e13613 Background: The combination of the multi-kinase inhibitor sorafenib (S) and the mTOR inhibitor everolimus (E) may increase anti-tumor efficacy by dual inhibition of key nodules of signaling pathways regulating angiogenesis and cellular proliferation. FDG-PET might be a suitable method for the assessment of pharmacodynamic activity of E.
METHODS
Patients with advanced solid tumors after failure of standard therapy were treated with E in a dose escalating schedule of 1x 2.5-10mg daily in combination with a fixed dose of 2x 400mg S daily. The primary objective was to determine the maximum tolerated dose (MTD) of the combination. Dose-limiting toxicity (DLT) was defined as any of the following toxicities occurring during the first 29 treatment days(DLT interval): hematological or non-hematological toxicity of CTC grade IV, any toxicity requiring hospitalization or any toxicity leading to delay of treatment for more than 2 weeks. In addition to pharmacokinetics, pharmacodynamic analyses using dynamic FDG-PET were performed on days 0, 5 and 14. Response after 8 weeks of treatment was assessed by CT.
RESULTS
Sixteen patients have been enrolled. The DLT was not reached according to protocol definition. However, at a dose level of 1x 10mg E daily and 2x 400mg S daily the following toxicities occurred in the non DLT interval: upper respiratory tract infection III°, treatment delay caused by leukopenia III° and thrombopenia III° and sudden cardiac death probably due to arrhythmia. Based on these observations the dose level of 1x 7.5mg E daily and 2x 400mg S daily was defined as MTD. Data analysis of patients treated on MTD is currently ongoing. Response after 8 weeks could be evaluated in 9 patients, showing progressive disease in one patient (pancreatic cancer) and stable disease in 8 patients (NSCLC, melanoma, CUP, ovarian, colorectal, vaginal and breast cancer).
CONCLUSIONS
Combination of S and E is feasible for the treatment of patients with advanced solid tumors. The full analysis including pharmacodynamics and pharmakokinetics will be presented.