Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors

摘要: Background: AZD4547 is an orally bioavailable, selective inhibitor of FGFR 1, 2, and 3, with activity in a wide range cell lines xenografts dependent upon signalling, including patient-derived explant models gene amplification.Methods: A 3-part study was initiated patients advanced solid tumors (NCT00979134): Part to determine the maximum tolerated dose (MTD) and/or continuous tolerable (RD); B characterize pharmacokinetic safety profile (Parts unselected for amplification); C1 assess clinical (80 mg bid dosing) prospectively selected amplification 1 2. status determined using fluorescent situ hybridization (FISH) analysis archival or fresh tumor tissue. Pharmacodynamic biomarkers phosphate FGF23 were assessed plasma samples.Results: At data cut-off (15 January 2013), 43 had been treated (dose 20-200 bid) dose-escalation phase (Part A) this study, RD as 80 dosing. Dose-limiting toxicities included increased liver enzymes, stomatitis, renal failure, hyperphosphataemia, mucositis. In dose-expansion B), total 6 confirm tolerability RD. C1, 21 2 amplified received bid; these diverse types copy number gain (mostly low <6). One squamous NSCLC patient arm, high who previous anti-cancer therapy, experienced partial response lasting 12 weeks (patient discontinued treatment due RECIST disease progression at 24 weeks). An additional 4 long periods stabilization (?24 weeks; breast cancer [n=1], [n=1] transitional carcinoma [n=2]). Pharmacokinetic generally both predictable linear. The most common adverse events (AEs) reported dry skin mucous membranes, retinal pigmented epithelial detachment (RPED). AEs mild moderate reversible. Parts C2 (squamous NSCLC) C3 (gastric cancer) are ongoing.Conclusions: dosing tolerated. Encouraging evidence anti-tumor seen some patients, notably level amplification. biomarker will be presented. Studies remain ongoing levels