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

Mateo, J; Ganji, G; Lemech, C; Burris, HA; Han, S-W; Swales, K; Decordova, S; ... Arkenau, H-T; + view all (2017) A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors. Clinical Cancer Research , 23 (19) pp. 5981-5992. 10.1158/1078-0432.CCR-17-0725. Green open access

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Abstract

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.

Type: Article
Title: A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-17-0725
Publisher version: https://doi.org/10.1158/1078-0432.CCR-17-0725
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, COMPREHENSIVE GENOMIC CHARACTERIZATION, RESISTANT PROSTATE-CANCER, CLINICAL-TRIALS, BREAST-CANCER, MOLECULAR PORTRAITS, ABIRATERONE ACETATE, PATHWAY INHIBITORS, ANTITUMOR-ACTIVITY, PI3K INHIBITION, PTEN
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10073237
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