Open AccessPositioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single‐arm efficacy
Author(s) -
Wilkins Martin R.,
Mckie Mikel A.,
Law Martin,
Roussakis Andreas A.,
Harbaum Lars,
Church Colin,
Coghlan J Gerry,
Condliffe Robin,
Howard Luke S,
Kiely David G,
Lordan Jim,
Rothman Alexander,
Suntharalingam Jay,
Toshner Mark,
Wort Stephen J,
Villar Sofía S.
Publication year - 2021
Publication title -
pulmonary circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.791
H-Index - 40
ISSN - 2045-8940
DOI - 10.1177/20458940211052823
Subject(s) - medicine , imatinib , pulmonary artery , vascular resistance , pulmonary hypertension , clinical endpoint , tyrosine kinase inhibitor , blood pressure , cardiology , surgery , clinical trial , cancer , myeloid leukemia
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.