Inositol in Preventing Lung Cancer in Current or Former Smokers With Bronchial Dysplasia

Study Overview
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Brief Summary
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This randomized phase II trial is studying inositol to see how well it works compared with a placebo in preventing lung cancer in current or former smokers with bronchial dysplasia. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of inositol may prevent lung cancer. It is not yet known whether inositol is more effective than a placebo in preventing lung cancer in smokers with bronchial dysplasia.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the efficacy of myo-inositol (inositol) 9 grams by mouth twice a day for 6 months versus placebo to revert bronchial dysplasia in current/former smokers with or without curatively treated Stage 0/I non-small cell lung cancer. SECONDARY OBJECTIVES: I. To further define the mechanism(s) of action of pharmacological doses of myo-inositol as a lung cancer chemopreventive agent by evaluating changes in: the number of dysplastic lesions, Ki-67, caspase-3, peroxisome proliferator-activated receptor (PPAR) gamma, cyclin D1, cyclin E and vascular endothelial growth factor (VEGF) immunostaining in bronchial biopsies; gene expression analysis of ribonucleic acid (RNA) from bronchial brush cells; and changes in inflammatory biomarkers (C-reactive protein [CRP], monocyte chemotactic protein-1 [MCP-1], myeloid progenitor inhibitory factor-1 [MPIF-1] and L-Selectin) levels in bronchoalveolar lavage (BAL) and plasma before and after treatment. II. To collect additional safety and adverse event profiles of participants enrolled in both intervention arms. III. To establish a biospecimen repository archive for future correlative studies. OUTLINE: Patients are stratified according to smoking status (current vs former), prior lung cancer (yes vs no), and number of dysplastic lesions at baseline (1 vs > 1). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity. ARM II: Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity. Patients undergo white light and autofluorescence bronchoscopy with bronchoalveolar lavage, bronchial brushings, and biopsies as well as optical coherence tomography imaging and blood sample collection at baseline and after completion of study treatment. Samples are analyzed for tissue biomarkers (e.g., PPAR gamma, Ki-67, caspase-3, cyclin D1, cyclin E, and VEGF) by immunohistochemistry (IHC); cytokine levels (e.g., CRP, MCP-1, MPIF-1, and L-selectin) by ELISA; and gene expression profiles of RNA by microarray. After completion of study treatment, patients are followed within 30 days.

Official Title
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Phase IIb Randomized Comparative Study of the Efficacy and Safety of Myo-inositol Versus Placebo in Smokers With Bronchial Dysplasia

Conditions
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Non-small Cell Lung Cancer, Squamous Lung Dysplasia

Intervention / Treatment
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* Other: placebo
* Drug: inositol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed bronchial dysplasia in ≥ 1 site AND meets one of the following criteria: Current or former smoker with ≥ a 30 pack-year smoking history and no history of lung cancer Stage 0 or I non-small cell lung cancer (NSCLC) curatively treated by surgery (local ablation or resection), adjuvant chemotherapy, or radiotherapy with a ≥ 30 pack-year smoking history At least 6 months since prior surgery, adjuvant chemotherapy, or radiotherapy No current evidence of lung cancer by CT scan No non-calcified lung nodules ≥ 10 mm diameter on spiral CT scan unless cancer is ruled out by PET/CT scan or by biopsy ECOG performance status 0-1 Hemoglobin normal Leukocyte count ≥ 3,000/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 1.5 times ULN ALT and AST ≤ 1.5 times ULN BUN ≤ 1.5 times ULN Chloride ≤ 1.5 times ULN Total CO_2 ≤ 1.5 times ULN Sodium ≤ 1.5 times ULN Calcium ≤ 1.5 times ULN Potassium ≤ 1.5 times ULN Phosphorus ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 30mL/min Fasting blood glucose normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No cancer within the past 3 years except stage 0 or I NSCLC, nonmelanomatous skin cancer, localized prostate cancer, carcinoma in situ of the cervix, or superficial bladder cancer that was treated > 6 months ago No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Severe chronic obstructive pulmonary disease requiring supplemental oxygen Uncontrolled hypertension Psychiatric illness or social situation that would limit compliance with study requirements No schizophrenia or bipolar disorder No diabetes No requirement for supplemental oxygen (continuous or intermittent) SaO_2 ≥ 90% on room air No history of allergic reactions attributed to inositol No history of allergies to any ingredient in the study agent or placebo No other concurrent investigational agents At least 7 days since prior anticoagulant use (e.g., coumadin or heparin) More than 6 months since prior participation in another chemoprevention clinical trial No prior pneumonectomy No prior solid organ transplantation No concurrent lithium, carbamazepine, or valproate No concurrent use of other natural health products containing inositol

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 79 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (inositol)<br>Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity. | Drug: inositol<br>* Given orally<br>* Other names: myo-inositol;|
| Experimental: Arm II (placebo)<br>Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity. | Other: placebo<br>* Given orally<br>* Other names: PLCB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Response Determined by Change in the Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples on Participant-specific Analysis. | The definitions of responses are: Complete response: regression of all dysplastic lesion (DL) found at baseline to lesions that were no worse than hyperplasia and no new DL that were mild dysplasia or worse; Partial response: regression of some but not all of the DL with no new lesions that are mild dysplasia or worse; Progressive disease: progression of one or more sites by two or more grades or new DL that were mild dysplasia or worse; Stable disease: no complete response, partial response or progression. | From baseline up to 6 months | 
| Percentage of Participants With Response Determined by Change in the Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples on Lesion-specific Analysis. | The definitions of responses are: Complete response: the regression of a dysplastic lesion (DL) of any grade to one classified as being hyperplastic/normal; Progressive disease: appearance of lesions that were classified as mild dysplasia or worse; Stable disease: lesions that are not classified as complete response or progressive disease | From baseline up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in the Number of Bronchial Dysplastic Lesions Before and After Treatment | The change in the number of bronchial dysplastic lesions is defined as disappearance or appearance of lesions. | From baseline up to 6 months | 
| Mean Percent Change in Ki-67 Expression Level in the Bronchial Biopsies With Dysplasia |  | From baseline up to 6 months | 
| Change in Gene Expression Profiles of RNA in Bronchial Brush Cell Samples as Assessed by Microarray |  | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (CC-16) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (IL-6) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (CCL-2) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (MPO) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (CC18) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (SFTPD) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (Total Glutathione) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (CC-16) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (CRP) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (IL-6) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (CCL-2) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (MPO) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (Nitrotyrosine) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (CC18) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months | 
| Change in Inflammatory Biomarkers Levels (SFTPD) in Plasma Samples as Assessed by ELISA | The biomarkers that were examined were: 1) pro-inflammatory proteins: C-reactive protein (CRP, R&D Systems), interleukin-6 (IL-6, R&D Systems), and CCL-2 (R&D Systems); 2) oxidant/antioxidants: myeloperoxidase (MPO, R&D Systems), nitrotyrosine (Hycult Biotech) and glutathione (Millipore-Calbiochem); and 3) pneumoproteins: Clara cell protein-16 (CC-16, Biovendor), surfactant protein-D (SFTPD, R&D Systems) and CC18 (R&D Systems). | From baseline up to 6 months |