Abstract CT215: A phase I trial of LY2874455, a fibroblast growth factor receptor inhibitor, in patients with advanced cance
Authors: Tie Jeanne , Bang Yung-Jue , Park Young Suk , Kang Yoon-Koo , Monteith David , Hartsock Kimberly , Thornton Donald E. , Michael Michael 
Published: May 2015

Abstract
Background: Deregulation of the fibroblast growth factor (FGF) and the FGF receptor (FGFR) pathway is implicated in several human cancers (1, 2). Inhibition of the FGF pathway has led to the attenuation of tumor growth in preclinical xenograft models. LY2874455 is a novel class of FGFR inhibitor with potent biochemical/cellular inhibitory activities and in vivo target inhibition in xenograft models (3).
Methods & Objectives: This phase I multicenter nonrandomized, open-label study of oral LY2874455 consisted of dose escalation (part A) and dose expansion (part B). The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included safety, pharmacokinetics, and pharmacodynamic response.
Results: Thirty-six patients were treated with escalating doses of oral LY2784455. Doses ranged from 2-10 mg once daily (QD) or 8-24 mg twice daily (BID). Patients were mostly male (69%) and ages ranged from 23-78. Nineteen patients were white and 17 were Asian. The most common type of treatment-emergent adverse events possibly related to study drug was gastrointestinal (n=2, n=1 Grade 3/4). One patient experienced grade 2 thrombosis, which was possibly related to study drug. There were no reported dose limiting toxicities. Pharmacokinetic analyses revealed the half-life was relatively short and without drug accumulation from a single dose; thus, a twice daily regimen was evaluated. Exposure increase was near proportional with dose. Plasma AUC increased 1.1 to 2.3 fold with twice daily administration from day 1 to 28. Serum phosphorus levels increased following dose with administration of ≥10 mg of LY2874455 but were adequately controlled by phosphate-binding agents. This result is consistent with inhibition of the FGF Receptor.
Conclusions: The 16 mg BID dose was selected for the starting dose in Part B based on the tolerability observed and in consideration of the tolerability of this dose with chronic administration. Recommended phase II dose was not yet established awaiting data from part B (ongoing).
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Citation Format: Jeanne Tie, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, David Monteith, Kimberly Hartsock, Donald E. Thornton, Michael Michael. A phase I trial of LY2874455, a fibroblast growth factor receptor inhibitor, in patients with advanced cance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT215. doi:10.1158/1538-7445.AM2014-CT215