Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors

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.