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Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer.

Gungor, H, Saleem, A, Agarwal, R, Blagden, S, Michael, A, Stronach, EA, Chen, M, Pickford, E, Rama, NR, Lewis, YL , Carme, SC, Salinas, C, Smith, DA, Krachey, E, Santiago-Walker, A, Gunn, RN, El-Bahrawy, M, Babar,, SA, Morris, R and Gabra, H Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer. In: ASCO, 2011-06-03 - 2011-06-07, Chicago USA.

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Background: GSK795 is a potent, ATP-competitive, pan AKT inhibitor. The purpose of this study was to characterize the relationship between AKT inhibition by GSK795 and downstream effects in platinum resistant ovarian cancer pts. Methods: Pts with recurrent platinum-resistant ovarian cancer received 25, 50 or 75mg of oral GSK795 daily. Dynamic FDG-PET scans and paired tumor biopsies (PTB) were performed prior to first dose and at 2 and/or 4 weeks post treatment. Semi-quantitative (SUV) and quantitative (Ki, MRglu) PET PD parameters were derived. PTB were analyzed by immunohistochemistry (IHC) for PD marker expression. PK samples were obtained in parallel. Response was monitored by RECIST and CA125 criteria. Results: 12 pts have been treated on study: 4 at 25mg, 4 at 50mg and 4 at 75mg. After completion of the 2 or 4 week post-treatment PD assessment, all eligible pts underwent intra-subject dose escalation to 75mg. The most common drug-related adverse events (≥ 10%) were decreased appetite (18%) and vomiting (18%), all G1/2. Mean Cmax and AUC24 increased with increasing doses and increased 1.2-fold from Week 2 to Week 4 where 2 and 4 week doses were the same. Median Tmax was 4 h. Overall tumor FDG metabolism decreased in 71% of tumors with treatment, although inter- and intra-patient variability in tumor uptake measurements following therapy was seen. There was no clear temporal or dose-response effect in FDG uptake. IHC analysis of PTB from 5 pts dosed at either 50 or75mg indicated that pAKT levels increased in 2/2 pts dosed at 75mg, pPRAS40 levels decreased in 4/5 pts, and Ki67 levels decreased in 4/5 pts after treatment with GSK795. 8/12 pts had stable disease and 4/12 had progressive disease by RECIST criteria at week 4. Currently 4 pts are still on the study, 2 > 24 weeks, with tumor regressions of 26% and 11% and CA125 decreases of 70% and 58% respectively. Conclusions: A dose response relationship between changes in FDG-PET and GSK795 was not observed in pts dosed from 25 to 75mg daily. Evidence of AKT pathway inhibition was observed in PTB from pts dosed with 50 or 75mg GSK795. Clinical activity evidenced by tumor regressions and CA125 decreases was also observed.

Item Type: Conference or Workshop Item (UNSPECIFIED)
Divisions : Surrey research (other units)
Authors :
Gungor, H
Saleem, A
Agarwal, R
Blagden, S
Stronach, EA
Chen, M
Pickford, E
Rama, NR
Lewis, YL
Carme, SC
Salinas, C
Smith, DA
Krachey, E
Santiago-Walker, A
Gunn, RN
El-Bahrawy, M
Babar,, SA
Morris, R
Gabra, H
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:38
Last Modified : 23 Jan 2020 15:40

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