Journal
CLINICAL CANCER RESEARCH
Volume 17, Issue 7, Pages 1956-1963Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-2061
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Funding
- Pharmacology Core of the University of Chicago Cancer Research Center [NIH P30 CA14599]
- Basic Research Training Grant in Medical Oncology [NIH/NCI T32 CA009566]
- Training Grant in Clinical Therapeutics [NIH/NIGMS T32 GM007019]
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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 C-max 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 C-max for any of the drugs alone compared with the C-max 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. Clin Cancer Res; 17(7); 1956-63. (C)2011 AACR.
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