Abstract C261: Pharmacokinetics (PK) and pharmacodynamics (PD) of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor LY2157299 monohydrate (LY) in hepatocellular carcinoma (HCC) compared to glioma patients.
Authors: Raymond Eric , Faivre Sandrine , Santoro Armondo , Kelley Robin K. , Kelley Robin K. , Merle Philippe , Gane Ed , Douillard Jean-Yves , Waldschmidt Dirk , Mulcahy Mary , Costentin Charlotte , Minguez Beatriz , Di Lena Luca , Gueorguieva Ivelina , Miles Colin , Cleverly Ann , Lahn Michael M. , Ameryckx Sophie , Benhadji Karim A. , Giannelli Gianluigi 
Published: August 2014

Background: TGF-β signaling is associated with HCC progression in moderate to poorly differentiated tumors. LY is a TGF-β receptor I kinase inhibitor currently in clinical testing in glioblastoma (GBM), hepatocellular, and pancreatic cancer. We report here the safety and PK/PD profile of LY in HCC patients. Methods: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib (SF), advanced Child-Pugh A/B7 HCC, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/14 days off (28 days = 1 cycle). Patients received either 160 mg/day or 300 mg/day. PK data were used to build a population PK model for HCC patients. This population PK model guided appropriate sampling and identification of potential demographic covariates. PD analysis included serum alpha-fetoprotein (AFP). AFP response was defined as at least 20% decrease. Results: Among 148 patients enrolled, 137 patients were evaluable for PK. There was dose-proportional increase in exposure (AUC0-∞ = 3.8 mg*h/L for 160 mg and AUC0-∞ = 7.0 mg*h/L for 300 mg dose). There were higher exposures in HCC patients than previously observed for exposures in GBM patients (AUC0-∞ = 2.1 mg*h/L for 160 mg and AUC0-∞ = 3.7 mg*h/L for 300mg dose)1. PK data suggested that total oral clearance (CL/F = 25.4 L/hr) of LY in HCC patients is lower than previously reported clearance in GBM patients (CL/F = 38.4 L/hr). Moderate between-patient variability on exposure was observed in HCC patients similar to GBM patients. LY appears to be fully eliminated at the end of the 14-days-off period of a cycle. Administration of 300 mg/day to patients with HCC may result in higher exposures compared to patients with GBM. These increased exposures did not result in increase of toxicities. Eight patients discontinued treatment due to a possibly drug-related adverse event (AE). LY was well tolerated, most adverse events being grade1-2. Most common grade 3/4 possibly drug-related AEs in patients were: neutropenia (n = 3), anemia (n = 3) and fatigue (n = 2). Thirty-nine percent of 69 patients with HCC who had baseline AFP of &gt;200 ng/mL had AFP response. The median time-to-progression of responders vs. non-responders was 18 vs. 10 weeks (p&lt;0.01), respectively. Conclusion: Clearance of LY in HCC patients with Child Pugh A/B7 liver function is lower than in GBM patients. LY had manageable safety profile in HCC patients and was associated with AFP responses.

Rodon AJ., et al. First human dose (FHD) study of the oral transforming growth factor-beta receptor I kinase inhibitor LY2157299 in patients with treatment-refractory malignant glioma. Abstract #3011. 2011 ASCO Annual Meeting, Chicago, IL, USA.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C261.

Citation Format: Eric Raymond, Sandrine Faivre, Armondo Santoro, Robin K. Kelley, Robin K. Kelley, Philippe Merle, Ed Gane, Jean-Yves Douillard, Dirk Waldschmidt, Mary Mulcahy, Charlotte Costentin, Beatriz Minguez, Luca Di Lena, Ivelina Gueorguieva, Colin Miles, Ann Cleverly, Michael M. Lahn, Sophie Ameryckx, Karim A. Benhadji, Gianluigi Giannelli. Pharmacokinetics (PK) and pharmacodynamics (PD) of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor LY2157299 monohydrate (LY) in hepatocellular carcinoma (HCC) compared to glioma patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C261.