title: A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma.
abstract: BACKGROUND
  Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range.
  
  
  METHODS
  A phase 2 study of rhIL-18 was conducted in untreated AJCC stage IV melanoma. Patients were randomized to 1 of 3 dose groups (0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily intravenous infusions repeated every 28 days. A 2-stage design with a stopping rule was used.
  
  
  RESULTS
  A total of 64 patients (median age, 57.5 years) with metastatic melanoma (M1a/b (30), M1c (34)) were accrued to stage I, and randomized to 3 groups (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Five patients experienced 10 grade 3 drug-related adverse events (AEs): polyarthritis (1 subject: 0.01 mg/kg); deep vein thrombosis, pulmonary embolism (1:0.01 mg/kg); cognitive disorder (1:0.1 mg/kg); fatigue, dyspnea, pleural effusion, lymphopenia (1:1.0 mg/kg); fatigue, lymphopenia (1:1.0 mg/kg). One patient experienced a grade 4 AE of increased lipase (0.1 mg/kg) that led to permanent discontinuation from the study. Among 63 subjects evaluable for response, 1 (M1c; 0.01 mg/kg) achieved a partial response after 4 cycles. Four subjects (3 at 0.01 mg/kg and 1 at 1.0 mg/kg) had stable disease maintained for 6 months or longer. Due to the low apparent level of clinical efficacy using RECIST criteria, the study was terminated at the end of stage 1. The median progression free survival for the 3 groups was 7.5 (0.01), 7.4 (0.1), and 7.3 (1.0) weeks.
  
  
  CONCLUSIONS
  rIL-18 as tested in this trial was well tolerated, but had limited activity as a single agent in patients with metastatic melanoma.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213-2584, USA.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Tarhini
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.forename: Paul
authors.initials: P
authors.lastname: Mainwaring
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.forename: Ted
authors.initials: T
authors.lastname: Logan
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kathman
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Laubscher
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Dar
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020382:Interleukin-18 / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009367:Neoplasm Staging; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D020382:Interleukin-18; D011994:Recombinant Proteins