Abstract
BackgroundCGM097 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.
Highlights
Tumour suppressor p53 is a transcription factor that controls the expression of a myriad of target genes involved in DNA repair, apoptosis, and cell-cycle arrest, which are all important processes counteracting the malignant growth of tumours
Results revealed the activation of p53 transcriptional function, with a 12-fold increase in BCL2-binding component 3 (BBC3), a pro-apoptotic member of the Bcl-2 protein family, known as p53-upregulated modulator of apoptosis (PUMA)
The activation of p53 caused a significant decrease in mRNA expression of E2F1 and TP73, while there was no effect on TP63 expression
Summary
Tumour suppressor p53 is a transcription factor that controls the expression of a myriad of target genes involved in DNA repair, apoptosis, and cell-cycle arrest, which are all important processes counteracting the malignant growth of tumours. 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). 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 generation HDM2 inhibitors to mitigate hematologic toxicity
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