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

J Nucl Med. 2015 Dec;56(12):1828-35. doi: 10.2967/jnumed.115.156505. Epub 2015 Oct 1.

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 (18)F-FDG PET markers of glucose metabolism in tumor tissue to determine whether (18)F-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 (18)F-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 (18)F-FDG PET pharmacodynamic measures; however, an exposure-response relationship was seen between maximum drug concentrations and maximal decrease in (18)F-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 (18)F-FDG uptake and is active and tolerable. This study's design integrating (18)F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment.

Keywords: AKT; FDG-PET; GSK2141795; imaging; ovarian cancer.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers
  • Biopsy
  • Blood Glucose / metabolism
  • Deoxyglucose
  • Diamines / administration & dosage*
  • Diamines / adverse effects
  • Diamines / therapeutic use*
  • Drug Interactions
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Fluorodeoxyglucose F18 / pharmacokinetics*
  • Genital Neoplasms, Female / diagnostic imaging*
  • Genital Neoplasms, Female / drug therapy*
  • Humans
  • Oncogene Protein v-akt / antagonists & inhibitors*
  • Oncogene Protein v-akt / genetics
  • Positron-Emission Tomography / methods*
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects
  • Pyrazoles / therapeutic use*
  • Radiopharmaceuticals / pharmacokinetics*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Blood Glucose
  • Diamines
  • GSK2141795
  • Pyrazoles
  • Radiopharmaceuticals
  • Fluorodeoxyglucose F18
  • 1,5-anhydroglucitol
  • Deoxyglucose
  • Oncogene Protein v-akt