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

3038 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 is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of fruquintinib. Methods: This phase I study used the 3+3 design for dose-escalation of fruquintinib given once daily (QD) in 28-day cycles in patients with solid tumors who had failed standard therapies. Endpoints included safety, PK, and preliminary efficacy measurements. Results: To date 16 patients were enrolled in 5 dose cohorts of 1-6 mg QD, with age 42-69 yr, 44% male, ECOG 0-1 and all heavily pretreated. Tumor types included 9 colorectal, 3 lung, 3 breast, and 2 gastric (one patient with bi-primary carcinoma of breast and colon). The most common adverse events included hypertension (50%), proteinuria (43.8%), hand-foot syndrome (HFS 43.8%), diarrhea (31.2%), and hoarseness (25%). Grade 3/4 AEs were diarrhea (25%), HFS (12.5%), thrombocytopenia (6.2%), and hyperbilirubinemia (6.2%). Three DLTs were observed: 2 grade 3 HFS both at 6mg and 1 grade 3 hyperbilirubinemia at 4mg. PK analysis showed good and rapid absorption followed by slow terminal elimination with a half-life of approximately 37 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. Among 8 evaluable patients, 2 (1 colorectal and 1 gastric) had confirmed partial response for more than 4 months; 5 had stable disease, including 3 SDs of 3-8 months. Conclusions: Fruquintinib was well tolerated at doses up to 4 mg QD to date and demonstrated excellent pharmacokinetic properties. Encouraging clinical activity was observed. Further clinical studies are warranted and under planning.