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.

Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer

“…8 It is known that TGF-β plays a pivotal role in repair mechanisms of the heart and in pre-clinical development, small-molecule ALK5 inhibitors like SD-208 were found to be cardiotoxic on prolonged application in rats, 22 while in clinical trials in humans cardiac toxicity was found to be acceptable. 23 A preferred strategy for combining TGF-β-receptor kinase inhibition with ROR1-CAR T-cell therapy may therefore be to use SD-208 shortly after CAR T-cell infusion to create a time window of protection from TGF-β. Ideally, a single (or short term) treatment with SD-208 may render CAR T-cells resistant to TGF-β for a sufficient amount of time to augment the antitumor effect.…”

Signaling Receptors for TGF-β Family Members

“…In a recent clinical doseescalation analysis, the TbRI kinase inhibitor LY2157299 monohydrate (also named galunisertib) proved to be efficacious against malignant glioma (Rodon et al 2015a,b). Previous animal experiments reported severe cardiac side effects of TbRI kinase inhibitors; however, no cardiotoxicity was recorded in patients treated with galunisertib, providing support for the possibility that anti-TGF-b drugs can be clinically useful (Kovacs et al 2015).…”

Targeting TGF-β Signaling for Therapeutic Gain

“…During hold of the clinical trial, considerable effort was invested in developing biomarkers of drug response and undertaking PK/PD modeling to define a better therapeutic window for drug response (Gueorguieva et al 2014). Phase I and II studies for galunisertib subsequently incorporated careful monitoring of possible adverse cardiac events using circulating biomarkers, such as troponin I, brain natriuretic protein (BNP) and highsensitivity C-reactive protein (hs-CRP), echocardiography Doppler imaging for possible mitral and tricuspid valve regurgitation, and screening for potential aneurysms of the ascending aorta and aortic arch by computer tomography (CT) or magnetic resonance imaging (MRI) Kovacs et al 2015;Rodó n et al 2015b;Brandes et al 2016). In a clinical safety study (Kovacs et al 2015), only one of 79 patients treated showed an increase in cardiopathologic grade, and then only from a baseline of normal to a mild pathology, as assessed by Doppler.…”

“…In the field of SMIs, some of the first clinical trials for TbRI inhibitors have recently been published Kovacs et al 2015;Rodó n et al 2015a,b;Sepulveda-Sánchez et al 2015;Brandes et al 2016), with more in the pipeline. So far, all published clinical studies used the TbRI SMI drug, galunisertib, whereas an additional 12 interventional trials are ongoing with this drug, and another trial uses the TbRI SMI TEW-7197 (Table 2) (Jin et al 2014;Son et al 2014;Naka et al 2016).…”