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

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.