title: Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel, Taxoprexin, in resistant solid tumor malignancies.
abstract: OBJECTIVE
  To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly docosahexaenoic acid-paclitaxel (DHA-paclitaxel), a taxane fatty acid conjugate.
  
  
  METHODS
  Docosahexaenoic acid-paclitaxel was administered by 2-hour i.v. infusion weekly for three out of four weeks. DHA-paclitaxel 200 mg/m(2) was dose escalated by 100 mg/m(2) per cohort to 600 mg/m(2). Blood samples for pharmacokinetics of DHA-paclitaxel and paclitaxel derived from DHA-paclitaxel were collected.
  
  
  RESULTS
  Twenty-one patients received 42 cycles of treatment over five dose levels. Grade 3/4 neutropenia occurred in five patients but was not dose limiting. Grade 3 hyperbilirubinemia, a DLT, and grade 1 sensory neuropathy occurred at the highest dose level. PK analyses demonstrated dose proportional C (max) and AUC(0-24). Limited accumulation of DHA-paclitaxel or paclitaxel occurred with weekly treatment. Increased DHA-paclitaxel and paclitaxel AUC(0-24) were associated with increased neutropenia. Of the 19 patients evaluable for response, three patients with esophageal, melanoma and colon carcinoma had stable disease for 11, 16, and 17 weeks, respectively.
  
  
  CONCLUSIONS
  Docosahexaenoic acid-paclitaxel administered weekly to a maximum dose of 600 mg/m(2) was well-tolerated. The slow release of paclitaxel from DHA-paclitaxel and the weekly schedule approximates continuous infusion paclitaxel which may be more active than every 3 week or weekly taxanes.
authors.affiliation: Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA. fracasso@virginia.edu
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wildi
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Goodner
authors.forename: Allison N
authors.initials: AN
authors.lastname: Creekmore
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Tan
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Linette
authors.forename: ChauHwei J
authors.initials: CJ
authors.lastname: Fu
authors.forename: Helen S
authors.initials: HS
authors.lastname: Pentikis
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Zumbrun
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Robert E
authors.initials: RE
authors.lastname: Bellet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D004281:Docosahexaenoic Acids / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D004281:Docosahexaenoic Acids; D017239:Paclitaxel