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Respiratory Tract Neoplasms

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Vasodilator Agents

Platelet Aggregation Inhibitors

All Drugs and Chemicals

Iloprost

Patients receive iloprost via inhalation using a nebulizer QID for 60 days.

Patients receive placebo via inhalation using a nebulizer QID for 60 days.

Patients receive iloprost via inhalation using a nebulizer BID for 60 days.

Patients receive placebo via inhalation using a nebulizer BID for 60 days.

Placebo Administration

Quality-of-Life Assessment

Questionnaire Administration

York E Miller

This phase I trial studies the side effects and best dose of iloprost compared with a placebo in preventing lung cancer in former smokers. Chemoprevention is the use of drugs to keep cancer from forming or coming back. Inhaled iloprost may help prevent lung cancer from forming in patients who used to smoke and who have been found to have abnormal cells in their mucus.

PRIMARY OBJECTIVES:

I. To evaluate the toxicity of inhalational iloprost administered to patients daily for 2 months, given four times a day (QID).

SECONDARY OBJECTIVES:

I. To evaluate the compliance QID dosing regimens. II. To evaluate the effect on endobronchial histology. III. To evaluate the effect on expectorated sputum cytology by both standard cytologic analysis and an automated three-dimensional morphologic analysis.

IV. To evaluate the effect on endobronchial brushing and biopsy gene expression of peroxisome proliferator-activated receptor gamma (PPARgamma), glutathione S-transferase mu (GSTmu), carboxylesterase 1 (Ces1), Fos-related antigen 1 (FosL1), cytochrome p4502e1, stearoyl coA desaturase 1, tumor necrosis factor (TNF) superfamily member 9, transforming growth factor beta (TGFbeta), Jun and a 46 gene panel associated with dysplasia persistence, using Affymetrix arrays.

V. To evaluate the improvement in chronic obstructive pulmonary disease (COPD) as measured by arterial blood gas (ABG) (improved ventilation perfusion matching), pulmonary function testing, 6-minute walk distance, quality of life (St. George's respiratory questionnaire, COPD assessment test \[CAT\]).

VI. To evaluate whether the in vitro response of cultured airway epithelial progenitor cells to iloprost is a predictor of in vivo response in study subjects.

OUTLINE: Patients are enrolled to Cohort A to completion prior to initiation of Cohort B.

COHORT A: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive iloprost via inhalation using a nebulizer QID for 60 days.

ARM II: Patients receive placebo via inhalation using a nebulizer QID for 60 days.

COHORT B: Patients are assigned to 1 of 2 arms. COHORT B DISCONTINUED AS OF 03/26/2019.

ARM III: Patients receive iloprost via inhalation using a nebulizer BID for 60 days.

ARM IV: Patients receive placebo via inhalation using a nebulizer BID for 60 days.

After completion of study treatment, patients are followed up at 90 days and then annually for up to 5 years.

Iloprost in Preventing Lung Cancer in Former Smokers

A Phase I Trial of Inhaled Iloprost for the Prevention of Lung Cancer in Former Smokers

Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Descriptive statistics (mean, standard deviation \[SD\], median, max, min and range) will be provided for toxicity. Approximate 95% confidence intervals will be used to assess the difference between treatment groups.

Descriptive statistics (mean, SD, median, max, min and range) will be provided for compliance. Approximate 95% confidence intervals will be used to assess the difference between treatment groups.

Will provide descriptive statistics for the effect on endobronchial histology, with the primary parameter being worst histology at matched sites; additional outcomes will be average histology, dysplasia index and response, as described.

Will provide descriptive statistics for the effect on serum proteins as quantitated by aptamer based analysis.

Will provide descriptive statistics for the effect on endobronchial brushing gene expression, focusing on prostacyclin-targeted pathways.

Will provide descriptive statistics for the improvement in COPD as measured by arterial blood gas (improved ventilation perfusion matching), pulmonary function testing, 6-minute walk distance, and quality of life (St. George's respiratory questionnaire, COPD assessment test).

Bronchial biopsies will be taken from an area suspicious for dysplasia and an area that appears normal. These will be cultured as described and transferred to an air liquid interface culture in which dysplasia is recapitulated. Cultures will be treated with either vehicle or iloprost and assessed for both self-renewal and differentiation to ciliated and secretory cells.

National Cancer Institute (NCI)

Rare Diseases

Lung Diseases, Obstructive

Pulmonary Disease, Chronic Obstructive

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Patients receive Iloprost PO BID for a 180 days in the absence of unacceptable toxicity. Patients undergo bronchoscopy with biopsies and brushings at day 180.

Patients receive placebo PO BID for a 180 days in the absence of unacceptable toxicity. Patients undergo bronchoscopy with biopsies and brushings at day 180.

Biospecimen Collection

Bronchial Brush Biopsy

Bronchoscopy

This phase II trial tests whether oral iloprost works in preventing lung cancer (chemoprevention) in former smokers. Oral iloprost has previously been shown to reduce abnormal lung cells in former smokers, suggesting a clinically significant impact on lung cancer risk. The use of oral iloprost may help keep cancer from forming and reduce abnormal cells in the lung in order to lower the risk of developing lung cancer in former smokers.

PRIMARY OBJECTIVE:

I.To determine if oral iloprost, starting at 50 ug twice daily (BID) and increased monthly to a final dose of 150 ug BID as tolerated, compared to placebo for 6 months is effective in reducing endobronchial dysplasia in former smokers who have mild or worse dysplasia on an endobronchial biopsy at baseline bronchoscopy.

SECONDARY OBJECTIVES:

I. To determine if treatment with oral iloprost compared to placebo results in a change in average dysplasia (over all sites of mild or greater dysplasia).

II. To determine safety of treatment with oral iloprost.

EXPLORATORY OBJECTIVES:

I. To determine if treatment with oral iloprost compared to placebo results in a change in response rate defined as \>= 1 point reduction in maximum dysplasia.

II. To determine if the in vitro differentiation response of bronchial epithelial cell progenitors cultured at the air liquid interface is predictive of the in vivo response of dysplasia improvement (to be done only in participants recruited in Colorado).

III. To determine if treatment with oral iloprost compared to placebo results in a decrease in the volume of pure ground glass opacities (GGOs) on chest computed tomography (CT).

IV. To determine if treatment with oral iloprost compared to placebo increases peripheral lung epithelial progenitor counts, measured by organoid formation in a three dimensional culture system seeded from distal airway brushings (to be done only in participants recruited in Colorado).

V. To determine if oral iloprost reduces the incidence of lung cancer compared to placebo.

VI. To evaluate the ability of 3-dimensional morphologic analysis of expectorated sputum by LuCED compared to standard sputum cytopathology to predict endobronchial dysplasia and measure response to iloprost.

VII. To evaluate histologic response by alternative criteria.

OUTLINE: Patients are randomized in 1 of 2 arms.

ARM I: Patients receive iloprost orally (PO) BID for a 180 days in the absence of unacceptable toxicity. Patients undergo bronchoscopy with biopsies and brushings at day 180.

ARM II: Patients receive iloprost placebo PO BID for a 180 days in the absence of unacceptable toxicity. Patients undergo bronchoscopy with biopsies and brushings at day 180.

After completion of study treatment, patients are followed up for 30 days.

Oral Iloprost for the Prevention of Lung Cancer In Former Smokers

Phase II Trial of Oral Iloprost for the Precision Chemoprevention of Lung Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Treatment response will be defined as \>= 1 point reduction in maximum dysplasia at end of treatment, and response rates will be compared between arms using a chisquared test.

Will compare the ability of iloprost exposure versus vehicle, to restore differentiation to ciliated and mucus secreting cells. This will then be compared to the in vivo response of the dysplastic lesion at the same biopsy site to iloprost or placebo as a potential predictive biomarker. This endpoint will only be assessed in biopsies from participants enrolled in Colorado.

Changes will be summarized using descriptive statistics, and a two-sample t-test or the Wilcoxon rank-sum test will be used to compare changes between the two arms.

Peripheral lung epithelial progenitor cells will be assessed for organoid formation in a three dimensional culture system before and after treatment with iloprost or placebo.The progenitor cells assay will be used to predict whether a participant will respond to iloprost (yes/no).

Will evaluate the ability of 3-dimensional morphologic analysis of expectorated sputum by LuCED compared to standard sputum cytopathology to predict endobronchial dysplasia and measure response to iloprost.

Bronchoscopic biopsies of standard and visually abnormal sites will be graded on the WHO scale of dysplasia and assigned numerical scores from 1 (normal) to 8 (invasive cancer). Each lesion will be classified as complete response, partial response, stable disease or progressive disease based on Lam et al. and each response rate will be calculated on a per-site and per-participant basis.

Histologic response is the mean change between baseline and 6 month follow up bronchoscopy in the numerical grade of the worst (highest grade on the World Health Organization \[WHO\] scale) dysplastic lesion per subject. Will be analyzed using a linear regression models with post-treatment worst grade dysplasia as the outcome variable, and treatment arm (iloprost and placebo) and baseline worst grade dysplasia as predictors.

Will be assessed using bronchial biopsies according to the WHO grading system, where 1 is normal and 8 is invasive cancer.

Safety will be assessed according to a comparison of adverse events (AEs) between iloprost and placebo participants. Descriptive statistics (frequency, percent) will be used to summarize participants' worst grade toxicity for each AE type. AE rates will be compared between treatment arms using Fisher's exact test since AE rates are expected to be low.

Carcinoma, Non-Small-Cell Lung

Precancerous Conditions

Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.

Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.

iloprost

placebo

Robert Keith, MD

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Iloprost may be effective in preventing lung cancer.

PURPOSE: This randomized phase II trial is studying how well iloprost works in preventing lung cancer in patients who are at high risk for this disease.

OBJECTIVES:

Primary

* Compare the reversal of premalignant histological changes in the bronchial epithelium of patients at high risk for lung cancer (defined by \> 20 pack years of smoking and sputum atypia) treated with iloprost vs placebo.
* Determine whether this drug modulates Ki-67 proliferation index (Antigen Ki-67) in these patients.
* Determine whether this drug affects prostaglandin metabolism in these patients.
* Determine the toxicity profile of this drug in these patients.

Secondary

* Determine whether this drug modulates a panel of biomarkers, including MCM-2(Minichromosome maintenance protein: forms DNA helicase), EGFR (Epidermal growth factor receptor: cell surface receptor for the epidermal growth factor family of proteins. Mutations in EGFR expression or activity can result in cancer.) , HER2/neu (Human epidermal growth factor receptor 2 HER2 is a member of the EGFR family), RARβ (Retinoic Acic Receptor Beta is a nuclear transcription regulator and a member of the thyroid-steroid hormone receptor superfamily), p53, FHIT (Fragile histidine triad protein is an enzyme involved in purine metabolism and had been demonstrated to be a tumor suppressor), apoptotic index, and microvessel density, in these patients.
* Determine the genes whose expression is altered by this drug in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to smoking status (current vs former) and participating center. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral iloprost twice daily.
* Arm II: Patients receive oral placebo twice daily. In both arms, treatment continues for 6 months in the absence of unacceptable toxicity.

Patients are followed at 1 month and then annually thereafter.

PROJECTED ACCRUAL: A total of 152 patients (76 \[38 current smokers and 38 former smokers\] per treatment arm) will be accrued for this study within 2 years.

Iloprost in Preventing Lung Cancer in Patients at High Risk for This Disease

A Randomized Phase II Chemoprevention Study of Iloprost Versus Placebo in Patients at High Risk for Lung Cancer

PGIS (Prostacyclin synthase: an enzyme in the eicosanoid pathway that catalyzes the conversion of prostaglandin H2 to prostaglandin I2 (prostacyclin). PPAR (Peroxisome proliferator-activated receptor: a group of nuclear receptor proteins that act as transcription factors regulating gene expression),

To determine if Iloprost can modulate a panel of biomarkers including MCM-2, EGFR, Her-2/neu, RARβ, p53, FHIT, apoptotic index, and microvessel density.

This outcome measure is created for each subject as follows:

From all biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

From all biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.Histology on bronchial biopsies pre-treatment and post-treatment will be compared. All biopsies will be graded according to the WHO classification for bronchial epithelium for this outcome, and all the following outcomes.

WHO Classification Grade Normal 1.0 Reserve Cell Hyperplasia 2.0 Metaplasia 3.0 Mild Dysplasia 4.0 Moderate Dysplasia 5.0 Severe Dysplasia 6.0 Carcinoma in Situ 7.0 Carcinoma 8.0

The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

From all biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

From all biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL (Right upper lobe: the superior region of the right lung), RML (Right middle lobe: an anatomic portion of the right lung), RB6 (The carina in the right lower lobe at the entrance to the superior segment), LUL (Left upper lobe: the superior portion of the lung), LUDB (Left upper division bronchus: the carina between the lingular orifice and the left upper lobe), and LB6 (The carina in the left lower lobe at the entrance to the superior segment).

From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.

The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6.

From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used.

From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used.

The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6.

From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies.

From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.

The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies.

From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used.

From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used.

The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies.

From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis.

From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.

The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis.

From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used.

From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used.

The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

This outcome measure is created for each subject as follows:

The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis.

From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

University of Colorado, Denver

Adverse event collection was obtained at monthly visits on all randomized participants according to the NCI CommonToxicity criteria version 2.0, entered in case report forms, and in the NCI Oracle Clinical Database

Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.

Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.This group consisted of current and former smokers.

Placebo

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Robert Keith, M.D.

Change in Average (Follow-up - Baseline) From All Biopsies

Change in Dysplasia Index (Follow-up - Baseline) Using All Biopsies

Change in Average (Follow-up - Baseline) Using Reference Sites

Change in Maximum (Follow-up - Baseline) Using Reference Sites

Change in Dysplasia Index (Follow-up - Baseline) Using Reference Sites

Change in Average (Follow-up - Baseline) Using Matched Sites

Change in Maximum (Follow-up - Baseline) Using Matched Sites

Change in Dysplasia Index (Follow-up - Baseline) Using Matched Sites

The analysis was restricted to the 107 subjects (52 in the iloprost group, 55 in the placebo group) with at least 1 non-normal biopsy at baseline, thereby excluding the 18 subjects (8 in the iloprost group and 10 in the placebo group) who had only normal biopsy tissue at baseline.

Change in Average (Follow-up - Baseline) Using Baseline Non-Normal Pairs

Change in Maximum (Follow-up - Baseline) Using Baseline Non-Normal Pairs

Change in Dysplasia Index (Follow-up - Baseline) Using Baseline Non-Normal Pairs

To Determine if Iloprost Can Modulate K-67 Proliferation Index in Patients at High Risk to Develop Lung Cancer

To Determine Whether Iloprost Affects Prostaglandin Metabolism by Examining 4 Markers, PGIS, COX-2, PPAR and PPAR.

To Determine the Toxicity Profile of Iloprost in Patients at High Risk to Develop Lung Cancer.

Define the Genes Whose Expression is Altered by Iloprost Treatment by Gene Expression Arrays and Quantitative PCR.

To Determine Whether Iloprost Can Modulate a Panel of Biomarkes.

Overall Study

Central Nervous System Depressants

Anesthetics

20μg(2ml) of inhaled iloprost (Ventavis®)

When anesthesia induction finishes, change patients' position from supine to lateral position and measure arterial blood gas analysis (ABGA), venous blood gas analysis (VBGA) while two lung is ventilated. After 20 minutes of applying one lung ventilation, measure ABGA. Apply iloprost or normal saline inhalation for each iloprost and control group and measure ABGA at the time of 20 min and 40 min after iloprost (or normal saline) inhalation has finished.

20μg(2ml) of inhaled normal saline

When anesthesia induction finishes, change patients' position from supine to lateral position and measure ABGA, VBGA while two lung is ventilated. After 20 minutes of applying one lung ventilation, measure ABGA. Apply iloprost or normal saline inhalation for each iloprost and control group and measure ABGA at the time of 20 min and 40 min after iloprost (or normal saline) inhalation has finished.

normal saline

One lung ventilation (OLV) is essential during thoracic surgery. During OLV, intrapulmonary shunt can be increased resulting hypoxemia. Although OLV technique had been advanced so far, hypoxemia during OLV reaches about 10% in spite of inspired oxygen fraction 100%. Iloprost is a prostaglandin analogue used for pulmonary hypertension, which can decrease pulmonary artery resistance by selectively dilating pulmonary artery. In this prospective, randomized, double blind study, investigators are planning to investigate the effects of iloprost on respiratory physiology (intrapulmonary shunt, deadspace, oxygenation, etc).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Iloprost in Preventing Lung Cancer in Former Smokers	NCT02237183	Lung Carcinoma	Iloprost Placebo Adminis... Quality-of-Life... Questionnaire A...	18 Years - 85 Years	National Cancer Institute (NCI)
Oral Iloprost for the Prevention of Lung Cancer In Former Smokers	NCT05411107	Bronchial Epith... Chronic Obstruc... Lung Carcinoma Stage I Lung Ca... Stage II Lung C... Tobacco-Related...	Biospecimen Col... Bronchial Brush... Bronchoscopy Iloprost Placebo Adminis... Questionnaire A...	50 Years -	National Cancer Institute (NCI)
Iloprost in Preventing Lung Cancer in Patients at High Risk for This Disease	NCT00084409	Lung Cancer Precancerous Co...	iloprost placebo	18 Years - 85 Years	University of Colorado, Denver
Effect of Iloprost on Pulmonary Oxygenation in Patients With Low Diffusing Capacity During One-lung Ventilation	NCT02784899	Lung Cancer	iloprost normal saline	40 Years - 80 Years	Yonsei University

Spots Global Cancer Trial Database for iloprost

Every month we try and update this database with for iloprost cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for iloprost

Every month we try and update this database with for iloprost cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for iloprost cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.