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)
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT01454102 |
|
Recruitment Status :
Completed
First Posted : October 18, 2011
Results First Posted : August 5, 2019
Last Update Posted : October 12, 2021
|
- Study Details
- Tabular View
- Study Results
- Disclaimer
- How to Read a Study Record
- 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Non-small Cell Lung Cancer | Biological: Nivolumab Drug: Gemcitabine Drug: Cisplatin Drug: Pemetrexed Drug: Paclitaxel Drug: Carboplatin Drug: Bevacizumab Drug: Erlotinib Biological: Ipilimumab | Phase 1 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 472 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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) |
| Actual Study Start Date : | December 16, 2011 |
| Actual Primary Completion Date : | July 20, 2016 |
| Actual Study Completion Date : | July 23, 2021 |
| 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 |
Biological: Nivolumab
Other Name: BMS-936558 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 |
Biological: Nivolumab
Other Name: BMS-936558 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 |
Biological: Nivolumab
Other Name: BMS-936558 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 |
Biological: Nivolumab
Other Name: BMS-936558 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 |
Biological: Nivolumab
Other Name: BMS-936558 Drug: Erlotinib |
|
Experimental: Arm F: Nivolumab
Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes
|
Biological: Nivolumab
Other Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: BMS-936558 Biological: Ipilimumab |
- 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
- 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.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01454102
| United States, California | |
| Ucla | |
| Los Angeles, California, United States, 90095 | |
| United States, Connecticut | |
| Yale University | |
| New Haven, Connecticut, United States, 06520 | |
| United States, Florida | |
| H. Lee Moffitt Cancer Center & Research Institute | |
| Tampa, Florida, United States, 33612 | |
| United States, Maryland | |
| Johns Hopkins Sidney Kimmel Comprehensive Cancer Center | |
| Baltimore, Maryland, United States, 21287 | |
| United States, New York | |
| Memorial Sloan Kettering Nassau | |
| New York, New York, United States, 10065 | |
| United States, North Carolina | |
| Duke University Medical Center | |
| Durham, North Carolina, United States, 27710 | |
| United States, Pennsylvania | |
| Fox Chase Cancer Center | |
| Philadelphia, Pennsylvania, United States, 19111 | |
| United States, Texas | |
| Ut Southwestern Medical Center At Dallas | |
| Dallas, Texas, United States, 75390-8852 | |
| United States, Washington | |
| University of Washington - Seattle Cancer Care Alliance | |
| Seattle, Washington, United States, 98109 | |
| Canada, Ontario | |
| Local Institution | |
| Hamilton, Ontario, Canada, L8V 5C2 | |
| Local Institution | |
| Ottawa, Ontario, Canada, K1H 8L6 | |
| Local Institution | |
| Toronto, Ontario, Canada, M5G 2M9 | |
| Study Director: | Bristol-Myers Squibb | Bristol-Myers Squibb |
Publications:
| Responsible Party: | Bristol-Myers Squibb |
| ClinicalTrials.gov Identifier: | NCT01454102 |
| Other Study ID Numbers: |
CA209-012 |
| First Posted: | October 18, 2011 Key Record Dates |
| Results First Posted: | August 5, 2019 |
| Last Update Posted: | October 12, 2021 |
| Last Verified: | September 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
|
Lung Neoplasms Carcinoma, Non-Small-Cell Lung Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms Paclitaxel Bevacizumab Carboplatin Gemcitabine Nivolumab |
Pemetrexed Erlotinib Hydrochloride Ipilimumab Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors |