title: Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.
abstract: BACKGROUND
  Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma.
  
  
  METHODS
  We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640.
  
  
  RESULTS
  The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group).
  
  
  CONCLUSIONS
  Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. wolchokj@mskcc.org
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.forename: Gerald
authors.initials: G
authors.lastname: Linette
authors.forename: Sylvie
authors.initials: S
authors.lastname: Negrier
authors.forename: Jose
authors.initials: J
authors.lastname: Lutzky
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.forename: William
authors.initials: W
authors.lastname: Waterfield
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Michael
authors.initials: M
authors.lastname: Smylie
authors.forename: Troy
authors.initials: T
authors.lastname: Guthrie
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
authors.forename: Kevin
authors.initials: K
authors.lastname: Chin
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.forename: Axel
authors.initials: A
authors.lastname: Hoos
authors.forename: Steven J
authors.initials: SJ
authors.lastname: O'Day
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbé
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab