title: A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma.
abstract: OBJECTIVE
  A Phase II study to screen for anti-melanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG.
  
  
  METHODS
  Patients with metastatic melanoma (progressive disease documented ≤6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of ≥25% at 6 months was considered compatible with 17-AAG having activity.
  
  
  RESULTS
  Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (performance status 0 or 1). Median age was 60 (range 29-81) years. The majority (93%) received prior chemotherapy and had stage M1c disease (71%). Toxicity was rarely ≥ Grade 2 in severity and commonly included fatigue, headache and gastrointestinal disturbances. One of eleven patients treated with 17-AAG had stable disease for 6 months and median survival for all patients was 173 days. The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses.
  
  
  CONCLUSIONS
  Some evidence of 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.forename: David
authors.initials: D
authors.lastname: Chao
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Sarah
authors.initials: S
authors.lastname: Sarker
authors.forename: Karen
authors.initials: K
authors.lastname: Owen
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Asad
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Mike
authors.initials: M
authors.lastname: Walton
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D004739:England; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin