title: Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial.
abstract: 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
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Comprehensive Cancer Center Vienna - MusculoSkeletal Tumors, Medical University Vienna - General Hospital, Vienna, Austria. thomas.brodowicz@meduniwien.ac.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brodowicz
authors.affiliation: Comprehensive Cancer Center Graz - Subunit Sarcoma, Institute of Pathology, Medical University Graz, Graz, Austria. bernadette.liegl-atzwanger@medunigraz.at.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl-Atzwager
authors.affiliation: Biostatistics Unit, Centre Oscar Lambret, Lille, France. e-tresch@o-lambret.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tresch
authors.affiliation: Medical Imaging, Centre Oscar Lambret, Lille, France. s-taieb@o-lambret.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Taieb
authors.affiliation: Biostatistics Unit, Centre Oscar Lambret, Lille, France. a-kramar@o-lambret.fr.|SIRIC OncoLille, Lille, France. a-kramar@o-lambret.fr.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kramar
authors.affiliation: Medizinische Hochschule Hannover, Hannover, Germany. Gruenwald.Viktor@mh-hannover.de.
authors.forename: Viktor
authors.initials: V
authors.lastname: Gruenwald
authors.affiliation: Clinical Reserch Unit, Centre Oscar Lambret, Lille, France. m-vanseymortier@o-lambret.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: Vanseymortier
authors.affiliation: SIRIC OncoLille, Lille, France. s-clisant@o-lambret.fr.|Clinical Reserch Unit, Centre Oscar Lambret, Lille, France. s-clisant@o-lambret.fr.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Clisant
authors.affiliation: Medical Oncology, Centre Léon Bérard, Lyon, France. jean-yves.blay@lyon.unicancer.fr.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Medical Oncology, Gustave Roussy, Villejuif, France. Axel.LECESNE@gustaveroussy.fr.
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.affiliation: SIRIC OncoLille, Lille, France. n-penel@o-lambret.fr.|Medical Oncology, Centre Oscar Lambret, Lille, France. n-penel@o-lambret.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Penel
mesh_terms: D001317:Austria / Q000453:epidemiology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D012509:Sarcoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib