First-in-human phase I study of selective VEGFR/FGFR dual inhibitor sulfatinib with milled formulation in patients with advanced solid tumours (EORTC 2015)

Abstract (download poster for full details):

Authors: Jian-Ming Xu, Lin Shen, Yan Wang, Yu-ling Chen, Ru Jia, Jian Wang, Ke Li, Yang Sai, Jing Li, Chuan Qi, Hua Ye, Su Weiguo

sulfatinib-phase-i-eortc-2015-thumb8bit Background: Sulfatinib is a highly selective oral small molecule inhibitor targeting both vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR).  A phase I dose-escalation study was carried out to determine sulfatinib maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), pharmacokinetic (PK) profiles, and preliminary antitumor activity in patients with advanced solid tumours.

Methods: Sulfatinib was administered orally in 28-day treatment cycles until disease progression or unacceptable toxicity.  The study utilized 3+3 dose escalation method, with ascending dose cohorts from 50mg to 350mg daily.  During the study, a milled formulation was developed to reduce the inter-patient PK variations and optimize drug absorption.  The milled formulation was used in 200mg once daily (QD) to 350mg QD dose cohorts.

Results: As of July 6, 2015, a total of 77 patients had been enrolled.  Forty‑three of the 77 patients received original formulation in dose cohorts from 50mg to 300mg daily.  The data of patients treated with original formulation dosing from 50 to 300mg once daily, or 125mg and 150mg twice daily were reported in ASCO 2012(#3040).  Thirty-four of the 77 patients received milled formulation.  Among the 34 patients, 23 were enrolled in the dose-escalation phase, receiving sulfatinib 200mg to 350mg QD whereas 11 patients were enrolled in the dose-expansion phase receiving sulfatinib 300mg or 350 mg QD.  Among the 34 patients, there were 24 male patients (70.6%) and 10 female patients (29.4%).  The median age was 55.97 (23.35-73.17) years.  The most common adverse events of 34 patients were hypertension, proteinuria, diarrhoea, elevated AST/ALT and decreased blood albumin, mostly grade1/2.  One DLT (grade 3 ALT/AST increase) was observed in the 200 mg QD dose group.  MTD was not reached up to 350mg QD.  Among the 34 subjects treated with milled formulation, 22 subjects were diagnosed with neuroendocrine tumours (NETs).  Eight NET patients (5 in 300mg QD and 3 in 350mg QD cohort) had confirmed partial response (PR) with median duration of response (DoR) of 13.8 months.  The tumour origins of the 8 NET patients include pancreas (3 patients), duodenum (1 patient), rectum (1 patient), thymus (1 patient) and unknown origin (2 patients).  Objective response rate among the 18 efficacy evaluable NET patients was 44.4% and disease control rate was 100%.  Sulfatinib half-life (t1/2) in plasma averaged 14-20 hours at the test dose levels, which supported sulfatinib QD dosing frequency.  Following QD multiple dosing, sulfatinib achieved steady state on Day 14.  The drug exposure increased when the dose increased from 200 mg to 300 mg, and then plateaued from 300 mg to 350 mg. Based on the clinical safety, efficacy, and PK data, the recommended Phase II dose is determined to be 300 mg QD.

Conclusions: Sulfatinib was well tolerated with an acceptable safety profile.  Promising anti-tumour activity was observed in NET patients.  Further clinical studies with sulfatinib are warranted.

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