Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies.
Sebastian BauerGeorge D DemetriEnsar HalilovicReinhard DummerChristophe MeilleDaniel S W TanNelson GuerreiroAstrid JullionStephane FerrettiSebastien JeayLaurence Van BreeFlorence Hourcade-PotelleretJens U WuerthnerClaire FabrePhilippe Alexandre CassierPublished in: British journal of cancer (2021)
Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.