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

Ann Oncol. 2012 Sep;23(9):2399-2408. doi: 10.1093/annonc/mds011. Epub 2012 Feb 22.


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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / drug therapy*
  • Colonic Neoplasms / diagnostic imaging
  • Colonic Neoplasms / drug therapy*
  • Diarrhea / chemically induced
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Imidazoles / adverse effects
  • Imidazoles / pharmacokinetics
  • Imidazoles / therapeutic use*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Nausea / chemically induced
  • Phosphoinositide-3 Kinase Inhibitors
  • Prostatic Neoplasms / diagnostic imaging
  • Prostatic Neoplasms / drug therapy*
  • Quinolines / adverse effects
  • Quinolines / pharmacokinetics
  • Quinolines / therapeutic use*
  • Radionuclide Imaging
  • Radiopharmaceuticals
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Treatment Outcome
  • Young Adult


  • 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one
  • Antineoplastic Agents
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinolines
  • Radiopharmaceuticals
  • Fluorodeoxyglucose F18
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AU 006