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

B. Markman, J. Tabernero, I. Krop, G. I. Shapiro, L. Siu, L. C. Chen, M. Mita, M. Melendez cuero, S. Stutvoet, D. Birle, Ö Anak, W. Hackl, J. Baselga

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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. 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. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Original languageEnglish
Article numbermds011
Pages (from-to)2399-2408
JournalAnnals of Oncology
Volume23
Issue number9
DOIs
Publication statusPublished - 1 Sep 2012

Keywords

  • Anticancer agent
  • BGT226
  • Dual inhibitor
  • MTOR catalytic inhibitor
  • PI3K pathway
  • Solid tumors

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    Markman, B., Tabernero, J., Krop, I., Shapiro, G. I., Siu, L., Chen, L. C., Mita, M., Melendez cuero, M., Stutvoet, S., Birle, D., Anak, Ö., Hackl, W., & Baselga, J. (2012). Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Annals of Oncology, 23(9), 2399-2408. [mds011]. https://doi.org/10.1093/annonc/mds011