Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies
Copyright policy )Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies
AbstractBackgroundCGM097 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).MethodsFifty-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.ResultsNo 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.ConclusionsDespite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors.Translational relevanceHaematologic 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.
- University of Zurich Switzerland
- Harvard University United States
- Novartis Institutes for BioMedical Research Switzerland
- Novartis Institutes for Biomedical Research United States
- University of Duisburg-Essen Germany
Adult, Male, Cancer Research, Growth Differentiation Factor 15, Cell Survival, Medizin, Administration, Oral, 610 Medicine & health, Article, Drug Administration Schedule, Piperazines, Mice, Cell Line, Tumor, Neoplasms, Biomarkers, Tumor, Animals, Humans, 1306 Cancer Research, Drug Dosage Calculations, Aged, Cell Proliferation, 10177 Dermatology Clinic, Middle Aged, Isoquinolines, Cell Line, Tumor [MeSH] ; Aged [MeSH] ; Cell Survival [MeSH] ; Piperazines/pharmacokinetics [MeSH] ; Administration, Oral [MeSH] ; Piperazines/administration ; Male [MeSH] ; Xenograft Model Antitumor Assays [MeSH] ; Isoquinolines/pharmacokinetics [MeSH] ; Drug discovery ; Piperazines/adverse effects [MeSH] ; Isoquinolines/administration ; Female [MeSH] ; Adult [MeSH] ; Drug development ; Humans [MeSH] ; Treatment Outcome [MeSH] ; Drug Administration Schedule [MeSH] ; Middle Aged [MeSH] ; Animals [MeSH] ; Growth Differentiation Factor 15/blood [MeSH] ; Drug Dosage Calculations [MeSH] ; Isoquinolines/adverse effects [MeSH] ; Mice [MeSH] ; Article ; Biomarkers, Tumor/blood [MeSH] ; Neoplasms/drug therapy [MeSH] ; Cell Proliferation/drug effects [MeSH] ; Neoplasms/blood [MeSH], Treatment Outcome, Oncology, 2730 Oncology, Female
Adult, Male, Cancer Research, Growth Differentiation Factor 15, Cell Survival, Medizin, Administration, Oral, 610 Medicine & health, Article, Drug Administration Schedule, Piperazines, Mice, Cell Line, Tumor, Neoplasms, Biomarkers, Tumor, Animals, Humans, 1306 Cancer Research, Drug Dosage Calculations, Aged, Cell Proliferation, 10177 Dermatology Clinic, Middle Aged, Isoquinolines, Cell Line, Tumor [MeSH] ; Aged [MeSH] ; Cell Survival [MeSH] ; Piperazines/pharmacokinetics [MeSH] ; Administration, Oral [MeSH] ; Piperazines/administration ; Male [MeSH] ; Xenograft Model Antitumor Assays [MeSH] ; Isoquinolines/pharmacokinetics [MeSH] ; Drug discovery ; Piperazines/adverse effects [MeSH] ; Isoquinolines/administration ; Female [MeSH] ; Adult [MeSH] ; Drug development ; Humans [MeSH] ; Treatment Outcome [MeSH] ; Drug Administration Schedule [MeSH] ; Middle Aged [MeSH] ; Animals [MeSH] ; Growth Differentiation Factor 15/blood [MeSH] ; Drug Dosage Calculations [MeSH] ; Isoquinolines/adverse effects [MeSH] ; Mice [MeSH] ; Article ; Biomarkers, Tumor/blood [MeSH] ; Neoplasms/drug therapy [MeSH] ; Cell Proliferation/drug effects [MeSH] ; Neoplasms/blood [MeSH], Treatment Outcome, Oncology, 2730 Oncology, Female
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