W Xiong (1), S El Bawab (2), F Bladt (2), M Meyring (3), M Klevesath (2), G Falchook (4), D Hong (5), A Johne (2), P Girard (1)
(1) Merck Institute for Pharmacometrics, Merck Serono, Lausanne, Switzerland, (2) Merck KGaA, Darmstadt, Germany, (3) Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany, (4) MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Houston, TX, USA, (5) MD Anderson Cancer Center, Department of Hematopathology, Houston, TX, USA
Objectives: To evaluate the dose/exposure/target inhibition/tumor growth relationship of MSC2156119J in order to determine the dose for the Phase II program. MSC2156119J is an orally administered, reversible, ATP-competitive, highly potent and selective c-Met receptor tyrosine kinase inhibitor.
Methods: Plasma PK and tumor c-Met inhibition data from Phase I solid tumor patients were analyzed by the population approach, using a prior structural model of target inhibition developed with data from KP4 xenografted mice. To help determine the recommended Phase II dose, human PK profiles and c-Met inhibition were simulated, aiming for a level of c-Met inhibition that achieves tumor regression in mice.
Results: In preclinical KP4 xenografted mice, c-Met inhibition in tumors (quantified as normalized phosphorylated c-Met expression [pMET]) was described by a turnover full inhibitory Imax model, and tumor growth inhibition was best described by the Simeoni model[1]. Simulations demonstrated that nearly complete pMET inhibition (≥95%) is required for tumor stasis or regression. In the first-in-human trial a 1-compartment linear model with first order absorption and a transit compartment best described the PK of MSC2156119J dosed from 30–700 mg. The turnover model developed from mice data was utilized to evaluate the level of c-Met inhibition in human tumors (1 pre-treatment and 1 on-treatment biopsy per patient). System turnover parameters (kin, kout) were set equal to the estimates in mice, while the potency parameter (1/IC50) in humans was found to be 1.7 times higher than in mice. Assuming a 30% interindividual variability of IC50, human simulations suggest that a 500-mg daily dose regimen could achieve continuous pMET inhibition of ≥95% in 90% of the population.
Conclusions: c-Met inhibition in human tumor lesions was described by a turnover model developed in KP4 xenografted mice, showing a 1.7-times higher potency in humans than in mice. With this translational modeling approach, a biologically active dose of 500 mg was proposed as the recommended Phase II dose for MSC2156119J.
References:
[1] Simeoni M, Magni P, Cammia C, De Nicolao G, Croci V, Pesenti E, Germani M, Poggesi I, Rocchetti M. Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents. Cancer Res (2004) 64(3):1094–101
Reference: PAGE 23 (2014) Abstr 3237 [www.page-meeting.org/?abstract=3237]
Poster: Drug/Disease modeling - Oncology