title: Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.
abstract: BACKGROUND
  Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival.
  
  
  METHODS
  This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov, number NCT00128102.
  
  
  RESULTS
  From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7-36·1) versus 27·1 weeks (23·1-31·9) for placebo (hazard ratio 0·98, 95% CI 0·83-1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 [16%] patients in the vorinostat group vs 25 [8%] in the placebo group]) and dyspnoea (35 [11%] vs 45 [14%]).
  
  
  CONCLUSIONS
  In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma.
  
  
  BACKGROUND
  Merck & Co.
authors: Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. Electronic address: krugl@mskcc.org.
authors: Lee M
authors: LM
authors: Krug
authors: University of Chicago, Chicago, IL, USA.
authors: Hedy L
authors: HL
authors: Kindler
authors: University College London Cancer Institute, London, UK.
authors: Hilary
authors: H
authors: Calvert
authors: Heidelberg University Medical Center, Mannheim, Germany.
authors: Christian
authors: C
authors: Manegold
authors: MD Anderson Cancer Center, Houston, TX, USA.
authors: Anne S
authors: AS
authors: Tsao
authors: University of Leicester, Leicester, UK.
authors: Dean
authors: D
authors: Fennell
authors: University Hospital of Skåne/Lund, Lund, Sweden.
authors: Ronny
authors: R
authors: Öhman
authors: Newcastle University, Newcastle upon Tyne, UK.
authors: Ruth
authors: R
authors: Plummer
authors: University Hospital Essen, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany.
authors: Wilfried E E
authors: WE
authors: Eberhardt
authors: Kinki University Faculty of Medicine, Osaka, Japan.
authors: Kazuya
authors: K
authors: Fukuoka
authors: National Cancer Institute, Cairo University, Cairo, Egypt.
authors: Rabab M
authors: RM
authors: Gaafar
authors: Centre Hospitalier Regional Universitaire de Lille, Lille, France.
authors: Jean-Jacques
authors: JJ
authors: Lafitte
authors: Karolinska Hospital, Stockholm, Sweden.
authors: Gunnar
authors: G
authors: Hillerdal
authors: Cross Cancer Institute/University of Alberta, Edmonton, Alberta, Canada.
authors: Quincy
authors: Q
authors: Chu
authors: Netherlands Cancer Institute and the Academic Medical Center, Amsterdam, Netherlands.
authors: Wieneke A
authors: WA
authors: Buikhuisen
authors: Merck & Co, Kenilworth, NJ, USA.
authors: Gregory M
authors: GM
authors: Lubiniecki
authors: Merck & Co, Kenilworth, NJ, USA; Sanofi US, Sanofi, Bridgewater, NJ, USA.
authors: Xing
authors: X
authors: Sun
authors: Merck & Co, Kenilworth, NJ, USA.
authors: Margaret
authors: M
authors: Smith
authors: Cross Cancer Institute/University of Alberta, Edmonton, Alberta, Canada; The Academic Medical Center, Amsterdam, Netherlands.
authors: Paul
authors: P
authors: Baas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D010919:Placebos; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D010919:Placebos; D000077337:Vorinostat