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

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Title: Dose-finding quantitative F-18-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecologic malignancies
Author(s): Gungor, H
Saleem, A
Babar, S
Dina, R
El-Bahrawy, MA
Curry, E
Rama, N
Chen, M
Pickford, E
Agarwal, R
Blagden, S
Carme, S
Salinas, C
Madison, S
Krachey, E
Santiago-Walker, A
Smith, DA
Morris, SR
Stronach, EA
Gabra, H
Item Type: Journal Article
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 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.
Publication Date: 1-Oct-2015
Date of Acceptance: 21-Sep-2015
URI: http://hdl.handle.net/10044/1/44102
DOI: http://dx.doi.org/10.2967/jnumed.115.156505
ISSN: 1535-5667
Publisher: Society of Nuclear Medicine
Start Page: 1828
End Page: 1835
Journal / Book Title: Journal of Nuclear Medicine
Volume: 56
Issue: 12
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
Funder's Grant Number: RDB01 79560
HTA PROJECT 14/31/04
Copyright Statement: This research was originally published in JNM. Gungor et al. 'Dose-finding quantitative FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies'. JNM. 2015;56(12):1828-1835. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.
Keywords: Science & Technology
Life Sciences & Biomedicine
Radiology, Nuclear Medicine & Medical Imaging
FDG-PET
GSK2141795
imaging
AKT
ovarian cancer
OVARIAN-CANCER
GLUCOSE-HOMEOSTASIS
MOLECULAR-CLONING
MICE LACKING
HETEROGENEITY
EXPRESSION
RESISTANCE
GUIDELINE
PI3K/AKT
THERAPY
AKT
FDG-PET
GSK2141795
imaging
ovarian cancer
Antineoplastic Agents
Biomarkers
Biopsy
Blood Glucose
Deoxyglucose
Diamines
Drug Interactions
Drug Resistance, Neoplasm
Female
Fluorodeoxyglucose F18
Genital Neoplasms, Female
Humans
Oncogene Protein v-akt
Positron-Emission Tomography
Pyrazoles
Radiopharmaceuticals
Treatment Outcome
Humans
Genital Neoplasms, Female
Diamines
Pyrazoles
Deoxyglucose
Fluorodeoxyglucose F18
Blood Glucose
Antineoplastic Agents
Radiopharmaceuticals
Positron-Emission Tomography
Biopsy
Treatment Outcome
Drug Interactions
Drug Resistance, Neoplasm
Female
Oncogene Protein v-akt
Biomarkers
Nuclear Medicine & Medical Imaging
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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