Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.
OBJECTIVE
To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474.


RESULTS
Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively.


CONCLUSIONS
The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.
Hidalgo
M
M
Institute for Drug Development, Cancer Therapy and Research Center and University of Texas Health Science Center at San Antonio, 78229, USA. manuelh@oncology.uthscsa.edu
Aylesworth
C
C
Hammond
L A
LA
Britten
C D
CD
Weiss
G
G
Stephenson
J
J
Schwartz
G
G
Patnaik
A
A
Smith
L
L
Molpus
K
K
Felton
S
S
Gupta
E
E
Ferrante
K J
KJ
Tortora
A
A
Sonnichsen
D S
DS
Skillings
J
J
Rowinsky
E K
EK
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives; D012995:Solubility; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; C426424:7-methylthiomethylpaclitaxel; D017239:Paclitaxel