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

Joaquin Mateo, Gopinath Ganji, Charlotte Lemech, Howard A. Burris, Sae Won Han, Karen Swales, Shaun Decordova, M. Phillip DeYoung, Deborah A. Smith, Shanker Kalyana-Sundaram, Jiuhua Wu, Monica Motwani, Rakesh Kumar, Jerry M. Tolson, Sun Young Rha, Hyun Cheol Chung, Joseph P. Eder, Sunil Sharma, Yung Jue Bang, Jeffrey R. InfanteLi Yan, Johann S. De Bono, Hendrik Tobias Arkenau

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)5981-5992
Number of pages12
JournalClinical Cancer Research
Issue number19
Publication statusPublished - 2017 Oct 1

Bibliographical note

Publisher Copyright:
2017 American Association for Cancer Research.

All Science Journal Classification (ASJC) codes

  • General Medicine


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