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6 versus 1.6 months; p Aldosterone the majority of patients benefited in the form of SD. However, the protocol-specified final analysis of OS showed that longer PFS with pazopanib did not translate into an improvement in OS (median OS: 12.5 versus 10.7 months; p = 0.25). The role of bevacizumab, a monoclonal antibody directed against VEGF, in addition to fixed-dose-rate gemcitabine plus docetaxel (GD), has also been investigated as first-line treatment for metastatic U-LMS in a phase III, double-blind, placebo-controlled trial [66]. In that study 102 patients were randomly assigned to either gemcitabine (900?mg/m2)/docetaxel (75?mg/m2) plus bevacizumab (B; 15?mg/kg; n = 50) or GD plus placebo (P; n = 52). Unfortunately, the addition of bevacizumab to the combination of GD failed to improve PFS (GD + B: 4.1 months versus GD?+?P: 6.2 months), OS (GD + B: 23.3 months versus GD?+?P: 19.4 months), or ORR (GD + B: 32% versus GD + P: 36%) and worsened the overall toxicity profile. Formerly, a phase Ib study of the combination of docetaxel, gemcitabine, and bevacizumab in chemotherapy-na?ve patients with advanced MLN8237 or recurrent STS reported the ORR of 31.4%, with five complete and six partial responses, and an additional C59 mouse 18 had SD lasting for a median of 6 months, similar to historical response rates with this cytotoxic combination alone [67]. Nevertheless, some concerning adverse events were attributed to bevacizumab as one patient died of a pulmonary embolism following surgery for a bowel perforation, one patient developed a grade 3 wound dehiscence, and another experienced a grade 3 tumor-related hemorrhage. Additionally, in a phase II study, the antitumor activity and tolerability of bevacizumab and doxorubicin were evaluated in 17 patients with metastatic STS (seven had U-LMS) who received up to one nonanthracycline prior therapy [68]. The ORR was lower than might be expected with single-agent doxorubicin in U-LMS, as there were only two partial responses (12%) and 11 disease stabilizations (65%). Of major concern, despite careful monitoring and the standard use of dexrazoxane, was the unexpected cardiac toxicity with the combination with a 35% incidence of grade 2 or worse cardiotoxicity. Two other multitargeted protein tyrosine kinase inhibitors with activity against multiple VEGF isoforms, sunitinib and sorafenib, have also been evaluated in U-LMS with disappointing results as neither has met prespecified criteria to warrant further clinical development [69, 70]. Currently, an ongoing EORTC randomized double-blind phase II study (ClinicalTrials.