Phase Ib trial of inhaled iloprost for the prevention of lung cancer with predictive and response biomarker assessment

Authors

York E. Miller, University of Colorado Anschutz Medical Campus
Moumita Ghosh, University of Colorado Anschutz Medical CampusFollow
Daniel T. Merrick, University of Colorado Anschutz Medical Campus
Brandi Kubala, University of Colorado Anschutz Medical Campus
Eva Szabo, National Cancer Institute (NCI)
Lisa Bengtson, National Cancer Institute (NCI)
Masha Kocherginsky, Northwestern University
Irene B. Helenowski, Northwestern University
Kelly Benante, Northwestern University Feinberg School of Medicine
Tia Schering, Northwestern University Feinberg School of Medicine
Jihye Kim, Cleveland Clinic Foundation
Hyunmin Kim, Case Western Reserve University
Duc Ha, RMR VAMC Rocky Mountain Regional Veteran Administration Medical Center
Raymond C. Bergan, University of Nebraska Medical Center
Seema A. Khan, Northwestern University
Robert L. Keith, University of Colorado Anschutz Medical Campus

Date of this Version

1-1-2023

Document Type

Article

Citation

Miller YE, Ghosh M, Merrick DT, Kubala B, Szabo E, Bengtson L, Kocherginsky M, Helenowski IB, Benante K, Schering T, Kim J, Kim H, Ha D, Bergan RC, Khan SA and Keith RL (2023) Phase Ib trial of inhaled iloprost for the prevention of lung cancer with predictive and response biomarker assessment. Front. Oncol. 13:1204726. doi: 10.3389/fonc.2023.1204726

Comments

Creative Commons Attribution License (CC BY).

Abstract

Introduction: Iloprost, a prostacyclin analog, has lung cancerpreventive activity in preclinical models and improved dysplasia in former smokers in a phase IIb trial. Oral iloprost is currently unavailable. We performed a phase Ib trial of inhaled iloprost in former smokers to assess tolerance and compliance. Methods: Participants self-administered nebulized iloprost (5ug) or placebo four (QID) or two (BID) times daily. As QID dose was well tolerated and due to expiration of the placebo, the BID dosing and placebo were eliminated early on in the trial. Bronchoscopy with biopsyat six standard sites was performed at treatment initiation and two months post-iloprost, with exploratory histological analysis. Bulk RNA sequencing, single cell RNA sequencing and an in vitro assay of epithelial progenitor cell iloprost response were performed on a subset of biopsies in an exploratory investigation of response mechanisms and predictive biomarkers. Results and discussion: Thirty-four of a planned 48 participants were recruited to the trial.Inhaled iloprost was well tolerated with no adverse events > grade 2. Compliance was 67% in the QID group. The trial was not powered to detect histologic response and none was found. Bulk RNA sequencing of biopsies pre/post iloprost suggest that iloprost is immunomodulatory and downregulates cell proliferation pathways. Single cell RNA sequencing showed an increase in CD8-positive T cells with upregulation of genes in interferon γ signaling. In vitro iloprost response by epithelial progenitor cells correlated with histologic response with kappa coefficient of 0.81 (95% CI 0.47, 1.0). Inhaled iloprost was well tolerated with suboptimal compliance. Molecular analysis suggested that iloprosthas immunomodulatory and antiproliferative effects.The progenitor cell iloprost response assay may be a promising avenue to develop predictive biomarkers. Clinical trial registration: https://clinicaltrials.gov/study/NCT02237183, identifier NCT02237183.