Abstract 672: Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1

Abstract

Abstract BAY 1179470 is a human immunoglobulin (IgG) antibody directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed on cancer cells during tumorigenesis and metastasis. Anti-tumor efficacy of BAY 1179470 has been demonstrated in FGFR2-expressing gastric cancer mouse and rat xenograft models. No toxicologically relevant findings were observed in the repeated dose preclinical safety studies in rats and monkeys. Therefore, toxicity was not an appropriate endpoint for the first-in-man (FIM) study and dose selection was decided to be based on PK/PD modeling and predictions from preclinical efficacy data. All preclinical PK and tumor response data from mouse models were used to create a model framework to describe the PK and PK/PD as functions of BAY 1179470 dose, regimen and time. In a subsequent confirmatory step the PK/PD model derived from mouse efficacy data was applied to predict the efficacy in rats. Human PK parameters based on scaling from monkey were used to predict PK profiles in humans for a range of doses and schedules. These sets of predicted exposure were combined with the PK/PD model developed from mouse models to assess the expected efficacy for a range of human tumor doubling rates. Minimal effective doses, maximum effect and maximum effect doses, and maximal effective doses in humans were derived for various dosing intervals (1 day to 6 weeks). From the maximum effect dose the target AUC in humans was calculated and doses for the FIM study selected accordingly. The FIM study is currently ongoing in Japan (NCT01881217). Citation Format: Sabine Wittemer-Rump, Charlotte Kopitz, Hung Huynh, Lars Lindbom, Bernhard Beckermann, Motonobu Osada, Dirk Laurent, Jörg Lippert. Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1. [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 672. doi:10.1158/1538-7445.AM2014-672