Clinical trial NCT00783705: Inositol in Preventing Lung Cancer in Current or Former Smokers With Bronchial Dysplasia
Official title: Phase IIb Randomized Comparative Study of the Efficacy and Safety of Myo-inositol Versus Placebo in Smokers With Bronchial Dysplasia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Squamous Lung Dysplasia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-11-02
Enrollment: 85
Sex: ALL
Minimum age (years): 45
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: From baseline up to 6 months
measure: 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.
timeFrame: From baseline up to 6 months
Secondary outcomes:
measure: Percent Change in the Number of Bronchial Dysplastic Lesions Before and After Treatment
timeFrame: From baseline up to 6 months
measure: Mean Percent Change in Ki-67 Expression Level in the Bronchial Biopsies With Dysplasia
timeFrame: From baseline up to 6 months
measure: Change in Gene Expression Profiles of RNA in Bronchial Brush Cell Samples as Assessed by Microarray
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (CC-16) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (IL-6) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (CCL-2) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (MPO) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (CC18) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (SFTPD) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (Total Glutathione) in Bronchoalveolar Lavage Samples as Assessed by Enzyme-linked Immunoassay (ELISA)
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (CC-16) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (CRP) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (IL-6) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (CCL-2) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (MPO) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (Nitrotyrosine) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (CC18) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
measure: Change in Inflammatory Biomarkers Levels (SFTPD) in Plasma Samples as Assessed by ELISA
timeFrame: From baseline up to 6 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Albuquerque
country: United States
facility: Albuquerque Veterans Administration Medical Center
state: New Mexico
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
Study officials:
affiliation: Mayo Clinic
name: Paul Limburg
role: PRINCIPAL_INVESTIGATOR
References: