Abstract 2413: Phase I study of safety and pharmacokinetics of fruquintinib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with advanced solid tumors.
Authors: Li Jin , Cao Junning , Zhang Jian , Chen Zhiyu , Peng Wei , Fan Songhua , Qi Charlie , Gu Yi , Sai Yang , Mu Hua 
Published: August 2014

Abstract
Background: Fruquintinib is a novel oral small molecule compound discovered and developed by Hutchison MediPharma that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has demonstrated potent inhibitory effects on multiple human tumor xenografts. This first-in-human study was conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs), safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of fruquintinib.
Methods: This phase I study used a 3+3 design for dose-escalation of fruquintinib given once daily continuously (QD) or 3 weeks on and 1 week off in 28-day cycles in patients with solid tumors who had failed standard therapies. Endpoints included safety, PK, and preliminary efficacy measurements.
Results: Forty patients were enrolled in 5 dose cohorts of 1-6 mg QD and 2 dose cohorts of 5mg and 6mg 3 wks on/1 wk off, with age 18-70 yr, 40% male, ECOG 0-1 and heavily pretreated cancers. Tumor types included CRC (12), breast (8), NSCLC (7), thyroid (3), gastric (2) and others (8). The most common adverse events (all grades) were hand-foot syndrome (HFS), elevation of serum thyroid stimulating hormone (TSH), stomatitis, hypertension, white blood cell decreased, proteinuria, hoarseness, fatigue, and diarrhea, each observed in ≥ 30% pts. Grade 3/4 AEs were relatively uncommon, with HFS and hypertension the only AEs occurred in ≥ 10% pts (15% for each). Only 6 pts terminated study treatment due to related AEs. 6 DLTs were observed: 2 grade 3 HFS both at 6mg, 1 grade 3 HFS and 1 grade 3 thrombocytopenia with subcutaneous bleeding at 5mg, 1 grade 3 hyperbilirubinemia at 4mg and 1 grade 3 fatigue at 6mg 3wks on/1 wk off. MTD was determined as 4mg QD or 6mg 3wks on/1 wk off. PK analysis showed good and rapid absorption followed by slow terminal elimination with a half-life of approximately 42 hours which was consistent across all dose groups. Both Cmax and AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. 34 patients were evaluable for tumor response, including 13 with confirmed partial response (PRs: 4 NSCLC, 3 CRC, 2 breast, 1 gastric, 1 pNET, 1 glandula submandibularis and 1 nasopharyngeal); and 15 with stable disease (SDs: 14 were 3-9 months). Conclusions: Fruquintinib was well tolerated at doses up to 4mg QD or 6mg 3wks on/1 wk off, and demonstrated excellent pharmacokinetic properties. Impressive clinical activity including durable PR and SD was observed in majority of patients with various heavily pre-treated advanced cancers. These promising results warrant further clinical development of fruquintinib.
Citation Format: Jin Li, Junning Cao, Jian Zhang, Zhiyu Chen, Wei Peng, Songhua Fan, Charlie Qi, Yi Gu, Yang Sai, Hua Mu. Phase I study of safety and pharmacokinetics of fruquintinib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2413. doi:10.1158/1538-7445.AM2013-2413