Abstract 3359: Translating preclinical PK/PD tumor volume modeling data to predict AMG172 PK and dose-escalation scheme in FIH.

Abstract

Abstract Background: AMG 172 is an antibody drug conjugate (ADC) comprised of a human IgG1 monoclonal antibody (mAb), a non-cleavable linker (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) conjugated to lysine residues in the antibody and DM1, a semi-synthetic derivative of maytansine. AMG 172 binding and internalization into target-expressing tumor cells, induces metaphase arrest and subsequent cellular apoptosis, leading to tumor cell death. AMG 172 is being developed as a treatment for clear cell renal cell carcinoma (ccRCC), and other indications, as a single agent or in combination with chemotherapy. The primary goals of this study were, 1) to predict human AMG 172 PK disposition from non-clinical data, 2) to determine AMG 172 exposure anti-tumor activity relationships in mouse xenograft models, and develop an AMG 172 anti-tumor PK/PD model, and 3) to integrate non-clinical toxicology, pharmacology and pharmacokinetic data to support selection of doses for the first in human (FIH) clinical study Materials and Methods: A PK model in cynomolgus monkey was developed from single and multiple-dose pharmacokinetics and toxicokinetics, and used to predict the human PK of AMG 172. In vivo anti-tumor activity was demonstrated by AMG 172 in human ccRCC subcutaneous tumor xenografts in mice. Tumor growth inhibition in mouse xenografts was modeled using a tumor inhibition PK/PD model. Primary model assumptions for extrapolation of non-clinical PK/PD to human were: a) AMG 172 PK can be scaled directly from cynomolgus monkey, and b) anti-tumor efficacy in mouse xenografts is drug dependent and species independent. Results: A two compartment open linear model best described AMG 172 pharmacokinetics in cynomolgus monkey. AMG 172 CL was estimated to be 9.45 mL/hr in a typical human (70 kg) based on species-invariant time scaling methods. At the STD10 in rats and the HNSTD in cynomolgus monkey, anticipated AUC margins are approximately 17.9/11.9 and 15.7/10.5 times for Q3wk/Q2wk dosing regimens, respectively, at the projected clinical starting dose of 0.15 mg/kg. Using the mouse xenograft PK and PD data, clinical dose projections were generated that attained model-based, putative target trough concentrations. Collectively, these results support potential AMG 172 dosing every 2–3 weeks, thereby providing flexibility in the clinic. Conclusions: This work demonstrates efficient integration of non-clinical toxicology, preclinical pharmacology and pharmacokinetic data in order to support rational selection of AMG 172 doses for FIH clinical studies. Citation Format: Nelson L. Jumbe, William Fanslow, Sonal Patel, Benny Amore, Marc Retter, Vincent Chow. Translating preclinical PK/PD tumor volume modeling data to predict AMG172 PK and dose-escalation scheme in FIH. [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 3359. doi:10.1158/1538-7445.AM2013-3359 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.