title: Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies.
abstract: BACKGROUND
  KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor.
  
  
  METHODS
  In this phase I, multicentre study, KW-2478 was administered intravenously over 1 h at doses ranging from 14 to 176 mg m(-2) once daily on days 1-5 of a 14-day cycle in a standard 3+3 design in 27 patients (22 with multiple myeloma and 5 with non-Hodgkin lymphoma). Patients enrolled had relapsed/refractory disease previously treated with ⩾2 regimens.
  
  
  RESULTS
  There were no dose-limiting toxicities, thus the maximum-tolerated dose was not reached. KW-2478 was well tolerated and did not manifest significant retinal or ocular toxicity. The most common treatment-related adverse events were diarrhoea (33.3%), fatigue (29.6%), headache (25.9%), hypertension (22.2%), nausea (14.8%), vomiting (7.4%), and dizziness (7.4%). Plasma concentrations peaked at the end of infusion and decayed in a biphasic manner with a terminal half-life of ∼6 h. Target inhibition was inferred from the increase in Hsp70 levels in peripheral blood mononuclear cells at doses ⩾71 mg m(-2). Twenty-four of 25 (96%) evaluable patients showed stable disease, with five being free of disease progression for ⩾6 months.
  
  
  CONCLUSIONS
  Preliminary clinical response data were encouraging and warrant further investigation of KW-2478 in combination regimens for relapsed/refractory B-cell malignancies.
authors.affiliation: UCL Cancer Institute, University College London, Huntley Street, London WC1E 6DD, UK.
authors.forename: K
authors.initials: K
authors.lastname: Yong
authors.affiliation: Department of Haematology, Christie Hospital/University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: J
authors.initials: J
authors.lastname: Cavet
authors.affiliation: Cancer Research UK Clinical Centre, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: P
authors.initials: P
authors.lastname: Johnson
authors.affiliation: Myeloma Institute for Research and Therapy, West Markham Street, Little Rock, AR 72205, USA.
authors.forename: G
authors.initials: G
authors.lastname: Morgan
authors.affiliation: Centre for Clinical Haematology, Nottingham University Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: C
authors.initials: C
authors.lastname: Williams
authors.affiliation: Kyowa Hakko Kirin Pharma Inc., Princeton, NJ, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nakashima
authors.affiliation: Kyowa Hakko Kirin Co. Ltd, Tokyo Research Triangle Park, Tokyo 194-8533, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Akinaga
authors.affiliation: Department of Haematology, St. Bartholomew's Hospital, West Smithfield, London SE24 9LG, UK.
authors.forename: H
authors.initials: H
authors.lastname: Oakervee
authors.affiliation: Department of Haematology, St. Bartholomew's Hospital, West Smithfield, London SE24 9LG, UK.
authors.forename: J
authors.initials: J
authors.lastname: Cavenagh
mesh_terms: D000368:Aged; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D009101:Multiple Myeloma / Q000188:drug therapy*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C551428:KW-2478; D009025:Morpholines