title: Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies.
abstract: OBJECTIVE
  To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials.
  
  
  METHODS
  This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated.
  
  
  RESULTS
  The highest dose level reached was 450 mg/m(2)/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m(2)/week and two at 450 mg/m(2)/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m(2)/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r(2) = .71) over the dose range 10 to 450 mg/m(2)/week, with peak plasma concentrations of 8,998 mug/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m(2)/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment.
  
  
  CONCLUSIONS
  It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m(2)/week. We recommend this dose for phase II clinical trials.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, Surrey SM2 5NG, UK.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.forename: Anne
authors.initials: A
authors.lastname: O'Donnell
authors.forename: Michelle
authors.initials: M
authors.lastname: Scurr
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.forename: Sarah
authors.initials: S
authors.lastname: Stapleton
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Asad
authors.forename: Laura
authors.initials: L
authors.lastname: Simmons
authors.forename: Alison
authors.initials: A
authors.lastname: Maloney
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Maeli
authors.initials: M
authors.lastname: Campbell
authors.forename: Michael
authors.initials: M
authors.lastname: Walton
authors.forename: Sunil
authors.initials: S
authors.lastname: Lakhani
authors.forename: Stanley
authors.initials: S
authors.lastname: Kaye
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; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin