Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors.

Autor:	Markman B; Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain., Tabernero J; Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain., Krop I; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA., Shapiro GI; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA., Siu L; Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada., Chen LC; Nevada Cancer Institute, Las Vegas., Mita M; Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, USA., Melendez Cuero M; Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland., Stutvoet S; Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland., Birle D; Novartis Institutes for Biomedical Research, Cambridge, USA., Anak Ö; Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland., Hackl W; Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland., Baselga J; Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: jbaselga@partners.org.
Jazyk:	angličtina
Zdroj:	Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2012 Sep; Vol. 23 (9), pp. 2399-2408. Date of Electronic Publication: 2012 Feb 22.
DOI:	10.1093/annonc/mds011
Abstrakt:	Background: This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor. Patients and Methods: Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples. Results: Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6-9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose-positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent. Conclusions: The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.
Databáze:	MEDLINE
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