| Summary: | AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study’s primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and FDG-PET markers of glucose metabolism in tumor tissue to determine if FDG-PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. <strong>METHODS:</strong> Twelve patients were enrolled in three cohorts; all had dynamic FDG-PET scans and serial pharmacokinetic sampling at baseline, Week 2 (W2) and Week 4 (W4) with tumor biopsies pre-treatment and at W4. Response was evaluated by RECIST v1.1 and GCIG criteria. Biopsy samples were analyzed for mutations and protein expression. <strong>RESULTS:</strong> GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics (PK) and FDG-PET pharmacodynamic (PD) measures; however an exposure-response-relationship was seen between maximum drug concentrations and maximal decrease in FDG uptake in the best responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT up-regulation at W4 in biopsies confirmed AKT inhibition by GSK2141795. Single agent activity was observed with clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study’s platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition. <strong>CONCLUSION:</strong> GSK2141795 demonstrated an exposure-response relationship with decreased FDG uptake and is active and tolerable. This study’s design integrating FDG-PET, PK and biomarker analyses demonstrate the potential for clinical development for personalized treatment.
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