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

Purpose: The phosphoinositide 3 kinase (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.<br /><br />Experimental Design: <p>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 phosphatase and tensin homolog (PTEN)-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily [QD]) 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> <br />Results: 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 QD was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including 2 other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg QD oral induced sufficient exposure and target inhibition with a manageable safety profile.<br /><br />Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771.

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