Phase I dose-escalation study of chiauranib, a novel angiogenic, mitotic, and chronic inflammation inhibitor, in patients with advanced solid tumors.
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.
['Sun|Yongkun|Y|', 'Yang|Lin|L|', 'Hao|Xuezhi|X|', 'Liu|Yutao|Y|', 'Zhang|Jinwen|J|', 'Ning|Zhiqiang|Z|', 'Shi|Yuankai|Y|0000-0002-8450-7583']
D000328:Adult D000368:Aged D020533:Angiogenesis Inhibitors D000893:Anti-Inflammatory Agents D050256:Antimitotic Agents D000970:Antineoplastic Agents D015331:Cohort Studies D004305:Dose-Response Relationship, Drug D005221:Fatigue D005260:Female D006801:Humans D008228:Lymphoma, Non-Hodgkin D008297:Male D020714:Maximum Tolerated Dose D008875:Middle Aged D009281:Naphthalenes D047428:Protein Kinase Inhibitors D011507:Proteinuria D011804:Quinolines D016896:Treatment Outcome D055815:Young Adult
Dose-escalation Chiauranib Advanced solid tumors Safety Pharmacokinetics Phase I study