolumab in combination with chemotherapy measured by frequency of clinical laboratory test by worst toxicity grade [ Time Frame: End of treatment (approximately 24 weeks) for subjects discontinued due to other reasons ] [ Designated as safety issue: Yes ]

• Safety and tolerability of BMS-936558 in combination with chemotherapy measured by frequency of adverse events [ Time Frame: Up to 30 days after last dose of study drug (or longer) ] [ Designated as safety issue: Yes ]
• Safety and tolerability of BMS-936558 in combination with chemotherapy measured by serious adverse events [ Time Frame: Up to 90 days after last dose of study drug (or longer) ] [ Designated as safety issue: Yes ]
• Safety and tolerability of BMS-936558 in combination with chemotherapy measured by laboratory abnormalities and death [ Time Frame: Up to 90 days after last dose of study drug (expect to be 24 month) ] [ Designated as safety issue: Yes ]

• ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of subjects treated in arms A, B, C and D [ Time Frame: At screening (up to 28 days prior to first treatment), C4D1 (Week 10), every 6 weeks until C8D1, and then every 3 months thereafter until progression or end of treatment (approximately 24 weeks) for subjects discontinued due to other reasons ] [ Designated as safety issue: No ]

  C4D1=Cycle 4 Day 1

  C8D1=Cycle 8 Day 1

  Objective Response Rate (ORR) is defined as the proportion of all treated subjects whose best overall response is either a complete response (CR) or partial response (PR)

• PFSR based on RECIST 1.1 of subjects treated in arms A, B, C and D [ Time Frame: At screening (up to 28 days prior to first treatment), C4D1 (Week 10), every 6 weeks until C8D1, and then every 3 months thereafter until progression or end of treatment (approximately 24 weeks) for subjects discontinued due to other reasons ] [ Designated as safety issue: No ]
  Progression Free Survival Rate (PFSR) is defined as the probability a subject remaining progression-free and/or surviving to 24 weeks. The probability will be calculated by the product limit method (Kaplan-Meier method) which takes into account censored data
• ORR based on RECIST 1.1 of subjects treated in arms E, F, K, L and M [ Time Frame: At screening (up to 28 days prior to first treatment), C6D1 (Week 11), C9D1 (Week 17), C12D1 (Week 23) and then every 3 months thereafter until progression (approximately 24 weeks) ] [ Designated as safety issue: No ]
  ORR is defined as the proportion of all treated subjects whose best overall response is either a CR or PR
• PFSR based on RECIST 1.1 of subjects treated in arms E, F, K, L and M [ Time Frame: At screening (up to 28 days prior to first treatment), C6D1 (Week 11), C9D1 (Week 17), C12D1 (Week 23) and then every 3 months thereafter until progression (approximately 24 weeks) ] [ Designated as safety issue: No ]
  PFSR is defined as the probability a subject remaining progression-free and/or surviving to 24 weeks. The probability will be calculated by the product limit method (Kaplan-Meier method) which takes into account censored data
• ORR based on RECIST 1.1 of subjects treated in arms G, H, I and J [ Time Frame: C4D1 (Week 10), C7D1 (Week 17), C10D1 (Week 23) and then every 3 months thereafter until disease progression (approximately 24 weeks) ] [ Designated as safety issue: No ]
  ORR is defined as the proportion of all treated subjects whose best overall response is either a CR or PR
• PFSR based on RECIST 1.1 of subjects treated in arms G, H, I and J [ Time Frame: C4D1 (Week 10), C7D1 (Week 17), C10D1 (Week 23) and then every 3 months thereafter until disease progression (approximately 24 weeks) ] [ Designated as safety issue: No ]
  PFSR is defined as the probability a subject remaining progression-free and/or surviving to 24 weeks. The probability will be calculated by the product limit method (Kaplan-Meier method) which takes into account censored data

• Objective response rate (ORR) defined as the proportion of all treated subjects whose best response is either a complete response (CR) or partial response (PR) [ Time Frame: From the date of first dose of study drug until the date of first documented progression, or date of death, whichever come first (expect to be 24 month) ] [ Designated as safety issue: No ]
• Disease control rate (DCR) defined as the proportion of all treated subjects whose best response is either a CR or PR or stable disease (SD) lasting for 24 weeks or greater [ Time Frame: From the date of first dose of study drug until date of first documented progression, or date of death, whichever come first (expect to be 24 month) ] [ Designated as safety issue: No ]

There is no formal research hypothesis to be statistically tested in this protocol.

• 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 have no evidence of cerebral edema.

• Biological: Nivolumab
  Other Name: BMS-936558
• Drug: Gemcitabine
• Drug: Cisplatin
• Drug: Pemetrexed
• Drug: Paclitaxel
• Drug: Carboplatin
• Drug: Bevacizumab
• Drug: Erlotinib
• Biological: Ipilimumab

• Experimental: Arm A: Nivolumab + Gemcitabine + Cisplatin

  Nivolumab 10 mg/kg solution intravenously every 3 weeks until progressive disease (PD) or discontinuation due to toxicity. Administered over 60 minutes prior to chemotherapy on Day 1 of each cycle. A cycle is 3 weeks.

  Gemcitabine 1250 mg/M² solution intravenously on Day 1 and Day 8 of every 3 weeks cycle for 4 cycles

  Cisplatin 75 mg/M² solution intravenously on Day 1 of each 3 weeks cycle for 4 cycles

  Interventions:

  • Biological: Nivolumab
  • Drug: Gemcitabine
  • Drug: Cisplatin
• Experimental: Arm B: Nivolumab + Pemetrexed + Cisplatin

  Nivolumab 5 mg/kg solution intravenously every 3 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes prior to chemotherapy on Day 1 of each cycle. A cycle is 3 weeks.

  Pemetrexed 500 mg/M² solution intravenously on Day 1 of every 3 weeks cycle for 4 cycles

  Cisplatin 75 mg/M² solution intravenously on Day 1 of each 3 weeks cycle for 4 cycles

  Interventions:

  • Biological: Nivolumab
  • Drug: Cisplatin
  • Drug: Pemetrexed
• Experimental: Arm C: Nivolumab + Paclitaxel + Carboplatin

  Nivolumab 0.3 mg/kg solution intravenously every 3 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes prior to chemotherapy on Day 1 of each cycle. A cycle is 3 weeks.

  Paclitaxel 200 mg/M² solution intravenously on Day 1 of every 3 weeks cycle for 4 cycles

  Carboplatin area under curve (AUC) 6 solution intravenously on Day 1 of every 3 weeks cycle for 4 cycles

  Interventions:

  • Biological: Nivolumab
  • Drug: Paclitaxel
  • Drug: Carboplatin
• Experimental: Arm D: Nivolumab + Bevacizumab maintenance

  Nivolumab 5 mg/kg solution intravenously every 3 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes prior to chemotherapy on Day 1 of each cycle. A cycle is 3 weeks.

  Bevacizumab 15 mg/kg administered over 90 minute intravenous infusion on Cycle 1 Day 1 followed by a 60 minute intravenous infusion every 3 weeks on Cycle 2 onwards and until PD or discontinuation due to toxicity.

  Interventions:

  • Biological: Nivolumab
  • Drug: Bevacizumab
• Experimental: Arm E: Nivolumab + Erlotinib

  Nivolumab 3 mg/kg solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes prior to chemotherapy on Day 1 of each cycle. A cycle is 2 weeks.

  Erlotinib 150 mg tablet by mouth daily until PD or discontinuation due to toxicity.

  Interventions:

  • Biological: Nivolumab
  • Drug: Erlotinib
• Experimental: Arm F: Nivolumab
  Nivolumab 3 mg/kg solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes. A cycle is 2 weeks.
  Intervention: Biological: Nivolumab
• Experimental: Arm G: Nivolumab + Ipilimumab

  In Squamous histology subjects (NSCLC)

  Nivolumab 1 mg/kg solution administered over 60 minutes intravenously prior to Ipilimumab on Day 1 of each cycle. A cycle is 3 weeks for combination regimen. Combination regimen will be provided for 4 cycles.

  Ipilimumab 3 mg/kg solution administered over 90 minutes intravenously on Day 1 of each cycle, every 3 weeks for 4 cycles.

  Followed by Nivolumab (3 mg/kg) administered every 2 weeks until PD or discontinuation due to toxicity.

  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab
• Experimental: Arm H: Nivolumab + Ipilimumab

  In non-squamous histology subjects (NSCLC)

  Nivolumab 1 mg/kg solution administered over 60 minutes intravenously prior to Ipilimumab on Day 1 of each cycle. A cycle is 3 weeks for combination regimen. Combination regimen will be provided for 4 cycles.

  Ipilimumab 3 mg/kg solution administered over 90 minutes intravenously on Day 1 of each cycle, every 3 weeks for 4 cycles.

  Followed by Nivolumab (3 mg/kg) administered every 2 weeks until PD or discontinuation due to toxicity.

  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab
• Experimental: Arm I: Nivolumab + Ipilimumab

  In squamous histology subjects (NSCLC)

  Nivolumab 3 mg/kg solution administered over 60 minutes intravenously prior to Ipilimumab on Day 1 of each cycle. A cycle is 3 weeks for combination regimen. Combination regimen will be provided for 4 cycles.

  Ipilimumab 1 mg/kg solution administered over 90 minutes intravenously on Day 1 of each cycle, every 3 weeks for 4 cycles.

  Followed by Nivolumab (3 mg/kg) administered every 2 weeks until PD or discontinuation due to toxicity.

  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab
• Experimental: Arm J: Nivolumab + Ipilimumab

  In non-squamous histology subjects (NSCLC)

  Nivolumab 3 mg/kg solution administered over 60 minutes intravenously prior to Ipilimumab on Day 1 of each cycle. A cycle is 3 weeks for combination regimen. Combination regimen will be provided for 4 cycles.

  Ipilimumab 1 mg/kg solution administered over 90 minutes intravenously on Day 1 of each cycle, every 3 weeks for 4 cycles.

  Followed by Nivolumab (3 mg/kg) administered every 2 weeks until PD or discontinuation due to toxicity.

  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab
• Experimental: Arm K: Nivolumab

  In squamous histology subjects (NSCLC)

  Nivolumab 3 mg/kg 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.

  Intervention: Biological: Nivolumab
• Experimental: Arm L: Nivolumab

  In non-squamous histology subjects (NSCLC)

  Nivolumab 3 mg/kg 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.

  Intervention: Biological: Nivolumab
• Experimental: Arm M: Nivolumab

  NSCLC subjects with untreated, asymptomatic brain metastases and have no evidence of cerebral edema

  Nivolumab 3 mg/kg solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes as monotherapy. A cycle is 2 weeks

  Intervention: Biological: Nivolumab

For additional information, please contact the BMS oncology clinical trial information service at 855-216-0126 or email MyCancerStudyConnect@emergingmed.com. Please visit www.BMSStudyConnect.com for more information on clinical trial participation.

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 pneumonia or pulmonary fibrosis by imaging diagnosis of the chest or clinical symptoms