Title |
Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies
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Published in |
Journal of Nuclear Medicine, October 2015
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DOI | 10.2967/jnumed.115.156505 |
Pubmed ID | |
Authors |
Hatice Gungor, Azeem Saleem, Syed Babar, Roberto Dina, Mona A. El-Bahrawy, Ed Curry, Nona Rama, Michele Chen, Emily Pickford, Roshan Agarwal, Sarah Blagden, Sabin Carme, Cristian Salinas, Sam Madison, Elizabeth Krachey, Ademi Santiago-Walker, Deborah A. Smith, Shannon R. Morris, Euan A. Stronach, Hani Gabra |
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. 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. 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. 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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United States | 1 | 100% |
Demographic breakdown
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Members of the public | 1 | 100% |
Mendeley readers
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Unknown | 30 | 97% |
Demographic breakdown
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Researcher | 8 | 26% |
Student > Bachelor | 5 | 16% |
Student > Ph. D. Student | 3 | 10% |
Student > Doctoral Student | 2 | 6% |
Other | 2 | 6% |
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Unknown | 5 | 16% |
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Biochemistry, Genetics and Molecular Biology | 2 | 6% |
Other | 1 | 3% |
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