title: A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma.
abstract: BACKGROUND
  This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
  
  
  METHODS
  Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo-sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab-sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review. Key secondary end points included progression-free survival, overall survival, and objective response.
  
  
  RESULTS
  In total, 101 patients were randomized (placebo-sorafenib arm: N = 51; mapatumumab-sorafenib arm: N = 50). There was no significant difference in median TTP between both arms [5.6 versus 4.1 months, respectively; adjusted hazard ratio (one-sided 90% confidence interval) 1.192 (0-1.737)]. No mapatumumab-related benefit was identified when TTP was evaluated in the stratified subgroups. The addition of mapatumumab to sorafenib did not demonstrate improvement in the secondary efficacy end points. The reported frequency of adverse events (AEs) and serious AEs was comparable in both treatment arms.
  
  
  CONCLUSIONS
  The addition of mapatumumab to sorafenib did not improve TTP or other efficacy end points, nor did it substantially change the toxicity profile of sorafenib in patients with advanced HCC. Based on these results, further development of the combination of mapatumumab and sorafenib in HCC is not planned.
authors.affiliation: Department of Medical Oncology, Prof. Dr Ion Chiricuţă Institute of Oncology and UMF Iuliu Hatieganu, Cluj Napoca, Romania tudor@iocn.ro.
authors.forename: T
authors.initials: T
authors.lastname: Ciuleanu
authors.affiliation: Federal State Budgetary Institution, Russian Oncology Research Center n.a. N.N. Blokhin under the Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: I
authors.initials: I
authors.lastname: Bazin
authors.affiliation: SC Oncolab SRL, Dolj County.
authors.forename: D
authors.initials: D
authors.lastname: Lungulescu
authors.affiliation: Iasi Regional Institute for Oncology, Iasi County, Romania.
authors.forename: L
authors.initials: L
authors.lastname: Miron
authors.affiliation: Department of Oncology and Medical Radiology, Dnipropetrovsk Medical Academy, City Multispeciality Clinical Hospital # 4, Dnipropetrovsk, Ukraine.
authors.forename: I
authors.initials: I
authors.lastname: Bondarenko
authors.affiliation: Department of Oncology and Hematology, CSK MSW, Warsaw Department of Cancer Prevention, WNOZ WUM, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Deptala
authors.affiliation: Fundacion de Investigacion, San Juan, Puerto Rico.
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.affiliation: Department of Hematology-Oncology, Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
authors.forename: B
authors.initials: B
authors.lastname: Giantonio
authors.affiliation: Clinical Development, Human Genome Sciences, Inc., Rockville.
authors.forename: N L
authors.initials: NL
authors.lastname: Fox
authors.affiliation: Clinical Development, GlaxoSmithKline, Upper Providence, USA.
authors.forename: P
authors.initials: P
authors.lastname: Wissel
authors.affiliation: Clinical Development, GlaxoSmithKline, Stockley Park, UK.
authors.forename: J
authors.initials: J
authors.lastname: Egger
authors.affiliation: Statistics, GlaxoSmithKline, Upper Providence.
authors.forename: M
authors.initials: M
authors.lastname: Ding
authors.affiliation: Clinical Development, Human Genome Sciences, Inc., Rockville.
authors.forename: R N
authors.initials: RN
authors.lastname: Kalyani
authors.affiliation: Oncology Research.
authors.forename: R
authors.initials: R
authors.lastname: Humphreys
authors.affiliation: Statistics, Human Genome Sciences, Inc., Rockville, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gribbin
authors.affiliation: Department of Hematology-Oncology, Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
authors.forename: W
authors.initials: W
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; C507357:mapatumumab
keywords: hepatocellular carcinoma; mapatumumab; progression-free survival; sorafenib