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• W2610067900 abstract "AACR Annual Meeting-- Apr 18-22, 2009; Denver, COPX-866 is an irreversible, pan-inhibitor of PI-3K with potent oral antitumor activity against a number of human xenograft models. Continuous or intermittent oral dosing in mice at 1 to 2 mg/kg daily is well tolerated, results in target inhibition in tumors, and produces good antitumor activity. PX-866 also potentiates the activity of chemotherapy, radiation, or other targeted molecules in human xenografts. Immunohistochemical staining of PX-866-treated tumors revealed sustained inhibition of activation of downstream markers including phosphorylated AKT, S6, and mTOR for 2-3 days following the last dose. Based on this pre-clinical activity, PX-866 has entered a Phase 1 clinical trial in advanced metastatic cancers on a dosing schedule of 5 days a week for two weeks of a 28 day cycle, with the initial objective of evaluating safety, pharmacokinetics, and a number of pharmacodynamic (PD) endpoints. To allow for an alternate clinical dosing schedule, it was the aim of the studies described herein to evaluate the safety and efficacy of PX-866 using continuous oral administration. In mice, with and without HT-29 human colon tumors, PX-866 was evaluated for efficacy and toxicity when delivered daily for 57 days. Continuous oral daily dosing was found to be well tolerated and also provided good growth delay. Animals evaluated for hematology, clinical chemistry, and target tissue histology showed no adverse findings different from previous intermittent studies. Additionally, a GLP toxicokinetic study in rats evaluated oral PX-866 delivered daily for 28 days with a 14 day recovery period. The toxicity and pharmacokinetic profiles of this study were compared to the previous intermittent dosing regimen. The NOAEL of both the continuous 28 day and the intermittent five days a week for two weeks schedules in the rat were the same at 0.25 mg/kg/day. Target organs and toxicities were identical in both studies and included changes in weight, liver enzymes, protein and electrolyte concentrations, and hematology parameters. There were no clinically significant changes in fasting glucose levels at the doses tested in either study. In the continuous dosing schedule, fewer macro- and microscopic observations on necropsy were found in the GI tract and lymphoid organs than were seen when animals received 10 doses over 12 days. Glycogen vacuoles in the liver were the only novel microscopic finding in the continuous dosing study. All findings were reversible irrespective of dosing schedule. The oral pharmacokinetic profile of PX-866 in rats was also similar between both schedules of administration, and there was no evidence of drug accumulation over 28 consecutive days of dosing. These data demonstrate that PX-866 can be safely administered daily on a continuous dosing schedule at a similar dose to the intermittent administration schedule.Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3716." @default.
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• W2610067900 date "2009-05-01" @default.
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• W2610067900 title "Abstract #3716: Preclinical toxicology comparing intermittent and continuous administration of PX-866, a novel irreversible phosphoinositide-3-kinase (PI-3K) inhibitor" @default.
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