Abstract CT120: Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer
Authors: Kang Yoon-Koo , Seery Tara E. , Kato Mina , Chakrabarti Debasis , Valota Olga , Chen Ying , Tang Jie , Pithavala Yazdi K. , Kudo Masatoshi 
Published: August 2015

Abstract
Introduction: Hepatobiliary excretion is the major elimination pathway for axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, approved for second-line treatment of advanced renal cell carcinoma. A formal hepatic impairment (HI) study was previously conducted in subjects with Child-Pugh A (CPA) and Child-Pugh B (CPB) disease but who were otherwise healthy to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of axitinib following a single 5 mg oral dose. The safety and PK of axitinib were further evaluated in CPA and CPB patients (pts) with advanced hepatocellular carcinoma (HCC) following continuous multiple axitinib dosing.
Methods: Two study portions (randomized double-blind portion of axitinib versus placebo, and non-randomized portion) were conducted in parallel in pts with advanced HCC after failure of one prior antiangiogenic therapy. In the non-randomized portion, the effect of HI on safety and PK were evaluated in HCC CPA (starting dose: 5 mg twice a day [BID]) and CPB (Score 7, starting dose: 2 mg BID) pts. This was also intended to identify the recommended starting dose of axitinib in HCC CPB pts. Serial PK samples up to 8 hour postdose were collected at steady state (Cycle 1 Day 15).
Results: Data from 15 CPA and 7 CPB pts were available for safety analysis. Most pts were male (n = 17) and Asian (n = 21). Overall, the most frequently reported all-causality treatment emergent adverse events (TEAE) in all, CPA and CPB pts were fatigue (63.6%, 80% and 28.6%), decreased appetite (54.5%, 46.7% and 71.4%), diarrhea (45.5%, 60% and 14.3%), hypertension (45.5%, 46.7% and 42.9%), and palmar-plantar erythrodysesthesia syndrome (45.5%, 53.3% and 28.6%). Overall, the most frequently reported Grade ≥3 TEAEs in all, CPA and CPB pts were hypertension (27.3%, 26.7% and 28.6%), fatigue (18.2%, 20% and 14.3%) and hyponatraemia (18.2%, 6.7% and 42.9%). One out of 6 evaluable CPB pts treated with 2 mg BID experienced Cycle 1 dose limiting toxicity (proteinuria; &gt;3.5 g/24 hours). PK samples were collected from 12 CPA and 7 CPB pts (AUC0-24 and CL/F reported for 8 CPA and 6 CPB pts, respectively). In CPA and CPB pts, the geometric mean (geometric% coefficient of variance [CV]) values for axitinib AUC0-24 were 311 (63) and 316 (118) ng.hr/mL, respectively. The geometric mean (geometric% CV) values for axitinib CL/F were 32.2 (63) and 12.7 (118) L/hour, respectively, indicating that axitinib CL/F is decreased with increasing HI.
Conclusions: The safety profile of axitinib in HCC CPA and CPB pts in this study was consistent with the known safety profile of axitinib. Axitinib plasma exposures were comparable in CPB pts receiving 2 mg BID axitinib and CPA pts receiving 5 mg BID axitinib. These data are in agreement with the previous single-dose HI study and further support that 2 mg BID is an appropriate axitinib starting dose for CPB pts with HCC.
Citation Format: Yoon-Koo Kang, Tara E. Seery, Mina Kato, Debasis Chakrabarti, Olga Valota, Ying Chen, Jie Tang, Yazdi K. Pithavala, Masatoshi Kudo. Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT120. doi:10.1158/1538-7445.AM2015-CT120