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

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.

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 or known bronchial dysplasia, 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. An ex-smoker is defined as no tobacco use in the prior 12 months
• 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
• Albumin > 2.5 mg/dL
• ECOG performance status ≤ 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