Abstract
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 language | English |
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Pages (from-to) | 5981-5992 |
Number of pages | 12 |
Journal | Clinical Cancer Research |
Volume | 23 |
Issue number | 19 |
DOIs | |
Publication status | Published - 2017 Oct 1 |
Bibliographical note
Funding Information:We acknowledge support from Cancer Research UK to The Institute of Cancer Research and the Royal Marsden Cancer Centre (grant No. C51/A6883); from an Experimental Cancer Medicine Centres network grant; and from a National Institute for Health Research Biomedical Research Centre grant to The Royal
Funding Information:
Marsden. J. Mateo was supported by a Prostate Cancer Foundation Young Investigator Award and a Medical Research Council/Prostate Cancer UK-Move-mber Foundation fellowship. K. Swales is supported by Cancer Research UK (grant No. C347/A18077). This study was funded by GSK.
Publisher Copyright:
2017 American Association for Cancer Research.
All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research