title: A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer.
abstract: OBJECTIVE
  Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy.
  
  
  METHODS
  Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite.
  
  
  RESULTS
  Sixty-three patients were treated with temsirolimus (0.75-24 mg/m(2)/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m(2)/d for patients with extensive prior treatment because, in the 19 mg/m(2)/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m(2)/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m(2)/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non-small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for >/=24 weeks.
  
  
  CONCLUSIONS
  Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, Brook Army Medical Center, San Antonio, TX, USA. mhidalg1@jhmi.edu
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Jan C
authors.initials: JC
authors.lastname: Buckner
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Pollack
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Boni
authors.forename: Gary
authors.initials: G
authors.lastname: Dukart
authors.forename: Bonnie
authors.initials: B
authors.lastname: Marshall
authors.forename: Lisa
authors.initials: L
authors.lastname: Speicher
authors.forename: Laurence
authors.initials: L
authors.lastname: Moore
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus