title: Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial.
abstract: BACKGROUND
  Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment.
  
  
  METHODS
  We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500.
  
  
  RESULTS
  From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment.
  
  
  CONCLUSIONS
  Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria.
  
  
  BACKGROUND
  Onconova Therapeutics, Leukemia & Lymphoma Society.
authors.affiliation: University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA. Electronic address: ggarciam@mdanderson.org.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Hôpital St Louis/Université Paris 7, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Aref
authors.initials: A
authors.lastname: Al-Kali
authors.affiliation: University of Maryland, Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: Leukemia Program, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Scott
authors.affiliation: Stanford Cancer Center, Stanford, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Greenberg
authors.affiliation: Universitätsklinikum Dresden, Medizinische Klinik und Poliklinik I, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.affiliation: University of Kansas Medical Center, Westwood, KS, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Kambhampati
authors.affiliation: Universitätsklinikum zu Köln, Klinik I für Innere Medizin, Köln, Nordhein-Westfalen, Germany.
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
authors.affiliation: University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: Froedtert Hospital and the Medical College of Wisconsin Division of Hematology and Oncology, Milwaukee, WI, USA.
authors.forename: Ehab
authors.initials: E
authors.lastname: Atallah
authors.affiliation: University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Collins
authors.affiliation: University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Onconova Therapeutics, Newtown, PA, USA.
authors.forename: Francois E
authors.initials: FE
authors.lastname: Wilhelm
authors.affiliation: Onconova Therapeutics, Newtown, PA, USA.
authors.forename: Nozar
authors.initials: N
authors.lastname: Azarnia
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Silverman
mesh_terms: D000368:Aged; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D012306:Risk; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D013450:Sulfones; C507134:ON 01910; D000077209:Decitabine; D001374:Azacitidine; D005998:Glycine