title: Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas.
  
  
  METHODS
  We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517.
  
  
  RESULTS
  Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group.
  
  
  CONCLUSIONS
  The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas.
  
  
  BACKGROUND
  Sanofi.
authors: Centre Léon Bérard, Department of Medicine, French Sarcoma Group, European Organisation for Research and Treatment of Cancer, University Claude Bernard Lyon I, Lyon, France. Electronic address: jean-yves.blay@lyon.unicancer.fr.
authors: Jean-Yves
authors: JY
authors: Blay
authors: State Medical Centre, Budapest, Hungary.
authors: Zsuzsanna
authors: Z
authors: Pápai
authors: South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA.
authors: Anthony W
authors: AW
authors: Tolcher
authors: Institut Bergonié, Bordeaux, France.
authors: Antoine
authors: A
authors: Italiano
authors: Centre Val d'Aurelle, Montpellier, France.
authors: Didier
authors: D
authors: Cupissol
authors: Hospital de la Santa Creu i Sant Pau and Networking Research Center, Barcelona, Spain.
authors: Antonio
authors: A
authors: López-Pousa
authors: St John's Hospital, Santa Monica, CA, USA.
authors: Sant P
authors: SP
authors: Chawla
authors: Centre René Gauducheau, Nantes, France.
authors: Emmanuelle
authors: E
authors: Bompas
authors: Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.
authors: Nada
authors: N
authors: Babovic
authors: Centre Oscar Lambret, Lille, France.
authors: Nicolas
authors: N
authors: Penel
authors: Centre Georges François Leclerc, Dijon, France.
authors: Nicolas
authors: N
authors: Isambert
authors: University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Arthur P
authors: AP
authors: Staddon
authors: Centre Antoine Lacassagne, Nice, France.
authors: Esma
authors: E
authors: Saâda-Bouzid
authors: Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Milan, Italy.
authors: Armando
authors: A
authors: Santoro
authors: CACON-Hospital de Caridade de Ijui, Ijui, Brazil.
authors: Fabio A
authors: FA
authors: Franke
authors: Sanofi, Vitry-sur-Seine, France.
authors: Patrick
authors: P
authors: Cohen
authors: Sanofi, Vitry-sur-Seine, France.
authors: Solenn
authors: S
authors: Le-Guennec
authors: Dana-Farber Cancer Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
authors: George D
authors: GD
authors: Demetri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D012694:Serine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D012694:Serine; C400245:AC 7700; D002945:Cisplatin; D007069:Ifosfamide