Abstract CT048: Population pharmacokinetics and pharmacodynamics for an oral Notch inhibitor, LY3039478, in the first-in-man study
Authors: Eunice Yuen, Bharvin Patel, Claire Smith, Maria Posada, Robert Bell, Ute Ohnmacht, Christophe Massard, Jordi Rodon, Karim Benhadji
Journal: Cancer Research (2016)

Abstract Background: Deregulation of Notch signalling is involved in multiple human cancers. LY3039478 is a potent Notch inhibitor that prevents release of the Notch Intracellular Domain (NICD) by inhibiting proteolytic activity of the gamma (γ) -secretase complex and thereby decreasing Notch signalling and its downstream biologic effects. Since γ-secretase also possesses proteolytic activity to cleave amyloid precursor proteins, LY3039478 is expected to inhibit production of plasma Amyloid-beta (Aβ), which can be used as a biomarker to determine pharmacodynamic (PD) effects of LY3039478 in patients. Additionally, expression of Notch regulated genes [Hairy and enhancer of split-1 (Hes1), Cyclin D1 (CCND1), and Notch-Regulated Ankyrin Repeat (NRARP)] in skin can be used to monitor additional PD effects. The evaluation of pharmacokinetic (PK) - PD (biomarker) relationships is explored in this phase I does escalation of LY3039478 in patients (pts) with advanced cancer. Methods: In the dose escalation part of the first human dose study of LY3039478, patients received oral doses of 2.5 up to 100 mg thrice weekly (TIW) via 25 or 50 mg capsules. Plasma samples were collected up to 24 to 30 hours after the 1st and 10th dose, and urine samples up to 8 to10 hours after the 1st dose. Skin samples were collected prior to and after approximately 6 to 8 hours after the 1st dose. PK and PD parameter estimations were performed using non-linear mixed effects models in NONMEM Version 7.3 using a sequential approach. Results: A population PK/PD model was developed using preliminary data collected from 55 pts with age range 30 to 75 years and weight between 43 to 103 kg. A PK model with 3 transit absorption compartments, central and peripheral plasma compartments, plus a urine compartment best described the LY3039478 disposition. LY3039478 was rapidly absorbed with peak concentrations occurring within 1 to 2 hours. Renal clearance contributed to ∼20% of the apparent plasma clearance. Simple maximal effects (Emax) models were used to describe the PK/PD relationships for maximal plasma A-beta inhibition and inhibition of gene expression in relation to LY3039478 exposure. The results showed that 80% of maximal effects of plasma Aβ inhibition occurred at approximately 3300 μg*h/L (90% prediction intervals (PI) 1200 - 13000 μg*h/L). For gene expression of HES1, NRARP and CCND1, 80% of maximal effects occurred at average exposures of 1600 μg*h/L (90% PI 1000-3000 μg*h/L), 1300 μg*h/L (90% PI 1000- 1800 μg*h/L) and 1000 μg*h/L (90% PI 600 - 2000 μg*h/L), respectively. These exposures correspond to a dose range of 15 to 50 mg of LY3039478. Conclusion: The plasma Aβ and gene expression data showed that 80% of maximal biomarker effects were obtained at approximately 15 to 50 mg LY3039478, supporting the use of the 50 mg TIW LY3039478 dosing regimen currently used in the dose-expansion phase of the first in man study. Citation Format: Eunice Yuen, Bharvin Patel, Claire Smith, Maria Posada, Robert Bell, Ute Ohnmacht, Christophe Massard, Jordi Rodon, Karim Benhadji. Population pharmacokinetics and pharmacodynamics for an oral Notch inhibitor, LY3039478, in the first-in-man study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT048.