PT - JOURNAL ARTICLE AU - Hatice Gungor AU - Azeem Saleem AU - Syed Babar AU - Roberto Dina AU - Mona A. El-Bahrawy AU - Ed Curry AU - Nona Rama AU - Michele Chen AU - Emily Pickford AU - Roshan Agarwal AU - Sarah Blagden AU - Sabin Carme AU - Cristian Salinas AU - Sam Madison AU - Elizabeth Krachey AU - Ademi Santiago-Walker AU - Deborah A. Smith AU - Shannon R. Morris AU - Euan A. Stronach AU - Hani Gabra TI - Dose-Finding Quantitative <sup>18</sup>F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies AID - 10.2967/jnumed.115.156505 DP - 2015 Dec 01 TA - Journal of Nuclear Medicine PG - 1828--1835 VI - 56 IP - 12 4099 - http://jnm.snmjournals.org/content/56/12/1828.short 4100 - http://jnm.snmjournals.org/content/56/12/1828.full SO - J Nucl Med2015 Dec 01; 56 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.