title: Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study.
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.
authors.affiliation: Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. rikovacs@iupui.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kovacs
authors.affiliation: Department of Cardiology, Vall d'Hebron, Barcelona, Spain. giulymaldonado@hotmail.com.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Maldonado
authors.affiliation: Medical Oncology, Vall d'Hebron, Barcelona, Spain. a.azaro@vhebron.net.
authors.forename: Analia
authors.initials: A
authors.lastname: Azaro
authors.affiliation: Department of Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain. sfcasares@gmail.com.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Fernández
authors.affiliation: Department of Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain. flombera@yahoo.es.
authors.forename: Federico L
authors.initials: FL
authors.lastname: Romero
authors.affiliation: Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. jmsepulveda76@gmail.com.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Sepulveda-Sánchez
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, MD, 21218, USA. mcorret1@jhmi.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: Corretti
authors.affiliation: Johns Hopkins Kimmel Cancer Center, Baltimore, MD, 21218, USA. carducci@jhmi.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.affiliation: Department of Cardiology and Cardiovascular Disease, Saint Louis University Hospital, St. Louis, MO, 63103, USA. melda@tetranet.net.
authors.forename: Melda
authors.initials: M
authors.lastname: Dolan
authors.affiliation: Eli Lilly and Company, Erl Wood, UK. gueorguieva_ivelina@lilly.com.
authors.forename: Ivelina
authors.initials: I
authors.lastname: Gueorguieva
authors.affiliation: Eli Lilly and Company, Erl Wood, UK. cleverly_ann_louise@lilly.com.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Cleverly
authors.affiliation: Eli Lilly and Company, Building 31/4, 893 S. Delaware St., Indianapolis, IN, 46285, USA. pillay_sada_n@lilly.com.
authors.forename: N Sokalingum
authors.initials: NS
authors.lastname: Pillay
authors.affiliation: Medical Oncology, Vall d'Hebron, Barcelona, Spain. baselgaj@mskcc.org.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Eli Lilly and Company, Building 31/4, 893 S. Delaware St., Indianapolis, IN, 46285, USA. MichaLahn@aol.com.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lahn
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D005260:Female; D006331:Heart Diseases / Q000097:blood / Q000139:chemically induced / Q000000981:diagnostic imaging; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D018125:Receptors, Transforming Growth Factor beta; C557799:LY-2157299; D008130:Lomustine; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Cardiac safety; First-in-human dose study; Glioma; LY2157299