A Phase I/Ii Study Of Cisplatin And Radiation In Combination With Sorafenib In Cervical Cancer: Evaluation Of Biomarkers

5037 Background: This is a single-arm, open-label, phase I/II trial in patients with early stage carcinoma of the cervix investigating the addition of sorafenib (S), a dual kinase inhibitor with anti-VEGF properties which may increase the affect of chemotherapy and radiation on tumor cells. Methods: All patients received conventional treatment with radiation and chemotherapy (RTCT) but a low risk/para-aortic group received S alone in escalating doses for 1 week prior to the start of (RTCT), while high risk patients received S alone in escalating doses for 1 week prior to the start of RTCT, plus concurrently with RTCT. Biomarkers of response to S were measured at baseline, after 7 days of S alone (400 or 800 mg daily) and after 1 week of RTCT. Three Magnetic Resonance (MR) biomarkers of perfusion and vascular permeability were evaluated: 1. Enhancement fraction at 25s (EF25) - indicative of early phase enhancement; 2. Relative signal intensity (RSI) - indicative of late phase enhancement; and 3. iAUC60. In addition, tumor median pO2 (mpO2), hypoxic proportion (HP) and interstitial fluid pressure (IFP) were measured using needle-based techniques. The paired Wilcoxin signed ranks test was used to evaluate differences in the biomarkers relative to baseline. Results: Thirteen patients have been enrolled onto the study and the low risk cohort is complete. Most common toxicities of any grade include diarrhea (82%), lymphopenia (82%), and nausea (82%). Tumor volume increased with 7 days of S alone (86 vs 78 cm3, p<0.01), and EF (73 vs 86%, p=0.02) were decreased and RSI (1.7 vs 1.9, p=0.07) was unchanged. The tumors also became more hypoxic (mpO2 3 vs 14 mm Hg, p=0.01; and HP 67 vs 51%, p=0.06) but there was no change in IFP (21 vs 24 mm Hg). MR biomarkers were also obtained in week 2 (after the start of RTCT) for 12/13 patients, IFP in 10 and mpO2/HP in 7. Tumor volume decreased (57 vs 81 cm3, p=0.01) and there was a significant reduction in IFP (16 vs 24 mm Hg, p=0.04). However, EF, RSI, mpO2 and HP were not significantly different from baseline. Conclusions: Thus study demonstrates that the combination of RTCT and S is tolerable and that biomarkers show increasing hypoxia, and indications of reductions in markers of vasculature with S.