Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study

Richard J. Kovacs, Giuliana Maldonado, Analia Azaro, Maria S. Fernández, Federico L. Romero, Juan M. Sepulveda-Sánchez, Mary Corretti, Michael Carducci, Melda Dolan, Ivelina Gueorguieva, Ann L. Cleverly, N. Sokalingum Pillay, Jose Baselga, Michael M. Lahn

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Transforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials.

Original languageEnglish (US)
Pages (from-to)309-323
Number of pages15
JournalCardiovascular Toxicology
Volume15
Issue number4
DOIs
StatePublished - Oct 26 2015

Keywords

  • Cardiac safety
  • First-in-human dose study
  • Glioma
  • LY2157299

ASJC Scopus subject areas

  • Molecular Biology
  • Toxicology
  • Cardiology and Cardiovascular Medicine

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    Kovacs, R. J., Maldonado, G., Azaro, A., Fernández, M. S., Romero, F. L., Sepulveda-Sánchez, J. M., Corretti, M., Carducci, M., Dolan, M., Gueorguieva, I., Cleverly, A. L., Pillay, N. S., Baselga, J., & Lahn, M. M. (2015). Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study. Cardiovascular Toxicology, 15(4), 309-323. https://doi.org/10.1007/s12012-014-9297-4