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• W2999154618 abstract "ABSTRACT Background GSK458 is an oral, potent inhibitor of PI3K (α, β, γ, δ), mTORC1, and mTORC2. Cell lines with activation of the PI3K pathway are more likely to be sensitive to GSK458. Methods Pts with advanced solid tumors received GSK458 until disease progression or intolerable toxicity. Dose escalation with once (QD) and twice daily dosing (BID) was explored. Pharmacodynamics (PD) (tumor biopsies and FDG–PET) in unselected populations, and clinical activity in specific populations (PIK3CA-mutant and wild-type [WT]) bladder cancer, renal cell carcinoma, PIK3CA-mutant metastatic breast cancer, and KRAS-WT metastatic endometrial cancer) were evaluated. Results 170 pts (49% female; mean age 57 [22-85] yrs) received doses ranging from 0.1 to 3 mg, the MTD for both QD and BID was 2.5 mg. The median (range) time above the target plasma concentration (20 ng/mL) was longer in BID versus QD dosing: 21hour (h) (14.8-24; n = 6) versus 8h (0-23.9; n = 18), respectively. Dose limiting toxicities were Grade 3 diarrhea. Most frequent (≥ 20%) drug related adverse events were diarrhea (28%), fatigue (24%) and nausea (23%). A dose response relationship between GSK458 plasma concentrations and increases in serum insulin levels was observed. 13 paired pre/post-dose tumor biopsies showed inconsistent changes in pAKT/total AKT, Ki67 and phospho-histone-H3. 9 pts had pre/post-dose FDG-PET; one pt had a mean SUV value decrease by ≥30% post-dose although none had responses per RECIST. Objective responses were seen in bladder cancer (1/3 PIK3CA mutant and 2/15 wild-type) and renal cell (2/23: 1 CR duration 25+ months, 1PR), but no responses were seen in PIK3CA-mutant breast cancer (1/10: stable for >6 months) or KRAS-WT endometrial cancer (1/12: stable disease for > 6 months). Conclusions Based on its superior pharmacokinetic profile, BID is the recommended schedule for GSK458 monotherapy. Surrogate PD markers (insulin) indicate on target activity. GSK458 showed promising activity in PIK3CA mutant bladder cancer and RCC. Disclosure P. Munster: Phase I Research: GSK J. Specht: Corporate-sponsored research: Pfizer, BMS, Genentech, BiPar Sciences, Boehringer Ingelheim E.C. Dees: Corporate-sponsored research: GSK, Novartis, Genentech/Roche, Millennium A. Tan: Corporate-sponsored research: GSK A. Daud: Membership on an advisory board or board of directors: Oncosec; Corporate-sponsored research: GSK, Pfizer, Merck, Oncosec, Exelixis G. Falchook: Corporate-sponsored research: GSK; GSK Travel reimbursement for ESMO 2010 J. F. Kleha: Stock ownership: GSK; GSK Employee M. Durante: Stock ownership: GSK; GSK Employee D.A. Smith: Stock ownership: GSK; GSK Employee L. Adams: Stock ownership: GSK; GSK Employee J. Greshock: Stock ownership: GSK; GSK Employee S.R. Morris: Stock ownership: GSK; GSK Employee All other authors have declared no conflicts of interest." @default.
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• W2999154618 date "2012-09-01" @default.
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• W2999154618 title "PI3K Kinase Inhibitor GSK2126458 (GSK458): Clinical Activity in Select Patient (PT) Populations Defined by Predictive Markers (STUDY P3K112826)" @default.
• W2999154618 doi "https://doi.org/10.1016/s0923-7534(20)33038-6" @default.
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