Abstract B167: Identifying first in human (FIH) doses and schedule of U3-1287 (AMG 888), a fully human anti-HER3 mAb, based on preclinical pharmacokinetic (PK), pharmacodynamic (PD) and efficacy data

Abstract

Abstract Background: HER3 is a member of the Human Epidermal Growth Factor Receptor (HER) family. Although HER3 lacks intrinsic kinase activity, it serves as a scaffold for PI3K/AKT signaling for the HER family via heterodimeric interactions. The goal of this study was to use preclinical modeling to predict a minimal effective dose regimen for objective response using preclinical PK and BxPC3 xenograft mice anti-tumor efficacy and PD data. Materials and Methods: U3-1287 (AMG 888) concentration-time data obtained from mice (0.025 to 2.5 mg/mouse), rats (1 to 100 mg/kg) and monkeys (1 to 200 mg/kg) were combined and analyzed using a target-mediated drug disposition model. Animal PK parameters were scaled based on body weight to predict human PK characteristics. An Emax model was used to relate drug concentration and inhibition of pHER (measure by ELISA) in BxPC3 xenograft tumors. A PK/PD/efficacy model (based on Simeoni et al 2004) was used to analyze tumor growth data from mice bearing BxPC3 pancreatic xenografts (∼200 mm3) treated twice per week at 25, 100, 200, or 500 g for a 1 month. The model was validated with tumor growth data following additional doses of 400 g biweekly and 200 g biweekly, weekly and twice a week. The relationship between drug concentration, the inhibition of pHER3 in animals and interspecies PK scaling was used to select the minimal effective dose for the first in human study. Results: U3-1287 (AMG 888) treatment of BxPC3 xenografts resulted in a statistically significant inhibition of tumor growth and pHER3 levels in a dose and schedule dependent manner (p<0.05). Treatment with U3-1287 (AMG 888) at 400 g/mouse biweekly and 200 g/mouse biweekly, weekly and twice a week resulted in a 50%, 33%, 74% and 70% inhibition of tumor growth (p<0.05), a 70%, 42%, 77% and 80% inhibition of pHER3 (measured by ELISA) versus the IgG control treated group, respectively. Serum concentrations of U3-1287 (AMG 888) at necropsy for the respective dose groups were (mean (SD)) of 2.07 (0.97), 0.45 (0.21), 3.08 (0.82) and 34.9 (9.1) g/mL, respectively. The estimated trough concentration needed to achieve 90% maximal pHER3 inhibition (IC90) was estimated to be ∼3 µg/mL. Based on interspecies scaling of PK parameters, a dose higher than 3 mg/kg given biweekly would achieve a steady-sate trough concentration that is above 3 µg/mL. Conclusion: The anti-tumor efficacy in the BxPC3 pancreatic xenograft model was correlated with an increased serum concentration of U3-1287 (AMG 888) and a decrease in pHER3 levels, allowing for the development of a PK/PD/Efficacy relationship. This relationship combined with interspecies PK scaling was used to determine a dose and schedule for U3-1287 (AMG 888) to investigate in a FIH study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B167.