Originally published as JCO Early Release 10.1200/JCO.2007.14.5482 on March 10 2008

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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

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

From the Medical Oncology and Pathology Departments, Vall d’Hebron University Hospital, Barcelona, Spain; Medical Oncology Department, Sarah Cannon Cancer Center, Nashville, TN; Medical Oncology Department, Royal Marsden Hospital, London, United Kingdom; Novartis Oncology, Basel, Switzerland; and Novartis Oncology, Florham Park, NJ

Corresponding author: José Baselga, MD, Medical Oncology Department, Vall d’Hebron University Hospital, P. Vall d’Hebron, 119-129, 08035, Barcelona, Spain; e-mail: jbaselga{at}vhebron.net

Purpose 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.

Patients and Methods 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.

Results 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).

Conclusion 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.

Submitted September 20, 2007; accepted November 16, 2007.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005; and at the 13th European Cancer Conference, Paris, France, October 30 to November 3, 2005.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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