Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers
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|ClinicalTrials.gov Identifier: NCT03347838|
Recruitment Status : Recruiting
First Posted : November 20, 2017
Last Update Posted : September 8, 2021
|Condition or disease||Intervention/treatment||Phase|
|Bronchial Dysplasia Tobacco Smoking History of Non-Small Cell Lung Cancer History of Head and Neck Cancer||Drug: Nivolumab||Phase 2|
This is a single-institution, open-label, single-arm, two-stage, phase II study of the PD-1 inhibitor nivolumab in patients at high risk for lung cancer. Simon's two-stage design will be used. In the first stage, 18 subjects will be enrolled. If at least 7 subjects respond to nivolumab, then an additional 24 subjects will be enrolled for a total of 42 subjects. The central hypothesis to be tested by this trial is that immune evasion contributes to malignant transformation of premalignant bronchial dysplastic lesions into invasive lung cancers, and that blocking PD-1 will allow the immune system to target and eradicate premalignant bronchial dysplastic lesions, thereby preventing the development of lung cancer.
Nivolumab 240 mg IV will be administered every two weeks for a total of four doses (8 weeks). Participants will undergo bronchoscopy with endobronchial biopsy at study entry, 2 months, and 6 months. The primary endpoint will be change in bronchial dysplasia between study entry and the 6 month timepoint. Secondary endpoints include safety and tolerability of nivolumab in patients with bronchial dysplastic lesions, and additional endobronchial histology endpoints. Exploratory endpoints will be used to identify predictive markers of response to nivolumab.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||42 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||The goal of this clinical research study is to determine whether the Programmed cell death protein 1 (PD-1) inhibitor nivolumab improves premalignant bronchial dysplastic lesions in subjects that are at high risk for the development of lung cancer, including those with a prior smoking history, or history of lung cancer or head and neck cancer. The safety and tolerability of nivolumab will also be studied.|
|Masking:||None (Open Label)|
|Official Title:||PD-1 Immune Checkpoint Inhibition for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers With or Without a History of Lung Cancer|
|Actual Study Start Date :||December 6, 2018|
|Estimated Primary Completion Date :||December 2021|
|Estimated Study Completion Date :||December 2021|
Experimental: Nivolumab Injection [Opdivo]
240 mg IV every 2 weeks for 4 doses
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
- Improvement in endobronchial histology [ Time Frame: 6 months ]The primary endpoint is the dichotomous endpoint of whether a subject responds to PD-1 immune checkpoint inhibition using nivolumab. Response will be based on the 6-month change (difference between 6-month score and baseline score) in worst (i.e., maximum) histologic classification score, using the 2004 World Health Organization (WHO) classification scale for pre-invasive squamous lesions of the bronchus. The histologic classification consists of: normal (grade 1.0), reserve cell hyperplasia (grade 2.0), squamous metaplasia (grade 3.0), mild dysplasia (grade 4.0), moderate dysplasia (grade 5.0), severe dysplasia (grade 6.0), carcinoma in situ (grade 7.0) and invasive cancer (grade 8.0).
- Incidence of immune-related adverse events (irAEs) [ Time Frame: Every 2 weeks through 3 months, then every 3 months through 1 year ]Patients will be evaluated every 2 weeks to determine whether they have any immune-related adverse events (irAEs) using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). In particular, patients will be monitored closely for evidence of dermatological, gastrointestinal, endocrine, renal, and pulmonary irAEs. Complete blood count, comprehensive metabolic profile, and thyroid function tests will be obtained at baseline and every 3 months for 1 year. A comprehensive metabolic profile will also be checked every 2 weeks. Subjects will be followed for a total of 1 year to monitor for development of irAEs after discontinuation of the study drug.
- Additional endobronchial histology endpoints using the 2004 WHO classification scale for pre-invasive squamous lesions of the bronchus [ Time Frame: 2 months and 6 months ]
- Two-month change (difference between 2-month score and baseline score) in worst (i.e., maximum) histologic classification score
- Using all dysplastic (i.e., histology score ≥ 4.0) baseline biopsy pairs, the change in average histology and dysplasia index
- Using all matched biopsies, the change in worst histology, average histology, and dysplasia index
- Using all matched biopsies from reference sites, the change in worst histology, average histology, and dysplasia index
- Response to treatment of completers, based on worst histology
- Proportion of T lymphocytes in bronchial dysplastic lesions that express PD-1 [ Time Frame: Baseline, 2 months, and 6 months ]The proportion of T lymphocytes that express programmed death receptor 1 (PD-1) in pre- and post-treatment biopsies will be compared by immunofluorescence staining of formalin-fixed, paraffin-embedded tissue sections
- Proportion of macrophages in bronchial dysplastic lesions that express PD-L1 [ Time Frame: Baseline, 2 months, and 6 months ]The proportion of macrophages that express programmed death ligand 1 (PD-L1) in pre- and post-treatment biopsies will be compared by immunofluorescence staining of formalin-fixed, paraffin-embedded tissue sections
- Quantification of CD4+ T lymphocyte subsets in bronchial dysplastic lesions [ Time Frame: Baseline, 2 months, and 6 months ]Pre- and post-treatment biopsies will be stained by immunofluorescence for Th1, Th2, and Treg CD4+ T lymphocytes
- Ratio of M1:M2 macrophages in bronchial dysplastic lesions [ Time Frame: Baseline, 2 months, and 6 months ]Pre- and post-treatment biopsies will be stained by immunofluorescence for CD68, HLA-DRA, and CD206. The ratio of M1 (CD68/HLA-DRA) to M2 (CD68/CD206) macrophages will be determined.
- Number of non-synonymous mutations in bronchial dysplastic lesions [ Time Frame: Baseline ]The number of non-synonymous mutations in bronchial dysplastic lesions will be determined by whole exsome sequencing
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): NCT03347838
|Contact: Brandi Kubalaemail@example.com|
|Contact: Michele Balonque Siqueirafirstname.lastname@example.org|
|United States, Colorado|
|University of Colorado Anschutz Medical Campus||Recruiting|
|Aurora, Colorado, United States, 80045|
|Contact: Brandi Kubala 303-724-1657 email@example.com|
|Contact: Michele Baloneque Siqueira 303-724-1662 firstname.lastname@example.org|
|Sub-Investigator: Robert Keith, M.D.|
|Denver VA Hospital||Recruiting|
|Denver, Colorado, United States, 80220|
|Contact: Brandi Kubala 303-724-1657 email@example.com|
|Contact: Michele Michele Baloneque Siqueira 303-724-1662 firstname.lastname@example.org|
|Principal Investigator: Robert Keith, MD|
|Principal Investigator:||Robert Keith, MD||University of Colorado, Denver|