title: A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors: a Children's Oncology Group study.
abstract: OBJECTIVE
  To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG).
  
  
  METHODS
  17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m(2)/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy.
  
  
  RESULTS
  Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C(max) and areas under the plasma concentration-time curves of 17-AAG were 5,303 +/- 1,591 ng/mL and 13,656 +/- 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 +/- 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m(2) dose level.
  
  
  CONCLUSIONS
  Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families.
authors.affiliation: University of Minnesota Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA. weige007@umn.edu
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.forename: Rochelle
authors.initials: R
authors.lastname: Bagatell
authors.forename: John
authors.initials: J
authors.lastname: Kersey
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Neglia
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Matthew
authors.initials: M
authors.lastname: Ames
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010372:Pediatrics; D012008:Recurrence; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; C515136:17-aminogeldanamycin