Bronchial Dysplasia, History of Head and Neck Cancer, History of Non-Small Cell Lung Cancer, Tobacco Smoking
Conditions
Keywords
PD-1, Precancerous Conditions, Nivolumab, Lung Cancer Immunoprevention
Brief summary
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
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.
Interventions
DRUGNivolumab
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Sponsors
Bristol-Myers Squibb
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged \> 18 years 4. 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 5. Endobronchial dysplasia (score \> 4) on screening bronchoscopy 6. Total granulocyte count \> 1500 7. Platelet count \> 100,000 8. Serum creatinine \< 1.5 mg/dL 9. Total bilirubin \< 2.0 mg/dL 10. Transaminases and alkaline phosphatase \< 2.5x upper limit of normal 11. Albumin \> 2.5 mg/dL 12. ECOG performance status ≤ 1 13. 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: 1. 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) 2. Patients cannot receive any other investigational anti-cancer agents while participating in the study 3. Participants cannot have used any other investigational agents within the previous six months 4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab 5. 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) 6. 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 7. 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 8. 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 9. History of hepatitis B or hepatitis C infection that is untreated and/or with a detectable viral load 10. Hypoxemia (less than 90% saturation with supplemental oxygen) 11. Severe obstructive lung disease (GOLD Stage III or IV, FEV1\<30% predicted) 12. Prior chemotherapy or thoracic radiation within the past 1 year 13. 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 14. 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. 15. 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. 16. History of stage IIIA NSCLC for which the only treatment was chemoradiation without surgery 17. 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 18. Conditions requiring systemic corticosteroids equivalent to \> 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of enrollment 19. Known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity 20. History of interstitial pneumonitis requiring treatment with systemic corticosteroids or other immunosuppressive agents (e.g., mycophenolate, azathioprine) 21. Life expectancy of \< 1 year 22. 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 23. Women must not be breastfeeding 24. Inability to give informed consent 25. Pneumonia or acute bronchitis for at least 2 weeks prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Endobronchial Histology | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Immune-related Adverse Events (irAEs) | 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 | 2 months and 6 months | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Ratio of M1:M2 Macrophages in Bronchial Dysplastic Lesions | 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. |
| Proportion of T Lymphocytes in Bronchial Dysplastic Lesions That Express PD-1 | 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 |
| Number of Non-synonymous Mutations in Bronchial Dysplastic Lesions | Baseline | The number of non-synonymous mutations in bronchial dysplastic lesions will be determined by whole exome sequencing |
| Proportion of Macrophages in Bronchial Dysplastic Lesions That Express PD-L1 | 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 | Baseline, 2 months, and 6 months | Pre- and post-treatment biopsies will be stained by immunofluorescence for Th1, Th2, and Treg CD4+ T lymphocytes |
Countries
United States
Participant flow
Recruitment details
Participants for this trial were recruited from pulmonary, oncology and nodule clinics from the Rocky Mountain Regional Veterans Affairs Medical Center (RMR VAMC) and the University of Colorado Hospital (UCHealth). The recruitment period for this study was January 2019 through January 2023. The trial included a sputum cytology pre-screening arm to screen for mild or worse sputum atypia, and an option for direct enrollment to full-study with a history of bronchial dysplasia.
Pre-assignment details
All participants who enrolled onto the full-study underwent a baseline bronchoscopy; if biopsy results showed either mild, moderate or severe bronchial dysplasia at least one biopsy site, participants were eligible to move forward to full-study registration. If all biopsy sites did not reveal at least mild dysplasia, or if at least one site showed persistent carcinoma in situ or invasive carcinoma, this rendered participants ineligible for full-study registration.
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab Injection [Opdivo] 240 mg IV every 2 weeks for 4 doses | 19 |
| Total | 19 |
Baseline characteristics
| Characteristic | Nivolumab Injection [Opdivo] |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 6 / 19 |
Outcome results
Primary
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).
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab Injection [Opdivo] | Improvement in Endobronchial Histology | 10 Participants |
Comparison: The null hypothesis is that the 6-month response rate is less than or equal to 0.3.p-value: 0.0395% CI: [0.32, 1]Fisher Exact
Secondary
Additional Endobronchial Histology Endpoints Using the 2004 WHO Classification Scale for Pre-invasive Squamous Lesions of the Bronchus
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
Time frame: 2 months and 6 months
Secondary
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.
Time frame: Every 2 weeks through 3 months, then every 3 months through 1 year
Other Pre-specified
Number of Non-synonymous Mutations in Bronchial Dysplastic Lesions
The number of non-synonymous mutations in bronchial dysplastic lesions will be determined by whole exome sequencing
Time frame: Baseline
Other Pre-specified
Proportion of Macrophages in Bronchial Dysplastic Lesions That Express PD-L1
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
Time frame: Baseline, 2 months, and 6 months
Other Pre-specified
Proportion of T Lymphocytes in Bronchial Dysplastic Lesions That Express PD-1
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
Time frame: Baseline, 2 months, and 6 months
Other Pre-specified
Quantification of CD4+ T Lymphocyte Subsets in Bronchial Dysplastic Lesions
Pre- and post-treatment biopsies will be stained by immunofluorescence for Th1, Th2, and Treg CD4+ T lymphocytes
Time frame: Baseline, 2 months, and 6 months
Other Pre-specified
Ratio of M1:M2 Macrophages in Bronchial Dysplastic Lesions
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.
Time frame: Baseline, 2 months, and 6 months