title: A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies.
abstract: BACKGROUND
  This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies.
  
  
  METHODS
  Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity.
  
  
  RESULTS
  Fifty-three patients were treated at doses escalating from 7 to 259 mg/m(2). The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m(2)), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m(2)). The MTD was 216 mg/m(2) and the recommended phase 2 dose was established at 200 mg/m(2) given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%.
  
  
  CONCLUSIONS
  Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m(2), and is associated with an acceptable tolerability profile.
  
  
  BACKGROUND
  NCT00687934.
authors.affiliation: UCLA Medical Center, Suite 600, 2020 Santa Monica Blvd, Santa Monica, CA 90404, USA. jwgoldman@mednet.ucla.edu
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Goldman
authors.forename: Robert N
authors.initials: RN
authors.lastname: Raju
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gordon
authors.forename: Iman
authors.initials: I
authors.lastname: El-Hariry
authors.forename: Florentina
authors.initials: F
authors.lastname: Teofilivici
authors.forename: Vojo M
authors.initials: VM
authors.lastname: Vukovic
authors.forename: Robert
authors.initials: R
authors.lastname: Bradley
authors.forename: Michael D
authors.initials: MD
authors.lastname: Karol
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Takayo
authors.initials: T
authors.lastname: Inoue
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004334:Drug Administration Schedule; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles