Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy
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Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy. / 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.
In: PULM CIRC, Vol. 11, No. 4, 07.12.2021, p. 20458940211052823.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy
AU - Wilkins, Martin R
AU - Mckie, Mikel A
AU - Law, Martin
AU - Roussakis, Andreas A
AU - Harbaum, Lars
AU - Church, Colin
AU - Coghlan, J Gerry
AU - Condliffe, Robin
AU - Howard, Luke S
AU - Kiely, David G
AU - Lordan, Jim
AU - Rothman, Alexander
AU - Suntharalingam, Jay
AU - Toshner, Mark
AU - Wort, Stephen J
AU - Villar, Sofía S
N1 - © The Author(s) 2021.
PY - 2021/12/7
Y1 - 2021/12/7
N2 - 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.
AB - 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.
U2 - 10.1177/20458940211052823
DO - 10.1177/20458940211052823
M3 - SCORING: Journal article
C2 - 34868551
VL - 11
SP - 20458940211052823
JO - PULM CIRC
JF - PULM CIRC
SN - 2045-8932
IS - 4
ER -
