NVP-CGM097 is a selective p53-HDM2 protein-protein interaction inhibitor currently in Phase I clinical development for the treatment of patients with p53 wild type malignancies. Delayed thrombocytopenia is the primary dose limiting toxicity reported upon NVP-CGM097 treatment. Anticipation of the onset and severity of thrombocytopenia is critical for improved patient outcome. The aim of this work was to develop mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models to provide an integrated quantitative understanding of safety and efficacy profiles.
Population PK, PK/PD models of thrombocytopenia and the cytokine Growth Differentiation Factor 15 (GDF-15, as a marker for p53 pathway activation), and a kinetic (K)/PD model of tumor size was developed based on data from 48 solid tumor patients collected from the first-in-human Phase I study (NCT01760525) conducted with orally administered NVP-CGM097.
The PK/PD model for thrombocytopenia was derived from Friberg et al. (2002)1 with an additional feedback mechanism and implementation of platelet (PLT) transfusion events. The model accurately reproduced the PLT time course after NVP-CGM097 administration, as well as the impact of drug on GDF-15 levels. An association between individual model-estimated drug potency on PLTs and drug potency on plasma GDF-15 levels was investigated as a descriptor of PLT change in addition to drug exposure, raising the possibility to use GDF-15 induction as a prospective marker for delayed thrombocytopenia. A kinetic (K)/PD efficacy model was also developed for the same patient population to describe tumor size as a function of dose. Large variability was seen in the tumor growth parameter while moderate variability was observed for drug potency on tumor size.
This work further supports the use of such approaches for the clinical development of HDM2 inhibitors, and explores the feasibility of utilizing these approaches as a rational tool for tailoring regimens and doses for individual patients at risk for thrombocytopenia while maximizing patient benefit. References 1. Friberg LE, et al. J Clin Oncol 2002;20:4713–4721.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharma AG
Novartis Pharma AG
C. Meille, L. Van Bree, A. Jullion: Novartis employee. N. Guerreiro: Novartis employee and stock owner. S. Bauer: Research support: Novartis, Blueprint Medicines, Ariad Consultant: GSK, Novartis, Pfizer, Bayer, Fresenius, Lilly, Blueprint Medicines Honoraria (CME): Pharmamar, GSK, Pfizer, Bayer Travel support: Pharmamar, Bayer. P. Cassier: Received honoraria and research funding from Novartis, Roche, BluePrint and Amgen, as well as research funding from Eli Lilly, Celgene, AstraZeneca, GlaxoSmithKline, Merck Sharp Dohme, Merck Serono. G. Demetri: With Novartis as study sponsor: 1. Consultant, consulting fees, 2. Patent on imatinib licensed to Novartis from Dana-Farber 3. Research support to Dana-Farber for clinical trial. R. Dummer: Research funding: Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, GlaxoSmithKline (GSK); and has a consultant/advisory board relationship with Novartis, MSD, BMS, Roche, GSK, Amgen outside the submitted work. D.S. Tan: Consulting or advisory fees from Novartis, Bayer, Boehringer Ingelheim and Eisai; honoraria from Novartis and Pfizer; research funding from Novartis, Bayer and GSK; and expense reimbursements from Novartis and MERCK, outside the submitted work. T. Ramkumar: Employee of Novartis Pharmaceuticals Corporation. E. Halilovic: Novartis employee and Novartis stock owner. S. Jeay: Employee and stockholder of Novartis A.G. F. Hourcade-Potelleret: Employee of Novartis AG J.U. Wuerthner: Employee of Novartis and has stock ownership of Novartis.