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Mateo, Joaquin,Ganji, Gopinath,Lemech, Charlotte,Burris, Howard A.,Han, Sae-Won,Swales, Karen,Decordova, Shaun,DeYoung, M. Phillip,Smith, Deborah A.,Kalyana-Sundaram, Shanker,Wu, Jiuhua,Motwani, Monic American Association for Cancer Research 2017 Clinical Cancer Research Vol.23 No.19
<P><B>Background:</B> The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.</P><P><B>Methods:</B> We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with <I>PTEN</I>-deficient advanced solid tumors received escalating doses of GSK2636771 (25–500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.</P><P><B>Results:</B> A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring <I>PIK3CB</I> amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with <I>PIK3CB</I> alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.</P><P><B>Conclusions:</B> Genomic aberrations of <I>PIK3CB</I> may be associated with clinical benefit from GSK2636771. <I>Clin Cancer Res; 23(19); 5981–92. ©2017 AACR</I>.</P>