Abstract C198: Phase I study on safety and pharmacokinetics of sulfatinib, a selective VEGFR/FGFR dual inhibitor, in Chinese patients with advanced solid tumors.
Authors: Xu Jianming , Wang Yan , Ye Chenyang , Shen Lin , Huang Cheng , Yang Li , Sai Yang , Mu Hua 
Published: June 2012

Background: Angiogenesis plays a key role in growth and metastasis of many tumors and is generally mediated by a variety of growth factors, including vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Sulfatinib is a highly selective small molecule dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR), developed by Hutchison MediPharma. It demonstrated potent in vivo inhibitory effects on a variety of human tumor xenografts. The current study was designed to evaluate safety and tolerability, pharmacokinetics, and preliminary anti-tumor activity of sulfatinib.

Methods: Eligible patients with histopathologically confirmed solid tumors that had previously failed standard therapies or for whom no standard therapies were available were to be enrolled in cohorts of escalating sulfatinib doses given orally once or twice daily of 28-day cycles until disease progression or unacceptable toxicity. Modified Fibonacci method was used for dose escalation, followed by an expanded cohort at the maximum tolerated dose (MTD).

Results: As of Aug 31, 2011, 28 patients have been enrolled in 8 sulfatinib dose cohorts of 50, 75, 110, 150, 200, 265 and 300mg once daily (QD) and 125mg twice daily (BID), respectively. Patients had a median age of 50 (36–70) yrs, with 46% male, ECOG performance status 0–2, and predominantly heavily pretreated. Patient tumor types included colorectal (9), GIST (5), liver (4), neuroendocrine (4), gastric (1), esophageal (1), duodenal (1), cervical (1), retroperitoneal liposarcoma (1), and solid-pseudopapillary tumor of the pancreas (1). Common adverse events (AEs) included fatigue, vomiting, nausea, diarrhea, hypertension, electrolyte disorder and elevated AST/ALT, mostly grade 1/2. Serious AEs and drug related grade 3 AEs were identified in 2 and 5 patients, respectively. Two dose limiting toxicities including a grade 3 coagulation disorders and a grade 3 upper gastrointestinal bleeding were observed in the 50 mg and 265mg cohort, respectively. No unexpected AE has been identified. MTD has not been reached and the dose escalation is ongoing at 300 mg QD and 125mg BID. Among 24 evaluable patients, 7 (29%) had stable disease, with the duration up to 5 months. Five of 9 (56%) patients at doses of ≥ 200mg had stable disease in comparison with 2/15 (13%) patients at doses of &lt; 200mg. There was a decrease in both sVEGFR2 and bFGF levels after 4-week treatment with sulfatinib at doses ≥ 110mg comparing to the baseline levels, indicating inhibition of both VEGFR and FGFR. The 4/5 patients who experienced hypertension on study had stable disease. Preliminary PK analyses showed that sulfatinib was rapidly absorbed at all studied doses with Tmax 1.3–2.8 hours and half-life of 15.3–19.1 hours. Cmax and AUC displayed good dose proportionality and no marked drug accumulation occurred at day 28.

Conclusions: Sulfatinib was well tolerated at doses up to 265 mg QD and demonstrated preliminary evidence of anti-tumor activity. PD marker analysis indicates dual inhibition of VEGFR and FGFR. Preliminary PK data suggests good dose proportionality in exposure without marked drug accumulation over the evaluated doses. Dose escalation is ongoing at 300 mg QD and 125mg BID.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C198.