A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors

Background: The PI3K/protein kinase B (AKT) pathway Results: A total of 65 patients were enrolled; dose-limiting is commonly activated in several tumor types. Selective toxicities were hypophosphatemia and hypocalcemia. Adverse targeting of p110b could result in successful pathway inhibi-events included diarrhea (48%), nausea (40%), and vomiting tion while avoiding the on- and off-target effects of pan-PI3K (31%). Single- and repeat-dose exposure increased generally dose inhibitors. GSK2636771 is a potent, orally bioavailable, proportionally. GSK2636771 400 mg once daily was the RP2D. adenosine triphosphate-competitive, selective inhibitor of Phospho/total AKT ratio decreased with GSK2636771 in tumor PI3Kb. and surrogate tissue. A castrate-resistant prostate cancer (CRPC) Methods: We evaluated the safety, pharmacokinetics, phar-patient harboring PIK3CB amplification had a partial response for macodynamics and antitumor activity of GSK2636771 to over a year; an additional 10 patients derived durable (24 define the recommended phase II dose (RP2D). During the weeks) clinical benefit, including two other patients with CRPC dose-selection and dose-escalation stages (parts 1 and 2), with PIK3CB alterations (34 weeks). GSK2636771 400 mg patients with PTEN-deficient advanced solid tumors received once daily orally induced sufficient exposure and target inhibition escalating doses of GSK2636771 (25–500 mg once daily) using with a manageable safety profile. a modified 3þ3 design to determine the RP2D; tumor type-Conclusions: Genomic aberrations of PIK3CB may be associ-specific expansion cohorts (part 3) were implemented to fur-ated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); ther assess tumor responses at the RP2D. 5981–92. 2017 AACR.