Abstract A11: Phase II trial of letrozole (L), cyclophosphamide (C) and sorafenib (S) as neoadjuvant therapy in breast cancer patients (BC): Pharmacokinetic (PK) and pharmacodinamic (PD) analysis

Abstract

Abstract Introduction: This trial assessed the PK and PD of letrozole-cyclophosphamide-sorafenib combination as neoadjuvant setting in patients (pts) with operable breast cancer (BC). Methods: 13 estrogen receptor-positive postmenopausal BC pts with T2-4 N0-1 were enrolled to receive oral letrozole (L) 2.5 mg daily, 50 mg daily metronomic cyclophosphamide (C) and 400 mg twice daily sorafenib (S). S was introduced after 6 days of LC therapy. For PK analysis blood samples were collected on day 5 of cycle 1 and on day 1 of cycle 2 (day 29). At basal time and after 14 days, tumour size evaluation, Ki67 expression and MRI were performed. Results: A significant reduction in Ki67 expression was observed in all the 13 patients after 14 days only (median 20.7% (range 3-36%) and 9.75% (range 0-20%) at 15th respectively, p<0.0001) with a concomitant reduction in tumour size detected by MRI (median 37 mm (range 15-90 mm) and 31 mm (range 13.4-90 mm) respectively, p=0.047). Three patients attained a partial response at MRI (RECIST criteria) after 15 days. The changes in ki67 expression did not correlate with changes in tumor size evaluated by MRI (Spearman r: −0.37). 10 patients out of 13 showed a clinical complete response at the end of the treatment. The most common drug-related grade 2 (G2) adverse events were skin rush (46%), hand-foot syndrome (46%), anorexia (38%), fatigue (15%), and G3 diarrhea (23%). Mean plasma concentrations of C were consistently lower following concomitant administrations of L, S and C compared to administration of L and C. This trend was confirmed by the comparison of corresponding AUC (0-24) and Cmax values from Day 5, Cycle 1 and Day 1 of Cycle 2. No influence was detected by co-administration with L. Conclusions: These toxicity and PK results indicated that the combination feasible but sorafenib interpheres in non significant manner with the bioavailability of C. Moreover, the PD data indicated that the association of the already tested LC combination (Bottini at al, JCO 2006) with S is promising. A randomised study of LC vs LCS is ongoing. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A11