title: A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors.
abstract: OBJECTIVE
  A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED).
  
  
  METHODS
  Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤ 1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual.
  
  
  RESULTS
  Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (≥ 20 mg/m(2)) and sustained for 96 hours (≥ 40 mg/m(2)). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m(2) client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively).
  
  
  CONCLUSIONS
  The recommended phase II dose of 17-DMAG is 80 mg/m(2) weekly i.v.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.forename: Richard H
authors.initials: RH
authors.lastname: Wilson
authors.forename: Mike
authors.initials: M
authors.lastname: Walton
authors.forename: Martin M
authors.initials: MM
authors.lastname: Eatock
authors.forename: Anthea
authors.initials: A
authors.lastname: Hardcastle
authors.forename: Anna
authors.initials: A
authors.lastname: Zetterlund
authors.forename: Hendrik-Tobias
authors.initials: HT
authors.lastname: Arkenau
authors.forename: Javier
authors.initials: J
authors.lastname: Moreno-Farre
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.forename: Belle
authors.initials: B
authors.lastname: Roels
authors.forename: Heidi
authors.initials: H
authors.lastname: Peachey
authors.forename: Wynne
authors.initials: W
authors.lastname: Aherne
authors.forename: Johan S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
mesh_terms: D000328:Adult; D000368:Aged; D016227:Benzoquinones / Q000494:pharmacology*; D001706:Biopsy; D015153:Blotting, Western; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin