Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors
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Open Access
- 4 October 2016
- journal article
- clinical trial
- Published by Springer Science and Business Media LLC in Journal of Hematology & Oncology
- Vol. 9 (1), 105
- https://doi.org/10.1186/s13045-016-0332-8
Abstract
Anlotinib is a novel multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. We aimed to evaluate the safety, pharmacokinetics, and antitumor activity of anlotinib in patients with advanced refractory solid tumors. Anlotinib (5–16 mg) was orally administered in patients with solid tumor once a day on two schedules: (1) four consecutive weeks (4/0) or (2) 2-week on/1-week off (2/1). Pharmacokinetic sampling was performed in all patients. Twenty-one patients were further enrolled in an expanded cohort study on the recommended dose and schedule. Preliminary tumor response was also assessed. On the 4/0 schedule, dose-limiting toxicity (DLT) was grade 3 hypertension at 10 mg. On the 2/1 schedule, DLT was grade 3 hypertension and grade 3 fatigue at 16 mg. Pharmacokinetic assessment indicated that anlotinib had long elimination half-lives and significant accumulation during multiple oral doses. The 2/1 schedule was selected, with 12 mg once daily as the maximum tolerated dose for the expanding study. Twenty of the 21 patients (with colon adenocarcinoma, non-small cell lung cancer, renal clear cell cancer, medullary thyroid carcinoma, and soft tissue sarcoma) were assessable for antitumor activity of anlotinib: 3 patients had partial response, 14 patients had stable disease including 12 tumor burden shrinkage, and 3 had disease progression. The main serious adverse effects were hypertension, triglyceride elevation, hand-foot skin reaction, and lipase elevation. At the dose of 12 mg once daily at the 2/1 schedule, anlotinib displayed manageable toxicity, long circulation, and broad-spectrum antitumor potential, justifying the conduct of further studies.Keywords
This publication has 23 references indexed in Scilit:
- Long-term Safety of Sunitinib in Metastatic Renal Cell CarcinomaEuropean Urology, 2016
- Risk of arterial thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: An up-to-date meta-analysisCritical Reviews in Oncology/Hematology, 2014
- Comprehensive overview of the efficacy and safety of sorafenib in advanced or metastatic renal cell carcinoma after a first tyrosine kinase inhibitorClinical and Translational Oncology, 2013
- Development and strategies of VEGFR-2/KDR inhibitorsFuture Medicinal Chemistry, 2012
- A Phase I Dose–Escalation Study of Regorafenib (BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid TumorsClinical Cancer Research, 2012
- Hallmarks of Cancer: The Next GenerationCell, 2011
- FGFR1 amplification in breast carcinomas: a chromogenic in situhybridisation analysisBreast Cancer Research, 2007
- Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With CancerJournal of Clinical Oncology, 2006
- Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid TumorsJournal of Clinical Oncology, 2005
- The Hallmarks of CancerCell, 2000