Defining a therapeutic window for the novel TGF‐β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model

Abstract

AIMSTo identify prospectively a safe therapeutic window for administration of a novel oral transforming growth factor β (TGF-β) inhibitor, LY2157299 monohydrate, based on a pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of population plasma exposures and biomarker responses in tumour were performed for future trials of LY2157299 in glioblastoma and other cancer populations. METHODSThe model was updated after completion of each cohort during the first-in-human dose (FHD) study. The flexible design allowed continuous assessment of PK variability by recruiting the required number of patients in each cohort. Based on 30% inhibition of TGF-β RI kinase phosphorylates (pSMAD), biologically effective exposures were anticipated to be reached from 160 mg onwards. The therapeutic window was predicted, based on animal data, to be between 160 and 360 mg. RESULTSNo medically significant safety issues were observed and no dose limiting toxicities were established in this study. Observed plasma exposures (medians 2.43 to 3.7 mg l −1 h, respectively) with doses of 160 mg to 300 mg were within the predicted therapeutic window. Responses, based on the MacDonald criteria, were observed in these patients. CONCLUSIONSA therapeutic window for the clinical investigation of LY2157299 in cancer patients was defined using a targeted PK/PD approach, which integrated translational biomarkers and preclinical toxicity. The study supports using a therapeutic window based on a PK/PD model in early oncology development. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• TGF-β signalling has been recognized as an important regulator of tumour growth in advanced cancers for the last 20 years. However, due to severe non-monitorable toxicities in animal studies, no small molecule TGF-β inhibitor has thus far progressed into clinical trials in oncology patients. WHAT THIS STUDY ADDS• Although similar cardiovascular toxicities were observed in animal studies for LY2157299 monohydrate, we applied a pharmacokinetic/pharmacodynamic model to establish prospectively a therapeutic window. Using a therapeutic window approach we identified doses and exposures where we observed responses in glioblastoma patients with this potential first in class treatment. This study supports using a therapeutic window approach based on a pharmacokinetic/ pharmacodynamic model in early oncology development.

Targeting TGF-β Signaling for Therapeutic Gain

“…Finally, if TGF-b blockade drugs are approved for widespread use, there will be considerable variation in both therapeutic and toxicological responses among patients (Bonyadi et al 1997;Akhurst 2004;Valle et al 2008;Benzinou et al 2012;Chung Kang et al 2013;Kawasaki et al 2014). There is therefore a growing need for development of predictive biomarkers of TGF-b blockade (Gueorguieva et al 2014;Kawasaki et al 2014).…”

“…Moreover, because these inhibitors block TbRI kinase activity, they will not prevent signaling independent of the kinase activity, such as TRAF6-p38 MAPK signaling (Hocevar et al 2005;Gudey et al 2014;Sundar et al 2015). SMIs have poor pharmacokinetics and are generally cleared from the body with a t 1/2 of 2-3 h, whereas pharmacodynamic markers, such as inhibition of Smad2 phosphorylation, persist for up to 8 h postdosing (Bueno et al 2008;Gueorguieva et al 2014). These negative features of SMIs are balanced by the ease of drug administration through the oral route.…”

“…Even once commenced, the clinical trials had long-term holds because of disquieting findings of hemorrhagic lesions within the heart valves, as well as aortic aneurysms in rats and dogs after long-term continuous exposure to the highest levels of TGF-b blockade Laping et al 2007;Anderton et al 2011). 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).…”

“…These studies were undertaken based on PK/ PD modeling in mouse, rat and dog, integrating plasma drug levels and magnitude of inhibition of Smad2 phosphorylation in circulating mononuclear cells, relative to onset of tumor responses versus valvulopathy (Gueorguieva et al 2014). The therapeutic window turned out to be narrow, between 160 mg and 300 mg per day (administered as two doses of 80 -150 mg), with dosing in cycles of 2 weeks on (bi-daily treatment) and 2 weeks off drug.…”

Brain perfusion and permeability in patients with advanced, refractory glioblastoma treated with lomustine and the transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate

“…Based on preclinical information, a pharmacokinetic and pharmacodynamic model was developed to prospectively describe a therapeutic window to facilitate the safe clinical evaluation of LY2157299 (9). In short-and long-term toxicological studies in rats and dogs, LY2157299 was considered to potentially have the required therapeutic window in which a dose escalation to a biologically active dose range may safely be implemented (10).…”