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)

Bristol-Myers Squibb (BMS)

Status and phase: Completed; Phase 1

Conditions: Non-small Cell Lung Cancer

Treatments: Drug: Cisplatin; Drug: Gemcitabine; Drug: Carboplatin; Biological: Nivolumab; Drug: Erlotinib; Biological: Ipilimumab; Drug: Bevacizumab; Drug: Paclitaxel; Drug: Pemetrexed

Study type: Interventional

Funder types: Industry

Identifiers

NCT01454102

CA209-012

Details and patient eligibility

About

• 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.

Enrollment: 472 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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472 participants in 19 patient groups

Arm A: Nivolumab + Gemcitabine + Cisplatin

Experimental group

Description:

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

Treatment:

Drug: Gemcitabine

Drug: Cisplatin

Biological: Nivolumab

Arm B: Nivolumab + Pemetrexed + Cisplatin

Experimental group

Description:

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

Treatment:

Drug: Cisplatin

Biological: Nivolumab

Drug: Pemetrexed

Arm C: Nivolumab + Paclitaxel + Carboplatin

Experimental group

Description:

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

Treatment:

Drug: Carboplatin

Drug: Paclitaxel

Biological: Nivolumab

Arm D: Nivolumab + Bevacizumab maintenance

Experimental group

Description:

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

Treatment:

Drug: Bevacizumab

Biological: Nivolumab

Arm E: Nivolumab + Erlotinib

Experimental group

Description:

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

Treatment:

Drug: Erlotinib

Biological: Nivolumab

Arm F: Nivolumab

Experimental group

Description:

Nivolumab solution intravenously every 2 weeks until PD or discontinuation due to toxicity. Administered over 60 minutes

Treatment:

Biological: Nivolumab

Arm G: Nivolumab + Ipilimumab

Experimental group

Description:

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

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm H: Nivolumab + Ipilimumab

Experimental group

Description:

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

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm I: Nivolumab + Ipilimumab

Experimental group

Description:

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

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm J: Nivolumab + Ipilimumab

Experimental group

Description:

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

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm K: Nivolumab

Experimental group

Description:

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

Treatment:

Biological: Nivolumab

Arm L: Nivolumab

Experimental group

Description:

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

Treatment:

Biological: Nivolumab

Arm M: Nivolumab

Experimental group

Description:

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

Treatment:

Biological: Nivolumab

Arm N: Nivolumab + Ipilimumab

Experimental group

Description:

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

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm O: Nivolumab + Ipilimumab

Experimental group

Description:

Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm P: Nivolumab + Ipilimumab

Experimental group

Description:

Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm Q: Nivolumab + Ipilimumab

Experimental group

Description:

Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm R: Nivolumab + Ipilimumab

Experimental group

Description:

Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity

Treatment:

Biological: Ipilimumab

Biological: Nivolumab

Arm S: Nivolumab + Ipilimumab

Experimental group

Description:

Nivolumab at specified dose/schedule until PD or discontinuation due to toxicity Ipilimumab at specified dose/schedule until PD or discontinuation due to toxicity

Treatment:

Biological: Ipilimumab

Biological: Nivolumab