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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Tobacco Smoking, Bronchial Dysplasia, History of Non-Small Cell Lung Cancer, History of Head and Neck Cancer

Intervention / Treatment
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* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged > 18 years A current or ex-smoker with a > 30 pack-year history of smoking and mild or worse sputum cytologic atypia, (an ex-smoker is defined as no tobacco use in the prior 12 months) OR History of non-small cell lung cancer (stage I, II, or IIIA) with > 10 pack-year history of smoking and no evidence of active disease at least 1 year after definitive treatment, OR History of head and neck cancer (stage I, II, III, or IVA) with > 10 pack-year history of smoking and no evidence of active disease at least 1 year after definitive treatment. Endobronchial dysplasia (score > 4) on screening bronchoscopy Total granulocyte count > 1500 Platelet count > 100,000 Serum creatinine < 1.5 mg/dL Total bilirubin < 2.0 mg/dL Transaminases and alkaline phosphatase < 2.5x upper limit of normal (ULN) Albumin > 2.5 mg/dL ECOG performance status ≤ 1 (Appendix 1) Participants must be able and willing to undergo three bronchoscopies: before, after four doses of nivolumab (8 weeks), and after 6 months Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Participants may not be currently receiving immune checkpoint inhibitor treatment or have been treated with immune checkpoint inhibitors in the past (including anti-programmed cell death receptor [PD]-1, anti-programmed death ligand 1 [PD-L1], and anti-cytotoxic T-lymphocyte associated protein 4 [CTLA4] monoclonal antibodies) Patients cannot receive any other investigational anti-cancer agents while participating in the study Participants cannot have used any other investigational agents within the previous six months History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Clinically apparent bleeding diathesis (i.e., bleeding that is spontaneous, excessive, or delayed in onset following tissue injury results from a localized pathologic process or a disorder of the hemostatic process, involving a complex interplay among vascular integrity, platelet number and function, coagulation factors, and fibrinolysis) Cardiac dysrhythmia that is potentially life-threatening, such as ventricular tachycardia, multifocal premature ventricular contractions or supraventricular tachycardias with a rapid ventricular response. Well-controlled atrial fibrillation or rare (< 2 minute) premature ventricular contractions are not exclusionary History of coronary artery disease, including myocardial infarction, congestive heart failure (LV ejection fraction <50% or clinically significant diastolic dysfunction), or any serious medical condition which would preclude a patient from undergoing a bronchoscopy or would jeopardize the goals of the study Individuals who are HIV-positive will be considered on a case-by-case basis, but will be required to meet criteria related to patient safety and data integrity, as assessed by the study investigators History of hepatitis B or hepatitis C infection that is untreated and/or with a detectable viral load Hypoxemia (less than 90% saturation with supplemental oxygen) Severe obstructive lung disease (GOLD Stage III or IV, FEV1<30% predicted) Prior chemotherapy or thoracic radiation within the past 1 year Participants with findings on CT chest suspicious for lung cancer (Lung-RADS category 4) will not be allowed to enroll until they have undergone additional evaluation for malignancy and an alternative (i.e., non-malignant) diagnosis has been established Current malignancy, with the exception of non-melanoma (i.e., basal cell or squamous cell) skin cancer. Patients with lung carcinoma in situ found during the study biopsy are also excluded. History of a malignancy except for adequately treated non-melanoma (i.e., basal cell or squamous cell) skin cancer or in situ cervical cancer for which the subject has not been disease-free for 5 years. Patients with a history of non-small cell lung cancer (stage I, II, or IIIA) or head and neck cancer (stage I, II, III, or IVA) must have no evidence of active disease at least 1 year after definitive treatment. History of stage IIIA NSCLC for which the only treatment was chemoradiation without surgery Known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll Conditions requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of enrollment Known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity History of interstitial pneumonitis requiring treatment with systemic corticosteroids or other immunosuppressive agents (e.g., mycophenolate, azathioprine) Life expectancy of < 1 year Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 4 weeks prior to the start of nivolumab Women must not be breastfeeding Inability to give informed consent Pneumonia or acute bronchitis for at least 2 weeks prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab Injection [Opdivo]<br>240 mg IV every 2 weeks for 4 doses | Drug: Nivolumab<br>* Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.<br>* Other names: ONO-4538;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in endobronchial histology | 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). | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of immune-related adverse events (irAEs) | 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. | Every 2 weeks through 3 months, then every 3 months through 1 year | 
| Additional endobronchial histology endpoints using the 2004 WHO classification scale for pre-invasive squamous lesions of the bronchus | 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 | 2 months and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-1, Precancerous Conditions, Nivolumab, Lung Cancer Immunoprevention