Phase I dose-escalation study of chiauranib, a novel angiogenic, mitotic, and chronic inflammation inhibitor, in patients with advanced solid tumors

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.

Keywords: Advanced solid tumors; Chiauranib; Dose-escalation; Pharmacokinetics; Phase I study; Safety.

Conflict of interest statement

Ethics approval and consent to participate

All patients provided written informed consent. The protocol was approved by the institutional review boards of the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

Consent for publication

The consent to publish has been obtained from the participants to report individual patient data.

Competing interests

ZQ Ning and JW Zhang are employees of Shenzhen Chipscreen Biosciences, Ltd. The other authors declared that they have no competing interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Pharmacokinetic analyses of chiauranib. a The mean plasma concentration-time curves of chiauranib in patients at a single-oral dose of 10, 20, 35, 50, and 65 mg chiauranib. The mean plasma concentration-time curves (b) and AUC-dose linear regression (c) of chiauranib on day 28 in the first treatment cycle at a multiple oral dose of 10, 20, 35, 50, and 65 mg chiauranib

Fig. 2

Steady-state mean trough concentration (Ctrough) of chiauranib. Mean Ctrough after a continuous oral dose of 10, 20, 35, 50, and 65 mg chiauranib capsules once daily in patients throughout the treatment cycles were shown

Fig. 3

Waterfall plot of changes in the target lesions with a representative case of clinical response. a Chiauranib dose cohorts are shown in parentheses as 1 = 10 mg, 2 = 20 mg, 3 = 35 mg, 4 = 50 mg, and 5 = 65 mg. Open bars represent patients who had progressive disease, and the filled bars represent patients who achieved stable disease as their best responses. Not shown, n = 3, due to unavailable tumor measurements. Coronal chest CT at baseline (b) and after 4 weeks chiauranib treatment (c) from a 59-year-old woman with poorly differentiated adenocarcinoma of the lung, who has been received surgery, adjuvant chemotherapy, chemo-radiation, and two salvage chemotherapies