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)

• ClinicalTrials.gov Identifier: NCT01454102
• Recruitment Status: Completed
• First Posted: October 18, 2011
• Results First Posted: August 5, 2019
• Last Update Posted: October 12, 2021
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: September 16, 2011
• First Posted Date: October 18, 2011
• Results First Submitted Date: December 19, 2017
• Results First Posted Date: August 5, 2019
• Last Update Posted Date: October 12, 2021
• Actual Study Start Date: December 16, 2011
• Actual Primary Completion Date: July 20, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 2, 2019)

• Number of Participants Who Experienced Serious Adverse Events (SAE), Adverse Events (AE) Leading to Discontinuation, or Death [ Time Frame: From first dose to 30 days after the last dose of study drug (assessed up to July 2016, approximately 55 months) ]
  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.
• Number of Participants Who Experienced Selected Adverse Events [ Time Frame: From first dose to 30 days after the last dose of study drug (assessed up to July 2016, approximately 55 months) ]
  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.
• Number of Participants With Abnormalities in Selected Hepatic Clinical Laboratory Tests [ Time Frame: From first dose to 30 days following last dose of study drug (assessed up to July 2016, approximately 55 months) ]
  The number of subjects with selected hepatic laboratory abnormalities is reported. AST= aspartate aminotransferase; ALT= alanine aminotransferase; ULN= upper limit of normal.
• Number of Participants With Abnormalities in Selected Thyroid Clinical Laboratory Tests [ Time Frame: From first dose to 30 days following last dose of study drug (assessed up to July 2016, approximately 55 months) ]
  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

Original Primary Outcome Measures (submitted: October 17, 2011)

• 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) ]
• 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) ]
• 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) ]

Current Secondary Outcome Measures (submitted: August 2, 2019)

• Objective Response Rate (ORR) [ Time Frame: From first dose until date of progression or subsequent anti-cancer therapy (assessed up to July 2016, approximately 55 months) ]
  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.
• Progression-Free Survival Rate (PFSR) at Week 24 [ Time Frame: 24 weeks ]
  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.

Original Secondary Outcome Measures (submitted: October 17, 2011)

• 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) ]
• 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) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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)

Brief Summary

• 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-small Cell Lung Cancer

Intervention

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

Study Arms

• 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

  Interventions:

  • Biological: Nivolumab
  • Drug: Gemcitabine
  • Drug: Cisplatin
• 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

  Interventions:

  • Biological: Nivolumab
  • Drug: Cisplatin
  • Drug: Pemetrexed
• 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

  Interventions:

  • Biological: Nivolumab
  • Drug: Paclitaxel
  • Drug: Carboplatin
• 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

  Interventions:

  • Biological: Nivolumab
  • Drug: Bevacizumab
• 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

  Interventions:

  • Biological: Nivolumab
  • Drug: Erlotinib
• Experimental: Arm F: Nivolumab
  Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes
  Intervention: Biological: Nivolumab
• 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Intervention: Biological: Nivolumab
• 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

  Intervention: Biological: Nivolumab
• 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

  Intervention: Biological: Nivolumab
• 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • 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

  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 1, 2017): 472
• Original Estimated Enrollment (submitted: October 17, 2011): 60
• Actual Study Completion Date: July 23, 2021
• Actual Primary Completion Date: July 20, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT01454102
• Other Study ID Numbers: CA209-012
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: September 2021