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

• Published in: British journal of cancer 2021-08, Vol.125 (5), p.687-698
• Main Authors: Bauer, Sebastian, Demetri, George D., Halilovic, Ensar, Dummer, Reinhard, Meille, Christophe, Tan, Daniel S. W., Guerreiro, Nelson, Jullion, Astrid, Ferretti, Stephane, Jeay, Sebastien, Van Bree, Laurence, Hourcade-Potelleret, Florence, Wuerthner, Jens U., Fabre, Claire, Cassier, Philippe A.
• Format: Article
• Language: English
• Subjects: 631/154; 692/4028/67/1059/153; Administration, Oral; Adult; Aged; Animals; Antitumor activity; Biomarkers; Biomarkers, Tumor - blood; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival; Disease control; Dosage; Drug Administration Schedule; Drug Dosage Calculations; Drug Resistance; Epidemiology; Female; Growth Differentiation Factor 15 - blood; Humans; Isoquinolines - administration & dosage; Isoquinolines - adverse effects; Isoquinolines - pharmacokinetics; Male; Mice; Middle Aged; Molecular Medicine; Neoplasms - blood; Neoplasms - drug therapy; Oncology; p53 Protein; Patients; Pharmacodynamics; Pharmacokinetics; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - pharmacokinetics; Platelets; Solid tumors; Thrombocytopenia; Toxicity; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01444-4

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.