TY - JOUR
T1 - Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study
AU - Kovacs, Richard J.
AU - Maldonado, Giuliana
AU - Azaro, Analia
AU - Fernández, Maria S.
AU - Romero, Federico L.
AU - Sepulveda-Sánchez, Juan M.
AU - Corretti, Mary
AU - Carducci, Michael
AU - Dolan, Melda
AU - Gueorguieva, Ivelina
AU - Cleverly, Ann L.
AU - Pillay, N. Sokalingum
AU - Baselga, Jose
AU - Lahn, Michael M.
N1 - Funding Information:
This study was sponsored by Eli Lilly and Company, IN, USA. The authors want to thank Biomedical Systems (St. Louis, MO, USA), in particular Beth Gregory, for conducting the central review of all echocardiography/Doppler data. The sponsor also acknowledges the contribution of Quintiles and ICON staff to the implementation and the execution of this study. The sponsor thanks Kriss Harris for the statistical contribution to the present study. The authors thank Durisala Desaiah, PhD, Eli Lilly and Company, for the assistance with medical writing of this disclosure.
Publisher Copyright:
© 2014, The Author(s).
PY - 2015/10/26
Y1 - 2015/10/26
N2 - 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.
AB - 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.
KW - Cardiac safety
KW - First-in-human dose study
KW - Glioma
KW - LY2157299
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UR - http://www.scopus.com/inward/citedby.url?scp=84942370577&partnerID=8YFLogxK
U2 - 10.1007/s12012-014-9297-4
DO - 10.1007/s12012-014-9297-4
M3 - Article
C2 - 25488804
AN - SCOPUS:84942370577
SN - 1530-7905
VL - 15
SP - 309
EP - 323
JO - Cardiovascular Toxicology
JF - Cardiovascular Toxicology
IS - 4
ER -