Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies

Gungor, H; Saleem, A; Babar, S; Dina, R; El-Bahrawy, M; Curry, E; Rama, N; Chen, M; Pickford, E; Agarwal, R; Blagden, S; Carme, S; Salinas, C; Madison, S; Krachey, E; Santiago-Walker, A; Smith, D; Morris, S; Stronach, E; Gabra, H

Journal article

Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies

Abstract:: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Gungor, H., Saleem, A., Babar, S., Dina, R., El-Bahrawy, M., Curry, E., Rama, N., Chen, M., Pickford, E., Agarwal, R., Blagden, S., Carme, S., Salinas, C., Madison, S., Krachey, E., Santiago-Walker, A., Smith, D., Morris, S., Stronach, E., & Gabra, H. (2015). Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies. Journal of Nuclear Medicine, 56(12), 1828–1835.

MLA Style

Gungor, H., et al. “Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecological Malignancies.” Journal of Nuclear Medicine, vol. 56, no. 12, Society of Nuclear Medicine, 2015, pp. 1828–35.

Chicago Style

Gungor, H, A Saleem, S Babar, R Dina, M El-Bahrawy, E Curry, N Rama, et al. 2015. “Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecological Malignancies.” Journal of Nuclear Medicine 56 (12): 1828–35.
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