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Tabernero, Josep; Rojo, Federico; Calvo, Emiliano; Burris, Howard; Judson, Ian; Hazell, Katharine; Martinelli, Erika; Cajal, Santiago Ramon y; Jones, Suzanne; Vidal, Laura; Shand, Nicholas; Macarulla, Teresa; Ramos, Francisco Javier; Dimitrijevic, Sasa; Zoellner, Ulrike; Tang, Pui; Stumm, Michael; Lane, Heidi A.; Lebwohl, David; Baselga, José

Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors

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  • Media type: E-Article
  • Title: Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors
  • Contributor: Tabernero, Josep; Rojo, Federico; Calvo, Emiliano; Burris, Howard; Judson, Ian; Hazell, Katharine; Martinelli, Erika; Cajal, Santiago Ramon y; Jones, Suzanne; Vidal, Laura; Shand, Nicholas; Macarulla, Teresa; Ramos, Francisco Javier; Dimitrijevic, Sasa; Zoellner, Ulrike; Tang, Pui; Stumm, Michael; Lane, Heidi A.; Lebwohl, David; Baselga, José
  • imprint: American Society of Clinical Oncology (ASCO), 2008
  • Published in: Journal of Clinical Oncology
  • Language: English
  • DOI: 10.1200/jco.2007.14.5482
  • ISSN: 0732-183X; 1527-7755
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:sec><jats:title>Purpose</jats:title><jats:p> Everolimus is a selective mammalian target of rapamycin (mTOR) inhibitor with promising anticancer activity. In order to identify a rationally based dose and schedule for cancer treatment, we have conducted a tumor pharmacodynamic phase I study in patients with advanced solid tumors. </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> Fifty-five patients were treated with everolimus in cohorts of 20, 50, and 70 mg weekly or 5 and 10 mg daily. Dose escalation depended on dose limiting toxicity (DLT) rate during the first 4-week period. Pre- and on-treatment steady-state tumor and skin biopsies were evaluated for total and phosphorylated (p) protein S6 kinase 1, eukaryotic initiation factor 4E (elF-4E) binding protein 1 (4E-BP1), eukaryotic initiation factor 4G (eIF-4G), AKT, and Ki-67 expression. Plasma trough levels of everolimus were determined on a weekly basis before dosing during the first 4 weeks. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> We observed a dose- and schedule-dependent inhibition of the mTOR pathway with a near complete inhibition of pS6 and peIF-4G at 10 mg/d and ≥ 50 mg/wk. In addition, pAKT was upregulated in 50% of the treated tumors. In the daily schedule, there was a correlation between everolimus plasma trough concentrations and inhibition of peIF4G and p4E-BP1. There was good concordance of mTOR pathway inhibition between skin and tumor. Clinical benefit was observed in four patients including one patient with advanced colorectal cancer achieving a partial response. DLTs occurred in five patients: one patient at 10 mg/d (grade 3 stomatitis) and four patients at 70 mg/wk (two with grade 3 stomatitis, one with grade 3 neutropenia, and one with grade 3 hyperglycemia). </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> Everolimus achieved mTOR signaling inhibition at doses below the DLT. A dosage of 10 mg/d or 50 mg/wk is recommended for further development. </jats:p></jats:sec>
  • Access State: Open Access