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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 472
- 试验地点
- 10
- 主要终点
- Number of Participants Who Experienced Serious Adverse Events (SAE), Adverse Events (AE) Leading to Discontinuation, or Death
研究概览
简要总结
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: Nivolumab (Biological)
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
干预措施: Gemcitabine (Drug)
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
干预措施: Cisplatin (Drug)
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
干预措施: Nivolumab (Biological)
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
干预措施: Cisplatin (Drug)
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
干预措施: Pemetrexed (Drug)
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
干预措施: Nivolumab (Biological)
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
干预措施: Paclitaxel (Drug)
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
干预措施: Carboplatin (Drug)
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
干预措施: Nivolumab (Biological)
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
干预措施: Bevacizumab (Drug)
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
干预措施: Nivolumab (Biological)
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
干预措施: Erlotinib (Drug)
Arm F: Nivolumab
Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes
干预措施: Nivolumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
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
干预措施: Nivolumab (Biological)
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
干预措施: Ipilimumab (Biological)
结局指标
主要结局
Number of Participants Who Experienced Serious Adverse Events (SAE), Adverse Events (AE) Leading to Discontinuation, or Death
时间窗: 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 With Abnormalities in Selected Hepatic Clinical Laboratory Tests
时间窗: 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
时间窗: 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
Number of Participants Who Experienced Selected Adverse Events
时间窗: 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.
次要结局
- Objective Response Rate (ORR)(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(24 weeks)