title: Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Royal Marsden Hospital, Sutton, Surrey, UK. anne.o'donnell@ccdhb.org.nz
authors.forename: Anne
authors.initials: A
authors.lastname: O'Donnell
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Daniel
authors.initials: D
authors.lastname: Rea
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: Nicholas
authors.initials: N
authors.lastname: Shand
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Lane
authors.forename: Katharine
authors.initials: K
authors.lastname: Hazell
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zoellner
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Cathryn
authors.initials: C
authors.lastname: Brock
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011494:Protein Kinases / Q000187:drug effects; D019893:Ribosomal Protein S6 Kinases / Q000097:blood; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus