Abstract A215: Integrated analysis of clinical pharmacokinetics (PK), nonclinical PK/efficacy (E) and pharmacodynamic (PD)/E relationships, and translational PK/PD simulations to guide clinical dose and schedule of MLN2480, an oral investigational pan-RAF kinase inhibitor.
Authors: Faucette Stephanie , Mettetal Jerome , Zhou Xiaofei , Chouitar Jouhara , Patel Mayank , Bargfrede Michael , Galvin Katherine , Bozon Viviana , Venkatakrishnan Karthik 
Published: August 2014

Abstract
Background: MLN2480 is an oral investigational pan-RAF kinase inhibitor currently in Phase I of clinical development. An integrated analysis of clinical PK, nonclinical PK/E and PD/E relationships, and translational PK/PD simulations was performed to help inform selection of dose and schedule for future clinical studies.
Methods: Nonclinical PK/E, PK/PD, and PD/E relationships were evaluated at doses of 2 to 37.5 mg/kg QD in the A375 (BRAF mutant) melanoma xenograft model. Tumor PD was characterized by decrease in phosphorylated ERK (pERK) from baseline. A sigmoidal Emax model was fitted to the PK/E data and an inhibitory Emax model to PK/PD data. The PK/E and PK/PD models were used to generate a PD/E relationship, which was characterized by a sigmoidal inhibitory Emax model. Clinical PK was characterized in an ongoing first-in-human (FIH) study and a base population PK model was developed (NONMEM version 7.2). The time course of decrease in tumor pERK was simulated at the clinical maximum tolerated dose (200 mg Q2D) using human population PK parameters and nonclinical PK/PD model parameters corrected for inter-species differences in free fraction. The clinical exposures and simulated PD at 200 mg Q2D were used to provide translational estimates of antitumor activity based on nonclinical PK/E and PD/E relationships.
Results: The nonclinical PK/E and PK/PD relationships were characterized by unbound EC50 or IC50 (coefficient of variation [CV]) of 62 ng/mL (20%) and 66 ng/mL (12%), respectively. PD/E analysis indicated that half-maximal tumor growth inhibition (TGI) was associated with a 44% decrease in pERK (CV 7.5%). Clinical PK (n=24) was characterized by rapid absorption (median Tmax 2 hr), low fluctuation at steady-state (mean peak to trough ratio 2.2), and 2.5-fold accumulation after Q2D dosing. Steady-state exposures (AUC0-tau) increased approximately dose-proportionally over 20 to 280 mg Q2D. A one-compartment PK model with first order absorption and elimination adequately described the data (n=26); parameter estimates and interindividual variability (CV%) were 0.73 hr−1 (65%) for Ka, 128 L (35%) for V/F, and 1.6 L/hr (41%) for CL/F. At 200 mg Q2D, time-averaged unbound exposure and predicted decrease in pERK levels were 62 ng/mL and 48%, respectively, translating to 86% and 101% TGI based on the respective nonclinical PK/E and PD/E relationships in the A375 xenograft model. Conclusions: Steady-state exposures at 200 mg Q2D are predicted to result in pERK decreases and antitumor activity associated with tumor stasis in nonclinial models of BRAF mutant melanoma. In ongoing expansion cohorts of an FIH study, tumor PD and antitumor activity are being evaluated in treatment-naïve or relapsed/refractory patients with locally advanced or metastatic melanoma, including those with BRAF mutations.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A215.
Citation Format: Stephanie Faucette, Jerome Mettetal, Xiaofei Zhou, Jouhara Chouitar, Mayank Patel, Michael Bargfrede, Katherine Galvin, Viviana Bozon, Karthik Venkatakrishnan. Integrated analysis of clinical pharmacokinetics (PK), nonclinical PK/efficacy (E) and pharmacodynamic (PD)/E relationships, and translational PK/PD simulations to guide clinical dose and schedule of MLN2480, an oral investigational pan-RAF kinase inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A215.