Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors.

Autor:	Dolly SO; The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom., Wagner AJ; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Bendell JC; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee., Kindler HL; The Gastrointestinal Oncology and Mesothelioma Programs, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois., Krug LM; Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York., Seiwert TY; The Gastrointestinal Oncology and Mesothelioma Programs, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois., Zauderer MG; Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York., Lolkema MP; The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Department of Medical Oncology, Cancer Institute Rotterdam, Erasmus MC, Rotterdam, the Netherlands., Apt D; Genentech, Inc., South San Francisco, California., Yeh RF; Genentech, Inc., South San Francisco, California., Fredrickson JO; Genentech, Inc., South San Francisco, California., Spoerke JM; Genentech, Inc., South San Francisco, California., Koeppen H; Genentech, Inc., South San Francisco, California., Ware JA; Genentech, Inc., South San Francisco, California., Lauchle JO; Genentech, Inc., South San Francisco, California., Burris HA 3rd; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee., de Bono JS; The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. johann.de-bono@icr.ac.uk.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Jun 15; Vol. 22 (12), pp. 2874-84. Date of Electronic Publication: 2016 Jan 19.
DOI:	10.1158/1078-0432.CCR-15-2225
Abstrakt:	Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases. Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed. Results: Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas). Conclusions: Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874-84. ©2016 AACR. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu