BACKGROUND: Angiogenesis, among other signaling pathways, plays a key-role in 
sarcoma biology. Regorafenib (RE) has recently been shown to be effective in 
imatinib and sunitinib-refractory GIST in a phase III trial.
METHODS/DESIGN: We are conducting an international trial (France, Austria and 
Germany) consisting in 4 parallel double-blind placebo-controlled randomized 
(1/1) phase II trials to assess the activity and safety of RE in 
doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II 
trial is dedicated to one of the 4 following histological subgroups: 
liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each 
randomized trial the following stratification factors will be applied: countries 
and prior exposure to pazopanib. Key-eligibility criteria are: measurable 
disease, age ≥18, not > 3 previous systemic treatment lines for metastatic 
disease, metastatic disease not amenable to surgical resection. The primary 
endpoint is progression-free survival (PFS) according to central radiological 
review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to 
progression; Growth modulation index in pts receiving RE after randomization; 3 
and 6 months PFS-Rates, best response rate and overall survival. Each phase II 
trial will be separately analyzed. In 3 trials, statistical assumptions are: 
PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; β = 0.05 with a total sample 
size of 192 pts. To take into account the rarity of synovial sarcoma, the 
statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; 
β = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 
months thereafter. After central radiological confirmation of tumor progression, 
an optional open-label option is offered to eligible patients.
DISCUSSION: The design of this trial allows an assessment of regorafenib 
activity over placebo in four sarcoma strata and might provide evidence for 
launching a phase III trial. This study includes both integrative and 
exploratory translational research program. The study is enrolling since June 
2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) 
February 2012).