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Ref Type Journal Article
PMID (26603258)
Authors Munster P, Aggarwal R, Hong D, Schellens JH, van der Noll R, Specht J, Witteveen PO, Werner TL, Dees EC, Bergsland E, Agarwal N, Kleha JF, Durante M, Adams L, Smith DA, Lampkin TA, Morris SR, Kurzrock R
Title First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 8
Date 2016 Apr 15
URL
Abstract Text 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.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.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 withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant).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,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown breast cancer not applicable GSK2126458 Phase I Actionable In a Phase I trial, GSK2126458 was well-tolerated and resulted in some efficacy in patients with breast cancer, including stable disease in 31% (7/22) and one patient with a partial response (PMID: 26603258). 26603258
Unknown unknown urinary bladder cancer not applicable GSK2126458 Phase I Actionable In Phase I trial, GSK2126458 treatment was well-tolerated and resulted in a partial response and stable disease in two patients and one patient with bladder cancer, respectively (PMID: 26603258). 26603258
PIK3CA mutant breast cancer no benefit GSK2126458 Phase I Actionable In a Phase I trial, GSK2126458 was well-tolerated and resulted in some efficacy in patients with breast cancer harboring a PIK3CA mutation including stable disease in 22% (2/9), however, objective response rate was not associated with PIK3CA mutations when compared to those without PIK3CA mutations (PMID: 26603258). 26603258
Unknown unknown endometrial cancer not applicable GSK2126458 Phase I Actionable In a Phase I trial, GSK2126458 treatment was well-tolerated and resulted in some efficacy in endometrial cancer patients including stable disease in 27% (4/15) and one patient with a partial response (PMID: 26603258). 26603258
Unknown unknown renal cell carcinoma not applicable GSK2126458 Phase I Actionable In a Phase I trial, GSK2126458 treatment was well-tolerated and resulted in some efficacy in renal cell carcinoma patients including stable disease in 13% (3/24), one patient with a complete response, and one patient with a partial response (PMID: 26603258). 26603258