S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors
- 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, Monica; Kumar, Rakesh; Tolson, Jerry M.; Rha, Sun Young; Chung, Hyun Cheol; Eder, Joseph P.; Sharma, Sunil; Bang, Yung-Jue; Infante, Jeffrey R.; Yan, Li; de Bono, Johann S.; Arkenau, Hendrik-Tobias
- Issue Date
- Clinical Cancer Research, Vol.23 No.19, pp.5981-5992
- Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110 beta 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 PI3K beta. 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 typespecific 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. (C) 2017 AACR.
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