title: Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.
abstract: OBJECTIVE
  Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer.
  
  
  METHODS
  17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable.
  
  
  CONCLUSIONS
  Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. kummars@mail.nih.gov
authors: Shivaani
authors: S
authors: Kummar
authors: Martin E
authors: ME
authors: Gutierrez
authors: Erin R
authors: ER
authors: Gardner
authors: Xiaohong
authors: X
authors: Chen
authors: William D
authors: WD
authors: Figg
authors: Maria
authors: M
authors: Zajac-Kaye
authors: Min
authors: M
authors: Chen
authors: Seth M
authors: SM
authors: Steinberg
authors: Christine A
authors: CA
authors: Muir
authors: Mary Ann
authors: MA
authors: Yancey
authors: Yvonne R
authors: YR
authors: Horneffer
authors: Lamin
authors: L
authors: Juwara
authors: Giovanni
authors: G
authors: Melillo
authors: S Percy
authors: SP
authors: Ivy
authors: Maria
authors: M
authors: Merino
authors: Len
authors: L
authors: Neckers
authors: Patricia S
authors: PS
authors: Steeg
authors: Barbara A
authors: BA
authors: Conley
authors: Giuseppe
authors: G
authors: Giaccone
authors: James H
authors: JH
authors: Doroshow
authors: Anthony J
authors: AJ
authors: Murgo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin