Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 26, Issue 10, Pages 1588-1595Publisher
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2007.14.0988
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Purpose To identify the optimal regimen and dosage of the oral mammalian target of rapamycin inhibitor everolimus (RAD001). Methods We 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. Results Ninety-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. Conclusion Everolimus 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.
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