Phase I and pharmacokinetic study of the new taxane analog BMS-184476 given weekly in patients with advanced malignancies.
OBJECTIVE
The study was designed to establish the maximum administered dose and maximum tolerated dose (MTD) of BMS-184476, an analogue of paclitaxel, given weekly for 3 consecutive weeks every 28 days, later amended to a regimen of weekly administration for 2 consecutive weeks every 21 days.


METHODS
Adult patients with solid tumors received BMS-184476 i.v. on days 1, 8, and 15 without premedication. The trial followed a modified accelerated titration design. Doses of 7, 14, 28, 40, 50, and 60 mg/m(2)/wk were investigated. Pharmacokinetics of BMS-184476 in plasma and urine were investigated by high-performance liquid chromatography assay.


RESULTS
Fifty-three patients were treated; the maximum administered dose was 60 mg/m(2)/wk, and the MTD was 50 mg/m(2)/wk. Dose-limiting neutropenia was the main toxicity. Neutropenia at the higher dose levels frequently prevented administration of the day 15 dose, and a modified schedule at MTD dosing on days 1 and 8 every 21 days was evaluated and found more feasible for Phase II studies. Diarrhea was the main nonhematological toxicity; other toxicities were vomiting, cumulative fatigue, and loss of appetite. Two patients died of neutropenia-related complications. Antitumor activity was observed in patients with breast and non-small cell lung cancer, with confirmed partial responses in 22% of patients. BMS-184476 was the main species found in the plasma with <5% present as paclitaxel or sulfoxide metabolites. The PKs of BMS-184476 appeared to be linear in the dose range of 7-60 mg/m(2).


CONCLUSIONS
The recommended dose and schedule of weekly BMS-184476 is 50 mg/m(2) on days 1 and 8 every 21 days.
Plummer
Ruth
R
Northern Centre for Cancer Treatment, Newcastle Upon Tyne, United Kingdom NE4 6BE.
Ghielmini
Michele
M
Calvert
Paula
P
Voi
Maurizio
M
Renard
Josette
J
Gallant
Gilles
G
Gupta
Elora
E
Calvert
Hilary
H
Sessa
Cristiana
C
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D012074:Remission Induction; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; C426424:7-methylthiomethylpaclitaxel; D017239:Paclitaxel