title: Preoperative therapy with pazopanib in high-risk soft tissue sarcoma: a phase II window-of-opportunity study by the German Interdisciplinary Sarcoma Group (GISG-04/NOPASS).
abstract: BACKGROUND
  For resectable soft tissue sarcoma (STS), radical surgery, usually combined with radiotherapy, is the mainstay of treatment and the only potentially curative modality. Since surgery is often complicated by large tumour size and extensive tumour vasculature, preoperative treatment strategies with the aim of devitalising the tumour are being explored. One option is treatment with antiangiogenic drugs. The multikinase inhibitor pazopanib, which possesses pronounced antiangiogenic effects, has shown activity in metastatic and unresectable STS, but has so far not been tested in the preoperative setting.
  
  
  METHODS
  This open-label, multicentre phase II window-of-opportunity trial assesses pazopanib as preoperative treatment of resectable STS. Participants receive a 21-day course of pazopanib 800 mg daily during wait time for surgery. Major eligibility criteria are resectable, high-risk adult STS of any location, or metachronous solitary STS metastasis for which resection is planned, and adequate organ function and performance status. The trial uses an exact single-stage design. The primary end point is metabolic response rate (MRR), that is, the proportion of patients with >50% reduction of the mean standardised uptake value (SUVmean) in post-treatment compared to pre-treatment fluorodeoxyglucose positron emission tomography CT. The MRR below which the treatment is considered ineffective is 0.2. The MRR above which the treatment warrants further exploration is 0.4. With a type I error of 5% and a power of 80%, the sample size is 35 evaluable patients, with 12 or more responders as threshold. Main secondary end points are histopathological and MRI response, resectability, toxicity, recurrence-free and overall survival. In a translational substudy, endothelial progenitor cells and vascular epithelial growth factor receptor are analysed as potential prognostic and predictive markers.
  
  
  BACKGROUND
  Approval by the ethics committee II, University of Heidelberg, Germany (2012-019F-MA), German Federal Institute for Drugs and Medical Devices (61-3910-4038155) and German Federal Institute for Radiation Protection (Z5-22463/2-2012-007).
  
  
  BACKGROUND
  NCT01543802, EudraCT: 2011-003745-18; Pre-results.
authors.affiliation: Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ronellenfitsch
authors.affiliation: Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Dimitrakopoulou-Strauss
authors.affiliation: Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Jakob
authors.affiliation: Medical Faculty Mannheim, Interdisciplinary Tumor Center, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kasper
authors.affiliation: Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Nowak
authors.affiliation: Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Lothar R
authors.initials: LR
authors.lastname: Pilz
authors.affiliation: Medical Faculty Mannheim, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Attenberger
authors.affiliation: Medical Faculty Mannheim, Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Gaiser
authors.affiliation: Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Egerer
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.affiliation: Department of Hematology and Oncology, Klinikum Frankfurt-Höchst, Frankfurt am Main, Germany.
authors.forename: Hans-Günter
authors.initials: HG
authors.lastname: Derigs
authors.affiliation: Department of Surgery, Klinikum Frankfurt-Höchst, Frankfurt am Main, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwarzbach
authors.affiliation: Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenberger
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D066026:Endothelial Progenitor Cells / Q000378:metabolism; D005858:Germany; D006801:Humans; D007191:Indazoles; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000097:blood; D012306:Risk; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000601:surgery; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Clinical trials < THERAPEUTICS; NUCLEAR MEDICINE; Sarcoma < ONCOLOGY; Surgical pathology < PATHOLOGY; VASCULAR MEDICINE