Phase I and pharmacokinetic study of the new taxane analog BMS-184476 given weekly in patients with advanced malignancies.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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).

CONCLUSION:

The recommended dose and schedule of weekly BMS-184476 is 50 mg/m(2) on days 1 and 8 every 21 days.

• Authors: Ruth Plummer, Michele Ghielmini, Paula Calvert, Maurizio Voi, Josette Renard, Gilles Gallant, Elora Gupta, Hilary Calvert, Cristiana Sessa
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 8 Issue 9 Pg. 2788-97 (Sep 2002) ISSN: 1078-0432 [Print] United States
• PMID: 12231518 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Taxoids
• 7-methylthiomethylpaclitaxel
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects, blood, pharmacokinetics, therapeutic use, urine)
• Diarrhea (chemically induced)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Molecular Structure
• Neoplasms (drug therapy)
• Neutropenia (chemically induced)
• Paclitaxel (administration & dosage, adverse effects, analogs & derivatives, blood, pharmacokinetics, therapeutic use, urine)
• Remission Induction
• Taxoids