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Ref Type Journal Article
PMID (22693357)
Authors Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, Vo AC, Klucher K, Herbst RS, Eckhardt SG, Peterson S, Hausman DF, Kurzrock R, Jimeno A
Title A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 18
Issue 15
Date 2012 Aug 01
URL
Abstract Text The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers.This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1-5 and 8-12 of a 28-day cycle) or continuous (arm 2; days 1-28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy.Eighty-four patients were treated in the arm 1 (n = 51), arm 2 (n = 20), and food effects (n = 13) cohorts. The most frequent study drug-related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866-associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months.This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA wild-type Advanced Solid Tumor sensitive PX-866 Phase I Actionable In a Phase I study, PX-866 demonstrated efficacy and was well tolerated in patients with advanced solid tumor with both PIK3CA wild-type and mutant status (PMID: 22693357). 22693357
PIK3CA mutant Advanced Solid Tumor sensitive PX-866 Phase I Actionable In a Phase I trial, PX-866 demonstrated efficacy and was well tolerated in patients with advanced solid tumor with both PIK3CA wild-type and mutant status (PMID: 22693357). 22693357