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

• DOI: 10.1200/jco.2007.14.5482
• Publication Date: 2008-03-11T01:28:47Z
• Authors: Josep Tabernero; Federico Rojo; Emiliano Calvo; Howard Burris; Ian Judson; Katharine Hazell; Erika Martinelli; Santiago Ramon y ...; Suzanne Jones; Laura Vidal; Nicholas Shand; Teresa Macarulla; Francisco Javier ...; Sasa Dimitrijevic; Ulrike Zoellner; Pui Tang; Michael Stumm; Heidi A. Lane; David Lebwohl; José Baselga
• Keywords: Everolimus; Pharmacodynamics; Solid tumor

Everolimus is a selective mammalian target of rapamycin (mTOR) inhibitor with promising anticancer activity. In order to identify rationally based dose and schedule for cancer treatment, we have conducted tumor pharmacodynamic phase I study in patients advanced solid tumors.Fifty-five were treated everolimus cohorts 20, 50, 70 mg weekly or 5 10 daily. Dose escalation depended on limiting toxicity (DLT) rate during the first 4-week period. Pre- on-treatment steady-state skin biopsies evaluated total phosphorylated (p) protein S6 kinase 1, eukaryotic initiation factor 4E (elF-4E) binding 1 (4E-BP1), 4G (eIF-4G), AKT, Ki-67 expression. Plasma trough levels determined basis before dosing 4 weeks.We observed dose- schedule-dependent inhibition mTOR pathway near complete pS6 peIF-4G at mg/d >or= 50 mg/wk. addition, pAKT was upregulated 50% tumors. daily schedule, there correlation between plasma concentrations peIF4G p4E-BP1. There good concordance tumor. Clinical benefit four including one patient colorectal achieving partial response. DLTs occurred five patients: (grade 3 stomatitis) mg/wk (two grade stomatitis, neutropenia, hyperglycemia).Everolimus achieved signaling doses below DLT. A dosage recommended further development.