Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

Jin Li,Ka Jia,Lei Chen,Fengqing Wang,Fangfang Lv,Chunlei Zheng,Haiyi Guo,Yunxia Zuo,Jun Qian,Xinmin Zhao,Ke Yv,Chuan Li

doi:10.1186/1471-2407-10-529

Abstract

BackgroundYN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies.MethodsThis dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death.ResultsForty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks.ConclusionsThe recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations.Trial registrationClinicalTrials.gov unique identifier: NCT00633490

Highlights

YN968D1 (Apatinib) selectively inhibits phosphorylation of Vascular endothelial growth factor receptors (VEGFRs)-2 and tumor angiogenesis in mice model
In addition to the VEGF-A neutralizing antibody, which is already a standard treatment for late-stage colorectal cancer in the USA [7], sorafenib was recently approved by the US Food and Drug Administration for the treatment of renal and hepatic cancers, and sunitinib was approved for the treatment of gastrointestinal stromal tumor (GIST) and renal cell carcinoma
The application of the VEGFR tyrosine kinase inhibitors (TKIs) to gastrointestinal adenocarcinoma remains a challenge, they have been found to be active for lung, breast, renal, and hepatic cancers, and GIST

Summary

Introduction

YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. Various VEGFR-2 inhibitors, including receptor-specific antibodies and low molecular weight chemicals such as sorafenib, vandetanib, cediranib, and sunitinib, have recently been developed [4,5,6]. In addition to the VEGF-A neutralizing antibody, which is already a standard treatment for late-stage colorectal cancer in the USA [7], sorafenib was recently approved by the US Food and Drug Administration for the treatment of renal and hepatic cancers, and sunitinib was approved for the treatment of gastrointestinal stromal tumor (GIST) and renal cell carcinoma. The application of the VEGFR tyrosine kinase inhibitors (TKIs) to gastrointestinal adenocarcinoma remains a challenge, they have been found to be active for lung, breast, renal, and hepatic cancers, and GIST

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