First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

Autor:	Sarker D; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom., Ang JE; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom., Baird R; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom., Kristeleit R; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom., Shah K; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom., Moreno V; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom., Clarke PA; The Institute of Cancer Research, London, United Kingdom., Raynaud FI; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom., Levy G; Genentech Inc., South San Francisco, California, United States of America., Ware JA; Genentech Inc., South San Francisco, California, United States of America., Mazina K; Genentech Inc., South San Francisco, California, United States of America., Lin R; Genentech Inc., South San Francisco, California, United States of America., Wu J; Genentech Inc., South San Francisco, California, United States of America., Fredrickson J; Genentech Inc., South San Francisco, California, United States of America., Spoerke JM; Genentech Inc., South San Francisco, California, United States of America., Lackner MR; Genentech Inc., South San Francisco, California, United States of America., Yan Y; Genentech Inc., South San Francisco, California, United States of America., Friedman LS; Genentech Inc., South San Francisco, California, United States of America., Kaye SB; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom., Derynck MK; Genentech Inc., South San Francisco, California, United States of America., Workman P; The Institute of Cancer Research, London, United Kingdom., de Bono JS; The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.; The Institute of Cancer Research, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Jan 01; Vol. 21 (1), pp. 77-86. Date of Electronic Publication: 2014 Nov 04.
DOI:	10.1158/1078-0432.CCR-14-0947
Abstrakt:	Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Results: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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