Oral Iloprost for the Prevention of Lung Cancer In Former Smokers

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Chronic Obstructive Pulmonary Disease; Lung Carcinoma; Stage II Lung Cancer AJCC v8; Stage I Lung Cancer AJCC v8; Tobacco-Related Carcinoma; Bronchial Epithelial Dysplasia
• Intervention / Treatment: Other: Questionnaire Administration; Drug: Placebo Administration; Procedure: Biospecimen Collection; Procedure: Bronchial Brush Biopsy; Procedure: Bronchoscopy; Drug: Iloprost

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Rocky Mountain Regional VA Medical Center
      • Contact: York E. Miller; Phone Number: 720-723-6091; Email: york.miller@cuanschutz.edu
      • Principal Investigator: York E. Miller
    • Denver, Colorado, United States, 80217-3364
      • University of Colorado
      • Contact: Nina Thomas; Phone Number: 720-848-0123; Email: NINA.THOMAS@CUANSCHUTZ.EDU
      • Principal Investigator: Nina Thomas
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
      • Contact: T. Betty Tran; Phone Number: 312-695-9392; Email: BETTY.TRAN@NORTHWESTERN.EDU
      • Principal Investigator: T. Betty Tran
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
      • Contact: David Wilson; Phone Number: 410-687-3355; Email: wilsondo@upmc.edu
      • Principal Investigator: David Wilson
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Hunter Holmes McGuire Veterans Administration Medical Center
      • Contact: Howard Li; Phone Number: 4523 804-675-5000; Email: howard.li@vcuhealth.org
      • Principal Investigator: Howard Li

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants must be former smokers (> 12 months abstinent and confirmed by serum cotinine) with at least a 30 pack-year cigarette history who are at high risk for the development of lung cancer with at least one of the following:

  • Stage I or II lung cancer survivors, surgically treated with curative intent, who have remained disease free for > 12 months. Participants may have been treated with adjuvant chemotherapy or targeted therapy [(e.g. Osimertinib for epidermal growth factor receptor (EGFR) mutation)], if appropriate, provided they are > 12 months from the last systemic adjuvant therapy dose.
  • Patients with chronic obstructive pulmonary disease (COPD), defined as either airflow obstruction (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] < 0.70) on spirometry or emphysema (as commented on in a Radiology report) on CT scan.
  • Patients who display a ground glass opacity (GGO) on CT with a largest diameter =< 10 mm and >= 4 mm on axial imaging. The GGO must either be documented to have remained the same size or slowly progressing, but not regressing, over a 6-month period of observation by serial CT scan such that further workup beyond observation is not planned. A solid component of =< 1/3 of the axial diameter may be present, providing the treating physician(s) do not plan on workup for resection within the next 6 months, taking both the character of the lesion and its rate of growth into consideration.
  • Patients who have had a previous endobronchial biopsy with mild World Health Organization (WHO) score 4 or greater dysplasia
• Participants must be able to safely undergo bronchoscopy in the judgement of the investigator
• Participants must have a biopsy showing mild (grade 4 on WHO score) or greater dysplasia on the baseline bronchoscopy
• Participants must be at least 50 years old. Because no dosing or adverse event (AE) data are currently available on the use of iloprost in participants <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Leukocytes >= 3,000/microliter
• Platelets >= 100,000/microliter
• Total bilirubin =< 2.0 mg/dl
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (ULN)
• Creatinine =< 2.0 mg/dl
• The effects of iloprost on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because prostacyclins are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• The use of any tobacco product or inhalational nicotine delivery device in the past year
• Taking any anticoagulant agent with the exception of aspirin
• Taking any antiplatelet agent
• Receiving any other investigational agents or the previous use of iloprost
• Participants may not have received radiation therapy directed to the thorax or head and neck or immunotherapy, including checkpoint inhibitors
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to iloprost
• A requirement of supplemental oxygen (O2) of >= 4 liter/minute to maintain an oxygen saturation of >= 90% at rest
• A biopsy on baseline bronchoscopy with a dysplasia score of 7 or 8 (carcinoma in situ or invasive cancer)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because iloprost is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with iloprost breastfeeding should be discontinued if the mother is treated with iloprost.
• Due to the risk for hypotension due to vasodilator effect of iloprost, participants must not have a blood pressure < 95 mm Hg systolic
• Participants must not have a current or prior invasive cancer within the past 12 months. History of the following cancers, curatively treated by surgery or locally ablative means, at any time prior to screening is allowed: non-melanoma skin cancer and cervical carcinoma in situ. Participants with prostate cancer undergoing active surveillance are allowed.
• Participants being treated with hormonal or immune therapies, including intravesicular bacillus calmette-guerin (BCG), are excluded
• Survivors of curatively treated stage III non-small cell lung cancer (NSCLC) or any stage lung small cell carcinoma (SCLC) are excluded
• Patients with known metastatic cancer of any kind are excluded
• Participants with known underlying bleeding disorders are excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (iloprost); 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.	Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo collection of sputum sample; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Bronchial Brush Biopsy; Undergo bronchial brush biopsy; Other Names: bronchial brushing; Procedure: Bronchoscopy; Undergo bronchoscopy; Drug: Iloprost; Given PO; Other Names: Ventavis; Ciloprost; Iloprost Clathrate; ZK 36374
Placebo Comparator: Arm II (placebo); 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.	Other: Questionnaire Administration; Ancillary studies; Drug: Placebo Administration; Given PO; Procedure: Biospecimen Collection; Undergo collection of sputum sample; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Bronchial Brush Biopsy; Undergo bronchial brush biopsy; Other Names: bronchial brushing; Procedure: Bronchoscopy; Undergo bronchoscopy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in numerical grade of the worst (highest grade on the WHO scale) dysplastic lesion per subject on bronchoscopy	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.	Baseline to 6 month follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the average WHO score of all biopsy sites with a baseline score of 4 or greater	Will be assessed using bronchial biopsies according to the WHO grading system, where 1 is normal and 8 is invasive cancer.	Up to 6 months
Incidence of adverse events with oral iloprost	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.	From first dose to end of study, assessed up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response rate	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.	Up to 6 months
In vitro response of bronchial epithelial progenitor cells cultured at the air-liquid interface	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.	Up to 6 months
Change in glass opacity (GGOs) volume	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.	Up to 6 months
Organoid formation	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).	Up to 6 months
Morphologic analysis of expectorated sputum by LuCED	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.	Up to 6 months
Histologic response by alternative criteria	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.	Up to 6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: York E Miller, Northwestern University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: June 8, 2022
• First Submitted That Met QC Criteria: June 8, 2022
• First Posted (Actual): June 9, 2022

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Respiratory Tract Neoplasms; Thoracic Neoplasms; Chronic Disease; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Lung Neoplasms; Carcinoma; Vasodilator Agents; Platelet Aggregation Inhibitors; Iloprost
• Other Study ID Numbers: NCI-2022-04698 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA060553 (U.S. NIH Grant/Contract); UG1CA242643 (U.S. NIH Grant/Contract); NCI21-08-01 (Other Identifier: Northwestern University); NWU21-08-01 (Other Identifier: DCP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No