Two drug interaction studies of sirolimus in combination with sorafenib or sunitinib in patients with advanced malignancies

Tara C. Gangadhar, Ezra E W Cohen, Kehua Wu, Linda Janisch, David Geary, Masha Kocherginsky, Larry K. House, Jackie Ramirez, Samir D. Undevia, Michael L. Maitland, Gini F. Fleming, Mark J. Ratain

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Purpose: Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination. Experimental Design: Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in Cmax for each drug alone compared with its C max during combination therapy. Results: The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in Cmax for any of the drugs alone compared with the Cmax during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib. Conclusions: Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug-drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling.

Original languageEnglish (US)
Pages (from-to)1956-1963
Number of pages8
JournalClinical Cancer Research
Volume17
Issue number7
DOIs
StatePublished - Apr 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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