Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients

Clin Cancer Res. 2012 Sep 1;18(17):4785-93. doi: 10.1158/1078-0432.CCR-12-0110. Epub 2012 Aug 7.


Purpose: 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.

Experimental design: 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibiotics, Antineoplastic* / administration & dosage
  • Antibiotics, Antineoplastic* / adverse effects
  • Antibiotics, Antineoplastic* / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacokinetics
  • Citrus paradisi
  • Female
  • Humans
  • Hyperglycemia / chemically induced
  • Hyperlipidemias / chemically induced
  • Ketoconazole / administration & dosage
  • Lymphopenia / chemically induced
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms* / drug therapy
  • Neoplasms* / pathology
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sirolimus* / administration & dosage
  • Sirolimus* / adverse effects
  • Sirolimus* / pharmacokinetics
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism


  • Antibiotics, Antineoplastic
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Ketoconazole
  • Sirolimus