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

University of Colorado Denver (CU Denver)

Status and phase

Active, not recruiting

Phase 2

Conditions

Bronchial Dysplasia

History of Non-Small Cell Lung Cancer

Tobacco Smoking

History of Head and Neck Cancer

Treatments

Drug: Nivolumab

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT03347838

17-1492.cc

Details and patient eligibility

About

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.

Full description

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.

Enrollment

36 patients

Sex

All

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

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