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)
Overview
- Phase
- Phase 1
- Intervention
- Nivolumab
- Conditions
- Non-small Cell Lung Cancer
- Sponsor
- Bristol-Myers Squibb
- Enrollment
- 472
- Locations
- 10
- Primary Endpoint
- Number of Participants Who Experienced Serious Adverse Events (SAE), Adverse Events (AE) Leading to Discontinuation, or Death
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
Investigators
Eligibility Criteria
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
- •No more than 4 brain metastases
- •Each brain metastases ≤3 cm in size
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
Arms & Interventions
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
Intervention: Nivolumab
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
Intervention: Gemcitabine
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
Intervention: Cisplatin
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
Intervention: Nivolumab
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
Intervention: Cisplatin
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
Intervention: Pemetrexed
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
Intervention: Nivolumab
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
Intervention: Paclitaxel
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
Intervention: Carboplatin
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
Intervention: Nivolumab
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
Intervention: Bevacizumab
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
Intervention: Nivolumab
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
Intervention: Erlotinib
Arm F: Nivolumab
Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes
Intervention: Nivolumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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: Nivolumab
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: Nivolumab
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: Nivolumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
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
Intervention: Nivolumab
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
Intervention: Ipilimumab
Outcomes
Primary Outcomes
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 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
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.
Secondary Outcomes
- 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)