Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel, Taxoprexin, in resistant solid tumor malignancies.
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.
Fracasso
Paula M
PM
Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA. fracasso@virginia.edu
Picus
Joel
J
Wildi
Jonathan D
JD
Goodner
Sherry A
SA
Creekmore
Allison N
AN
Gao
Feng
F
Govindan
Ramaswamy
R
Ellis
Matthew J
MJ
Tan
Benjamin R
BR
Linette
Gerald P
GP
Fu
ChauHwei J
CJ
Pentikis
Helen S
HS
Zumbrun
Stephen C
SC
Egorin
Merrill J
MJ
Bellet
Robert E
RE
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
D004281:Docosahexaenoic Acids; D017239:Paclitaxel