title: A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas.
abstract: OBJECTIVE
  Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS).
  
  
  METHODS
  IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging.
  
  
  RESULTS
  Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST.
  
  
  CONCLUSIONS
  In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.
authors.affiliation: Authors' Affiliations: Dana-Farber Cancer Institute and Harvard Medical School; Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts; University of Michigan, Ann Arbor, Michigan; UCLA Division of Hematology-Oncology, Santa Monica, California; Pinnacle Oncology, Scottsdale, Arizona; and Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Morgan
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.forename: Michael
authors.initials: M
authors.lastname: Gordon
authors.forename: Joi
authors.initials: J
authors.lastname: Dunbar
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.forename: David
authors.initials: D
authors.lastname: Grayzel
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000401:mortality; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; C112765:tanespimycin
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