Abstract LB-145: Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors .
Authors: Andre Fabrice , Ranson Malcolm , Dean Emma , Varga Andrea , van der Noll Ruud , Stockman Paul K. , Ghiorghiu Dana , Kilgour Elaine , Smith Paul D. , Macpherson Merran , Lawrence Peter , Hastie Andrew , Schellens Jan HM 
Published: August 2014

Abstract
Background: AZD4547 is an orally bioavailable, selective inhibitor of FGFR 1, 2, and 3, with activity in a wide range of cell lines and xenografts dependent upon FGFR signalling, including patient-derived explant models with FGFR gene amplification.
Methods: A 3-part study of AZD4547 was initiated in patients with advanced solid tumors (NCT00979134): Part A to determine the maximum tolerated dose (MTD) and/or continuous tolerable dose (RD); Part B to characterize the pharmacokinetic and safety profile (Parts A and B unselected for FGFR amplification); Part C1 to assess safety and clinical activity of AZD4547 (80 mg bid continuous dosing) in patients with advanced solid tumors prospectively selected for amplification of FGFR 1 and 2. FGFR gene amplification status was determined using fluorescent in situ hybridization (FISH) analysis of archival or fresh tumor tissue. Pharmacodynamic biomarkers including phosphate and FGF23 were assessed in plasma samples.
Results: At data cut-off (15 January 2013), 43 patients had been treated (dose range 20-200 mg bid) in the dose-escalation phase (Part A) of this study, and the RD was determined as 80 mg bid continuous dosing. Dose-limiting toxicities included increased liver enzymes, stomatitis, renal failure, hyperphosphataemia, and mucositis. In the dose-expansion phase of the study (Part B), a total of 6 patients were treated to confirm the tolerability of the RD. In Part C1, 21 patients with FGFR 1 or 2 amplified tumors received AZD4547 80 mg bid; these patients had diverse tumor types and a range of gene copy number gain (mostly low gene copy number &lt;6). One squamous NSCLC patient in the C1 arm, with high copy number FGFR 1 amplification and who had received 2 previous lines of anti-cancer therapy, experienced a partial response lasting 12 weeks (patient discontinued study treatment due to RECIST disease progression at 24 weeks). An additional 4 patients in Part C1 had long periods of disease stabilization (≥24 weeks; advanced breast cancer [n=1], squamous NSCLC [n=1] and transitional cell carcinoma [n=2]). Pharmacokinetic data were generally both predictable and linear. The most common adverse events (AEs) reported were hyperphosphataemia, dry skin and mucous membranes, and retinal pigmented epithelial detachment (RPED). AEs were generally mild to moderate and reversible. Parts C2 (squamous NSCLC) and C3 (gastric cancer) are ongoing.
Conclusions: AZD4547 80 mg bid continuous dosing was generally tolerated. Encouraging evidence of anti-tumor activity was seen in some patients, most notably a partial response in a patient with squamous NSCLC who had a high level FGFR gene amplification. Pharmacodynamic plasma biomarker data will be presented. Studies remain ongoing in patients with tumors selected for high levels of FGFR amplification.
Citation Format: Fabrice Andre, Malcolm Ranson, Emma Dean, Andrea Varga, Ruud van der Noll, Paul K. Stockman, Dana Ghiorghiu, Elaine Kilgour, Paul D. Smith, Merran Macpherson, Peter Lawrence, Andrew Hastie, Jan HM Schellens. Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), 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 LB-145. doi:10.1158/1538-7445.AM2013-LB-145