A phase I safety and pharmacologic study of a twice weekly dosing regimen of the oral taxane BMS-275183.
OBJECTIVE
BMS-275183, an orally administered C-4 methyl carbonate paclitaxel analogue, showed promising activity in a phase I trial investigating a weekly treatment regimen, but was associated with a relatively high incidence of neuropathic side effects. The current dose escalation phase I trial was initiated to investigate whether twice weekly administration of BMS-275183 would improve its safety and tolerability. Additionally, the pharmacokinetics and possible antitumor activity were studied.


METHODS
A cycle consisted of 4 weeks (i.e., eight twice weekly oral doses). The starting dose was 60 mg/m(2) and the dose was increased by 20 mg/m(2) increments. Cohorts consisted of three patients and were expanded to at least six patients when toxicity was encountered. Plasma pharmacokinetics were done on days 1 and 15.


RESULTS
A total of 38 patients were enrolled. The maximum tolerated dose was 100 mg/m(2) twice weekly. Seventeen patients were treated at the maximum tolerated dose; 3 of 17 patients experienced a dose-limiting toxicity, consisting of a combination of neutropenia, neuropathy, and diarrhea. BMS-275183 seemed to have a considerably lower incidence of neuropathic side effects compared with the weekly treatment regimen. Confirmed partial responses were observed in two patients with non-small cell lung cancer, one patient with prostate cancer, and one patient with melanoma. In addition, a long-lasting prostate-specific antigen response was observed in a patient with prostate carcinoma with nonmeasurable disease.


CONCLUSIONS
BMS-275183 is preferably given in a twice weekly regimen and has considerable antitumor activity. A phase II trial in non-small cell lung cancer using the twice weekly schedule has been initiated.
Bröker
Linda E
LE
VU University Medical Center, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Veltkamp
Stephan A
SA
Heath
Elisabeth I
EI
Kuenen
Bart C
BC
Gall
Helen
H
Astier
Ludovic
L
Parker
Susan
S
Kayitalire
Louis
L
Lorusso
Patricia M
PM
Schellens
Jan H M
JH
Giaccone
Giuseppe
G
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D019540:Area Under Curve; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000737:chemistry / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C437188:BMS-275183; D001952:Bridged-Ring Compounds; D043823:Taxoids