Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy.
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Authors
Mckie, Mikel A
Harbaum, Lars
Church, Colin
Coghlan, J Gerry
Condliffe, Robin
Howard, Luke S
Kiely, David G
Lordan, Jim
Suntharalingam, Jay
Wort, Stephen J
Villar, Sofía S
Publication Date
2021Journal Title
Pulm Circ
ISSN
2045-8932
Publisher
Wiley
Volume
11
Issue
4
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Wilkins, M. R., Mckie, M. A., Law, M., Roussakis, A. A., Harbaum, L., Church, C., Coghlan, J. G., et al. (2021). Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy.. Pulm Circ, 11 (4) https://doi.org/10.1177/20458940211052823
Abstract
Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.
Keywords
Safety, efficacy, Tolerability, Adaptive Design
Sponsorship
Medical Research Council (MC_UU_00002/15)
Efficacy and Mechanism Evaluation Programme (NIHR128465)
National Institute for Health Research (NIHR) (NIHR128465)
British Heart Foundation (RE/18/4/34215)
Identifiers
34868551, PMC8642118
External DOI: https://doi.org/10.1177/20458940211052823
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333071
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