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

J Clin Oncol. 2008 Apr 1;26(10):1588-95. doi: 10.1200/JCO.2007.14.0988. Epub 2008 Mar 10.


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 >or= 20 mg/wk. Area under the curve increased proportional to dose, but maximum serum concentration increased less than proportionally at doses >or= 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 >or= 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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Everolimus
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protein Kinases / drug effects
  • Ribosomal Protein S6 Kinases / blood
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacokinetics
  • TOR Serine-Threonine Kinases
  • Treatment Outcome


  • Antineoplastic Agents
  • Everolimus
  • Protein Kinases
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases
  • Sirolimus