Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies

Journal of Nuclear Medicine

Syed Babar¹  Cristian Salinas¹  Sam Madison¹  Ed Curry¹  Ademi Santiago-Walker¹  Euan A. Stronach¹  Sabin Carme¹  Elizabeth Krachey¹  Shannon R. Morris¹  Hatice Gungor¹  Emily Pickford¹  Mona A. El-Bahrawy¹  Michele Chen¹  Nona Rama¹  Roberto Dina¹  Roshan Agarwal¹  Deborah A. Smith¹  Hani Gabra¹  Sarah Blagden¹  Azeem Saleem¹ 

关键词: FDG-PET;    GSK2141795;    imaging;    AKT;    ovarian cancer;   

DOI  :  10.2967/jnumed.115.156505

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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.

【 授权许可】

Unknown