title: Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.
abstract: BACKGROUND
  Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia.
  
  
  METHODS
  This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801.
  
  
  RESULTS
  Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]).
  
  
  CONCLUSIONS
  Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia.
  
  
  BACKGROUND
  Sunesis Pharmaceuticals.
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: fravandi@mdanderson.org.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: Weill Cornell Medical Center, New York, NY, USA.
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Ritchie
authors.affiliation: Indiana University Cancer Center, Indianapolis, IN, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Sayar
authors.affiliation: Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.affiliation: West Virginia University, Morgantown, WV, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Craig
authors.affiliation: Institut Paoli-Calmettes and Aix-Marseille University, Marseille, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Strickland
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schiller
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Division of Hematology and Oncology, University of Alabama, Birmingham, AL, USA.
authors.forename: Harry P
authors.initials: HP
authors.lastname: Erba
authors.affiliation: Université de Bordeaux, CHU de Bordeaux, Bordeaux, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pigneux
authors.affiliation: Medizinische Klinik und Poliklinik, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Heinz-August
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Institut Universitaire du Cancer de Toulouse Oncopole, Université de Toulouse III, CHU de Toulouse, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Klimek
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Weill Cornell Medical Center, New York, NY, USA.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Olatoyosi
authors.initials: O
authors.lastname: Odenike
authors.affiliation: Hôpital Edouard Herriot, Lyon, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.affiliation: Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Violaine
authors.initials: V
authors.lastname: Havelange
authors.affiliation: Universitair Ziekenhuis, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.affiliation: Klinikum Frankfurt Main, Frankfurt, Germany.
authors.forename: Hans-Günter
authors.initials: HG
authors.lastname: Derigs
authors.affiliation: Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Damon
authors.affiliation: Wake Forest University Baptist Medical Center-Comprehensive Cancer Center, Winston-Salem, NC, USA.
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.affiliation: Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Hematology Unit, IRCCS AOU San Martino-IST, Genova, Italy.
authors.forename: Angelo-Michele
authors.initials: AM
authors.lastname: Carella
authors.affiliation: The Alfred Hospital and Monash University, Melbourne, VIC, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wei
authors.affiliation: Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Donna
authors.initials: D
authors.lastname: Hogge
authors.affiliation: Sunesis Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Craig
authors.affiliation: Sunesis Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Fox
authors.affiliation: Sunesis Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Ward
authors.affiliation: Sunesis Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Sunesis Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Acton
authors.affiliation: Cytel, Cambridge, MA, USA; Harvard School of Public Health, Cambridge, MA, USA.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Mehta
authors.affiliation: Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Stuart
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009287:Naphthyridines / Q000008:administration & dosage*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D012074:Remission Induction; D013844:Thiazoles / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D009287:Naphthyridines; D013844:Thiazoles; D003561:Cytarabine; C485113:vosaroxin