title: Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients.
abstract: OBJECTIVE
  Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.
  
  
  METHODS
  Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined.
  
  
  RESULTS
  Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma.
  
  
  CONCLUSIONS
  Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.
authors.affiliation: Departments of Medicine, University of Chicago, Chicago, IL 60637, USA. ecohen@medicine.bsd.uchicago.edu
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.forename: Kehua
authors.initials: K
authors.lastname: Wu
authors.forename: Christine
authors.initials: C
authors.lastname: Hartford
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.forename: Kimberly Napoli
authors.initials: KN
authors.lastname: Eaton
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zha
authors.forename: Anitha
authors.initials: A
authors.lastname: Nallari
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
authors.forename: Kammi
authors.initials: K
authors.lastname: Fox-Kay
authors.forename: Kristin
authors.initials: K
authors.lastname: Moshier
authors.forename: Larry
authors.initials: L
authors.lastname: House
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramirez
authors.forename: Samir D
authors.initials: SD
authors.lastname: Undevia
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D032083:Citrus paradisi; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D006949:Hyperlipidemias / Q000139:chemically induced; D007654:Ketoconazole / Q000008:administration & dosage; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D007654:Ketoconazole; D020123:Sirolimus