Abstract
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.
Highlights
The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is deregulated in many human cancers, leading to decreased expression of proapoptotic genes and increased expression of cell proliferation and cell survival genes, making it an attractive cancer target [1]
PX-866–associated inhibition of platelet pAKTSER473 was observed at the arm 2 maximum tolerated dose (MTD)
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, when using a continuous dosing schedule
Summary
The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is deregulated in many human cancers, leading to decreased expression of proapoptotic genes and increased expression of cell proliferation and cell survival genes, making it an attractive cancer target [1]. PI3K and AKT are oncogenes overexpressed or activated by mutation in many human cancers [2,3,4,5,6]. The PTEN (phosphatase and tensin homologue) tumor suppressor gene, which negatively regulates PI3K signaling, may be lost via deletion (25% of melanoma, breast, and prostate cancers), mutation, or epigenetic suppression [14,15,16,17,18]. Upstream growth factor receptors with increased activity in some cancers, such as EGF receptor (EGFR), activate downstream PI3K signaling [19]
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