title: Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors.
abstract: 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.
  
  
  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.
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Markman
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
authors.forename: I
authors.initials: I
authors.lastname: Krop
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
authors.forename: G I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Siu
authors.affiliation: Nevada Cancer Institute, Las Vegas.
authors.forename: L C
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mita
authors.affiliation: Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Melendez Cuero
authors.affiliation: Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Stutvoet
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, USA.
authors.forename: D
authors.initials: D
authors.lastname: Birle
authors.affiliation: Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Ö
authors.initials: Ö
authors.lastname: Anak
authors.affiliation: Oncology Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Hackl
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: jbaselga@partners.org.
authors.forename: J
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C117172:AU 006