Abstract
BACKGROUND: Chiauranib is a novel orally active multi-target inhibitor that simultaneously inhibits the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα, and c-Kit), mitosis-related kinase Aurora B, and chronic inflammation-related kinase CSF-1R. This phase I dose-escalation study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor activity of chiauranib in patients with refractory advanced solid tumor and lymphoma. METHODS: Eighteen patients were treated with continuous dosing of chiauranib from 10 to 65 mg once daily in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Pharmacokinetic profile of plasma chiauranib was analyzed in both single and multiple dose studies. RESULTS: Dose-limiting toxicity (DLT) as of grade 3 hypertension occurred in two patients at 65 mg/day, and one dose level below as MTD was 50 mg/day. The most common treatment-related adverse events included fatigue (61.1%), proteinuria (44.4%), hematuria (38.9%), hypothyroidism (38.9%), hypertriglyceridemia (33.3%), and hypertension (33.3%). A linear and dose-dependent pharmacokinetic profile of chiauranib was characterized with rapid absorption and slow elimination feature in both single and multiple dose studies. The accumulative exposure of chiauranib reached the steady state within 8 days and was approximately increased by twofold as those in the single dose study. No complete or partial response was observed, and 12 patients (66.7%) achieved stable disease (SD). CONCLUSIONS: Chiauranib demonstrated an acceptable safety and favorable pharmacokinetic profile with potential antitumor activity. Several phase Ib/II clinical studies are currently under further investigation. TRIAL REGISTRATION: NCT, NCT02122809 . Registered 25 April 2014.