RT Journal Article SR Electronic T1 Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1828 OP 1835 DO 10.2967/jnumed.115.156505 VO 56 IS 12 A1 Gungor, Hatice A1 Saleem, Azeem A1 Babar, Syed A1 Dina, Roberto A1 El-Bahrawy, Mona A. A1 Curry, Ed A1 Rama, Nona A1 Chen, Michele A1 Pickford, Emily A1 Agarwal, Roshan A1 Blagden, Sarah A1 Carme, Sabin A1 Salinas, Cristian A1 Madison, Sam A1 Krachey, Elizabeth A1 Santiago-Walker, Ademi A1 Smith, Deborah A. A1 Morris, Shannon R. A1 Stronach, Euan A. A1 Gabra, Hani YR 2015 UL http://jnm.snmjournals.org/content/56/12/1828.abstract AB 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 18F-FDG PET markers of glucose metabolism in tumor tissue to determine whether 18F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. Methods: Twelve patients were enrolled in 3 cohorts; all underwent dynamic 18F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression. Results: GSK2141795 did not significantly influence blood glucose levels. No dose–response relationship was observed between GSK2141795 pharmacokinetics and 18F-FDG PET pharmacodynamic measures; however, an exposure–response relationship was seen between maximum drug concentrations and maximal decrease in 18F-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 upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a 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. Conclusion: GSK2141795 demonstrated an exposure–response relationship with decreased 18F-FDG uptake and is active and tolerable. This study’s design integrating 18F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment.