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

Abstract

BACKGROUND:

YN968D1 (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.

METHODS:

This 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.

RESULTS:

Forty-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.

CONCLUSIONS:

The 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 REGISTRATION:

ClinicalTrials.gov unique identifier: NCT00633490.

• Authors: Jin Li, Xinmin Zhao, Lei Chen, Haiyi Guo, Fangfang Lv, Ka Jia, Ke Yv, Fengqing Wang, Chuan Li, Jun Qian, Chunlei Zheng, Yunxia Zuo
• Journal: BMC cancer (BMC Cancer) Vol. 10 Pg. 529 (Oct 05 2010) ISSN: 1471-2407 [Electronic] England
• PMID: 20923544 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Pyridines
• apatinib
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Neoplasms (drug therapy)
• Pyridines (pharmacokinetics, pharmacology, therapeutic use)
• Tomography, X-Ray Computed
• Treatment Outcome
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)