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Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm

Martin R Wilkins1, Mikel A Mckie2, Martin Law2

  • 1National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.

Pulmonary Circulation
|December 6, 2021
PubMed

Insights

This study investigates a better-tolerated dose of imatinib for pulmonary arterial hypertension. The research aims to find an optimal imatinib dosage to improve patient outcomes and functional capacity.

Area of Science:

  • Cardiology
  • Pharmacology
  • Clinical Trials

Background:

  • Pulmonary arterial hypertension (PAH) presents a significant unmet clinical need.
  • Imatinib, a tyrosine kinase inhibitor, shows potential in reducing pulmonary artery pressure and improving functional capacity in PAH patients.
  • However, imatinib's tolerability is a concern, particularly at higher doses (200-400 mg daily).

Purpose of the Study:

  • To identify the best tolerated dose of imatinib within the 100-400 mg range for PAH patients.
  • To evaluate the efficacy of the determined best tolerated dose over 24 weeks.
  • To explore potential genotype-based responses to imatinib treatment in PAH.

Main Methods:

  • An open-label, single-arm clinical study comprising two parts.
  • Part 1 utilized a Bayesian Continuous Reassessment Method to find the optimal imatinib dose.
  • Part 2 employed a Simon's two-stage design to assess efficacy based on pulmonary vascular resistance (PVR) reduction.

Main Results:

  • The study successfully identified a best tolerated dose of imatinib for PAH patients.
  • Efficacy was measured by a significant reduction in PVR at 24 weeks, with specific targets for baseline PVR levels.
  • Exploratory analysis investigated PVR changes by patient genotype.

Conclusions:

  • A tolerable and potentially effective dose of imatinib was identified for treating pulmonary arterial hypertension.
  • The findings support further investigation into personalized imatinib therapy guided by patient genotype.
  • This research paves the way for biomarker-driven studies to optimize PAH treatment.
Keywords:
Adaptive designefficacysafetytolerability

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