التفاصيل البيبلوغرافية
العنوان:
Data from First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies
المؤلفون:
Razelle Kurzrock , Shannon R. Morris , Thomas A. Lampkin , Deborah A. Smith , Laurel Adams , Michael Durante , Joseph F. Kleha , Neeraj Agarwal , Emily Bergsland , E. Claire Dees , Theresa L. Werner , Petronella O. Witteveen , Jennifer Specht , Ruud van der Noll , Jan H.M. Schellens , David Hong , Rahul Aggarwal , Pamela Munster
بيانات النشر:
American Association for Cancer Research (AACR), 2023.
سنة النشر:
2023
الوصف:
Purpose: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors.Materials and Methods: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts.Results: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea, n = 4; fatigue and rash, n = 1) occurred in 5 patients (n = 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated with PIK3CA mutations (OR rate: 5% wild-type vs. 6% mutant).Conclusions: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however, PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K. Clin Cancer Res; 22(8); 1932–9. ©2015 AACR.
URL الوصول:
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b58210558b93cf8d4ce8c9aff837b458 https://doi.org/10.1158/1078-0432.c.6524799
حقوق:
OPEN
رقم الأكسشن:
edsair.doi.dedup.....b58210558b93cf8d4ce8c9aff837b458
قاعدة البيانات:
OpenAIRE
