Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Head and Neck Neoplasms

Precancerous Conditions

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Nivolumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

Brandi Kubala

Robert Keith, M.D.

Robert Keith, MD

The goal of this clinical research study is to determine whether the PD-1 inhibitor (Programmed cell death protein 1) 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.

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.

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.

Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers

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

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

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

Pre- and post-treatment biopsies will be stained by immunofluorescence for Th1, Th2, and Treg CD4+ T lymphocytes

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.

The number of non-synonymous mutations in bronchial dysplastic lesions will be determined by whole exsome sequencing

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).

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.

1. Two-month change (difference between 2-month score and baseline score) in worst (i.e., maximum) histologic classification score
2. Using all dysplastic (i.e., histology score ≥ 4.0) baseline biopsy pairs, the change in average histology and dysplasia index
3. Using all matched biopsies, the change in worst histology, average histology, and dysplasia index
4. Using all matched biopsies from reference sites, the change in worst histology, average histology, and dysplasia index
5. Response to treatment of completers, based on worst histology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers	NCT03347838	Bronchial Dyspl... Tobacco Smoking History of Non-... History of Head...	Nivolumab	18 Years - 80 Years	University of Colorado, Denver
Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers	NCT03347838	Bronchial Dyspl... Tobacco Smoking History of Non-... History of Head...	Nivolumab	18 Years - 80 Years	University of Colorado, Denver

Spots Global Cancer Trial Database for history of head and neck cancer