Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With Advanced Solid Tumors

Author:

O'Donnell Anne1,Faivre Sandrine1,Burris Howard A.1,Rea Daniel1,Papadimitrakopoulou Vassiliki1,Shand Nicholas1,Lane Heidi A.1,Hazell Katharine1,Zoellner Ulrike1,Kovarik John M.1,Brock Cathryn1,Jones Suzanne1,Raymond Eric1,Judson Ian1

Affiliation:

1. From the Royal Marsden Hospital, Sutton, Surrey; Queen Elizabeth Hospital, Birmingham, United Kingdom; Institut Gustave-Roussy, Villejuif, France; Sarah Cannon Research Institute, Nashville, TN; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Novartis Pharma AG; and Novartis Institutes for BioMedical Research, Oncology, Basel, Switzerland

Abstract

PurposeTo identify the optimal regimen and dosage of the oral mammalian target of rapamycin inhibitor everolimus (RAD001).MethodsWe performed a dose-escalation study in advanced cancer patients administering oral everolimus 5 to 30 mg/wk, with pharmacokinetic (PK) and pharmacodynamic (PD) studies. PD data prompted investigation of 50 and 70 mg weekly and daily dosing at 5 and 10 mg.ResultsNinety-two patients were treated. Dose-limiting toxicity was seen in one patient each at 50 mg/wk (stomatitis and fatigue) and 10 mg/d (hyperglycemia); hence, the maximum-tolerated dose was not reached. S6 kinase 1 activity in peripheral-blood mononuclear cells was inhibited for at least 7 days at doses ≥ 20 mg/wk. Area under the curve increased proportional to dose, but maximum serum concentration increased less than proportionally at doses ≥ 20 mg/wk. Terminal half-life was 30 hours (range, 26 to 38 hours). Partial responses were observed in four patients, and 12 patients remained progression free for ≥ 6 months, including five of 10 patients with renal cell carcinoma.ConclusionEverolimus was satisfactorily tolerated at dosages up to 70 mg/wk and 10 mg/d with predictable PK. Antitumor activity and PD in tumors require further clinical investigation. Doses of 20 mg/wk and 5 mg/d are recommended as appropriate starting doses for these studies.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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5. Beuvink I, O'Reilly T, Zumstein S, et al: Antitumor activity of RAD001, an orally active rapamycin derivative. Proc Am Assoc Cancer Res 42:366,2001, (suppl, abstr 1972)

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