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Clin Cancer Res. 2017 Oct 1;23(19):5981-5992. doi: 10.1158/1078-0432.CCR-17-0725. Epub 2017 Jun 23.

A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors.

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Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
GSK, Collegeville, Pennsylvania, USA.
Sarah Cannon Research Institute UK, University College London Cancer Centre, London, United Kingdom.
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee, USA.
Seoul National University Hospital, Seoul National University College of Medicine Seoul, South Korea.
PAREXEL International, 2560 Meridian Parkway, Durham, North Carolina, USA.
Biostat Consulting, Inc., Portage, Michigan, USA.
AbbVie Ltd., Translational Oncology & Precision Medicine, Chicago, Illinois, USA.
MedImmune, Gaithersburg, Maryland, USA.
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
Yale Cancer Center, New Haven, Connecticut, USA.
University of Utah Huntsman Cancer Institute, Salt Lake City, Utah, USA.
GSK, Collegeville, Pennsylvania, USA.
Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.


Background: 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.Methods: 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 PTEN-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.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 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 PIK3CB 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 PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981-92. ©2017 AACR.

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