Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies.

Autor: Bauer S; Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University of Duisburg-Essen, Duisburg-Essen, Germany. sebastian.bauer@uk-essen.de., Demetri GD; Dana-Farber Cancer Institute and Ludwig Center at Harvard Medical School, Boston, MA, USA., Halilovic E; Novartis Institutes for BioMedical Research (NIBR), Cambridge, MA, USA., Dummer R; University Hospital Zurich, Zurich, Switzerland., Meille C; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland., Tan DSW; National Cancer Center Singapore, Singapore, Singapore., Guerreiro N; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.; F. Hoffmann-La Roche AG, Basel, Switzerland., Jullion A; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland., Ferretti S; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland., Jeay S; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.; Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Van Bree L; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland., Hourcade-Potelleret F; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland., Wuerthner JU; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.; ADC Therapeutics, Epalinges, Switzerland., Fabre C; Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland., Cassier PA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2021 Aug; Vol. 125 (5), pp. 687-698. Date of Electronic Publication: 2021 Jun 17.
DOI: 10.1038/s41416-021-01444-4
Abstrakt: Background: CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525).
Methods: Fifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics.
Results: No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined.
Conclusions: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors.
Translational Relevance: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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