Background: Angiogenesis plays a key role in sarcoma biology. RE, targeting VEGFR-2 and -3, and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf), has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial [Demetri, Lancet 2013]. Furthermore, the Palette trial has shown that pazopanib, another anti-angiogenic agent, significantly improved the PFS without OS advantage in anthracycline-refractory STS [Van Der Graaf, Lancet 2012]. Methods: We are conducting a multinational (France, Austria and Germany) double-blind placebo-controlled randomized (1/1) phase II trial to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Key eligibility criteria are: measurable disease, age ≥18, less than 4 previous lines of CT, metastatic disease not amenable to surgical resection. Applied stratification criteria are: histological types (liposarcoma, leiomyosarcoma, synovial s., and others), countries and previous use of pazopanib. The primary endpoint is PFS according to central radiological review. Each stratum defined by histology will be separately analyzed. Statistical assumptions are: PFS0=1.6 and PFS1=4.6 months; 1-sided α=0.1; β=0.05 with a total sample size of 192 pts. Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional cross-over is proposed. Secondary endpoints are: toxicity (NCI-CTC AE V4.0); TTP; growth modulation index in pts receiving RE after randomization (GMI=TTP with RE/TTP with the prior treatment), 3 and 6 months PFS-Rates, best RR, OS. The exploratory translational research program will further characterize the nature of the genetic change by exploring the mutational status of the tumor samples using the Ion AmpliSeq Cancer Panel. In addition tissue-micro arrays (TMA) from FFPE material will be generated to allow a large-scale evaluation of molecular aberrations and downstream effects on pathway activation. The study is enrolling since June 2013. Clinical trial information: ClinicalTrials.gov: NCT01900743.