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

Phase 2

Completed

Conditions: Squamous Lung Dysplasia
Non-small Cell Lung Cancer

Interventions: Drug: inositol
Other: placebo

Registration Number: NCT00783705

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 85

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (inositol)	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.
Arm II (placebo)	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.

Primary Outcome Measures

Name	Time	Method
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.	From baseline up to 6 months	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.	From baseline up to 6 months	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

Secondary Outcome Measures

Name	Time	Method
Percent Change in the Number of Bronchial Dysplastic Lesions Before and After Treatment	From baseline up to 6 months	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	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)	From baseline up to 6 months	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)	From baseline up to 6 months	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)	From baseline up to 6 months	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)	From baseline up to 6 months	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)	From baseline up to 6 months	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)	From baseline up to 6 months	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)	From baseline up to 6 months	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	From baseline up to 6 months	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	From baseline up to 6 months	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	From baseline up to 6 months	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	From baseline up to 6 months	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	From baseline up to 6 months	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	From baseline up to 6 months	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	From baseline up to 6 months	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	From baseline up to 6 months	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).

Trial Locations

Locations (4): Mayo Clinic in Arizona
🇺🇸
Scottsdale, Arizona, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Albuquerque Veterans Administration Medical Center
🇺🇸
Albuquerque, New Mexico, United States
BCCA-Vancouver Cancer Centre
🇨🇦
Vancouver, British Columbia, Canada