Dataset Information

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

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.

SUBMITTER: Miller YE

PROVIDER: S-EPMC10499515 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

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

Miller York E YE Ghosh Moumita M Merrick Daniel T DT Kubala Brandi B Szabo Eva E Bengtson Lisa L Kocherginsky Masha M Helenowski Irene B IB Benante Kelly K Schering Tia T Kim Jihye J Kim Hyunmin H Ha Duc D Bergan Raymond C RC Khan Seema A SA Keith Robert L RL

Frontiers in oncology 20230830

<h4>Introduction</h4>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.<h4>Methods</h4>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 pla ...[more]

PMID: 37711198

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Project description:AimsAssessing reversibility of pulmonary vascular changes through vasoreactivity testing (VRT) optimizes end-stage heart failure patient selection for heart transplant. All efforts should be made to unload the left ventricle and reduce pulmonary vascular resistance to effectively exclude irreversible pulmonary hypertension.Methods and resultsWe reviewed our centre's cardiac transplant registry database (2009-2017) for VRT and compared haemodynamic responses with 40 ppm inhaled NO (n = 14), 14-17 μg inhaled iloprost (n = 7), and 24 h 0.1 μg/kg/min intravenous levosimendan (n = 14). Response to levosimendan was assessed by repeat right heart catheterization within 72 h. Baseline clinical and haemodynamic features were similar between groups. VRT was well tolerated in all patients. All drugs effectively reduced pulmonary artery pressures and transpulmonary gradient while increasing cardiac index, although levosimendan had a greater impact on cardiac index increase (P = 0.036). Levosimendan was the only drug that reduced pulmonary artery wedge pressure (P = 0.004) and central venous pressures (P < 0.001) and increased both left and right ventricular stroke work indexes (P = 0.020 and P = 0.042, respectively) and cardiac power index (P < 0.001) compared with NO and iloprost. Right ventricular end-diastolic pressures and central venous pressure were only decreased by levosimendan. The rate of positive responses (≥10 mmHg decrease or final mean pulmonary artery pressure ≤40 mmHg with increased/unaltered cardiac index) was lower with inhaled iloprost (14%) than with either levosimendan or NO (71% and 64%, respectively; P < 0.05).ConclusionsLevosimendan may be a safe and effective alternative for pulmonary hypertension reversibility assessment or a valuable pre-test medical optimization tool in end-stage heart failure patient assessment for heart transplantation offering extended haemodynamic benefits. Whether it increases the rate of positive responses or allows a better selection of candidates to heart transplantation remains to be established.

Dataset Information

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

Introduction

Methods

Results and discussion

Clinical trial registration

Publications

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

Similar Datasets

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