title: Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.
abstract: OBJECTIVE
  To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules.
  
  
  METHODS
  Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m(2) daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily x 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies.
  
  
  RESULTS
  Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m(2) on the daily x 5 schedule; 112 mg/m(2) on the daily x 3 schedule; and 220 mg/m(2) on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily x 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies.
  
  
  CONCLUSIONS
  The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Catherine
authors.initials: C
authors.lastname: Kopil
authors.forename: Rachel
authors.initials: R
authors.lastname: Sikorski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Susan F
authors.initials: SF
authors.lastname: Slovin
authors.forename: W Kevin
authors.initials: WK
authors.lastname: Kelly
authors.forename: Anthony
authors.initials: A
authors.lastname: DeLaCruz
authors.forename: Tracy
authors.initials: T
authors.lastname: Curley
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Steven
authors.initials: S
authors.lastname: Larson
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schwartz
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D051058:Oncogene Protein v-akt