title: Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors.
abstract: OBJECTIVE
  To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks.
  
  
  METHODS
  Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m(2)) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells.
  
  
  RESULTS
  Toxicity was acceptable at doses up to 28 mg/m(2). The cohort was expanded to three patients at 40 mg/m(2) because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m(2) had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m(2); none had dose-limiting toxicity. The maximum plasma concentrations (C(max)) of 17-AAG at 40 and 56 mg/m(2) were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours.ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with >/= 14 mg/m(2) and decreased protein content of either Lck or Raf1 with >/= 28 mg/m(2) of 17-AAG.
  
  
  CONCLUSIONS
  17-AAG 40 mg/m(2) (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.
authors.affiliation: Nebraska Medical Center, Omaha, NE 68198-7680, USA. jgrem@unmc.edu
authors.forename: Jean L
authors.initials: JL
authors.lastname: Grem
authors.forename: Geraldine
authors.initials: G
authors.lastname: Morrison
authors.forename: Xiao-Du
authors.initials: XD
authors.lastname: Guo
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Agnew
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Rebecca
authors.initials: R
authors.lastname: Thomas
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.forename: Louise
authors.initials: L
authors.lastname: Grochow
authors.forename: Frank
authors.initials: F
authors.lastname: Grollman
authors.forename: J Michael
authors.initials: JM
authors.lastname: Hamilton
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Richard H
authors.initials: RH
authors.lastname: Wilson
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016227:Benzoquinones; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017828:Rifabutin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin