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

• 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. [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]

  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.

• 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. [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]

  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

• Percent Change in the Number of Bronchial Dysplastic Lesions Before and After Treatment [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  The change in the number of bronchial dysplastic lesions is defined as disappearance or appearance of lesions.
• Mean Percent Change in Ki-67 Expression Level in the Bronchial Biopsies With Dysplasia [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
• Change in Gene Expression Profiles of RNA in Bronchial Brush Cell Samples as Assessed by Microarray [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
• Change in Inflammatory Biomarkers Levels (CC-16) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (IL-6) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (CCL-2) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (MPO) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (CC18) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (SFTPD) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (Total Glutathione) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA) [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (CC-16) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (CRP) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (IL-6) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (CCL-2) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (MPO) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (Nitrotyrosine) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (CC18) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).
• Change in Inflammatory Biomarkers Levels (SFTPD) in Plasma Samples as Assessed by ELISA [ Time Frame: From baseline up to 6 months ] [ Designated as safety issue: No ]
  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).

• Change in the number of dysplastic lesions before and after treatment [ Designated as safety issue: No ]
• Change in tissue biomarkers (e.g., Ki-67, caspase-3, PPAR gamma, cyclin D1, cyclin E, and VEGF) in bronchial biopsy samples as assessed by IHC before and after treatment [ Designated as safety issue: No ]
• Change in inflammatory biomarker (e.g., CRP, MCP-1, MPIF-1, and L-selectin) levels in bronchoalveolar lavage and plasma samples as assessed by ELISA before and after treatment [ Designated as safety issue: No ]
• Change in gene expression profiles of RNA in bronchial brush cell samples as assessed by microarray before and after treatment [ Designated as safety issue: No ]
• Safety [ Designated as safety issue: Yes ]

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.

• Non-small Cell Lung Cancer
• Squamous Lung Dysplasia

• Other: placebo
  Given orally
  Other Name: PLCB
• Drug: inositol
  Given orally
  Other Name: myo-inositol

• Experimental: Arm I (inositol)
  Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
  Intervention: Drug: inositol
• Experimental: Arm II (placebo)
  Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.
  Intervention: Other: placebo

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