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)

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)

• 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.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Gemcitabine; Drug: Cisplatin; Drug: Pemetrexed; Drug: Erlotinib; Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab; Biological: Nivolumab; Biological: Ipilimumab

• Study Type: Interventional
• Enrollment (Actual): 472
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Local Institution
    • Ottawa, Ontario, Canada, K1H 8L6
      • Local Institution
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Nassau
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390-8852
      • UT Southwestern Medical Center at Dallas
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

19

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Nivolumab + Gemcitabine + Cisplatin; 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	Drug: Gemcitabine; Drug: Cisplatin; Biological: Nivolumab; Other Names: BMS-936558
Experimental: Arm B: Nivolumab + Pemetrexed + Cisplatin; 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	Drug: Cisplatin; Drug: Pemetrexed; Biological: Nivolumab; Other Names: BMS-936558
Experimental: Arm C: Nivolumab + Paclitaxel + Carboplatin; 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	Drug: Carboplatin; Drug: Paclitaxel; Biological: Nivolumab; Other Names: BMS-936558
Experimental: Arm D: Nivolumab + Bevacizumab maintenance; 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	Drug: Bevacizumab; Biological: Nivolumab; Other Names: BMS-936558
Experimental: Arm E: Nivolumab + Erlotinib; 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	Drug: Erlotinib; Biological: Nivolumab; Other Names: BMS-936558
Experimental: Arm F: Nivolumab; Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes	Biological: Nivolumab; Other Names: BMS-936558
Experimental: Arm G: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm H: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm I: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm J: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm K: Nivolumab; 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; Other Names: BMS-936558
Experimental: Arm L: Nivolumab; 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; Other Names: BMS-936558
Experimental: Arm M: Nivolumab; 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; Other Names: BMS-936558
Experimental: Arm N: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm O: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm P: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm Q: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm R: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab
Experimental: Arm S: Nivolumab + Ipilimumab; 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; Other Names: BMS-936558; Biological: Ipilimumab

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens RA, Shepherd FA, Laurie SA, Geese WJ, Agrawal S, Young TC, Li X, Antonia SJ. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017 Jan;18(1):31-41. doi: 10.1016/S1470-2045(16)30624-6. Epub 2016 Dec 5.
• Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, Chow LQ, Gerber DE, Laurie SA, Goldman JW, Shepherd FA, Chen AC, Shen Y, Nathan FE, Harbison CT, Antonia S. Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Sep 1;34(25):2969-79. doi: 10.1200/JCO.2016.66.9861. Epub 2016 Jun 27.
• Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, Gerber DE, Shepherd FA, Antonia S, Goldman JW, Juergens RA, Laurie SA, Nathan FE, Shen Y, Harbison CT, Hellmann MD. Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Sep 1;34(25):2980-7. doi: 10.1200/JCO.2016.66.9929. Epub 2016 Jun 27.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2011
• Primary Completion (Actual): July 20, 2016
• Study Completion (Actual): July 23, 2021

Study Registration Dates

• First Submitted: September 16, 2011
• First Submitted That Met QC Criteria: October 17, 2011
• First Posted (Estimate): October 18, 2011

Study Record Updates

• Last Update Posted (Actual): October 12, 2021
• Last Update Submitted That Met QC Criteria: September 20, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Folic Acid Antagonists; Gemcitabine; Carboplatin; Paclitaxel; Erlotinib Hydrochloride; Nivolumab; Bevacizumab; Pemetrexed; Ipilimumab
• Other Study ID Numbers: CA209-012

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No