This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bröker, L. E. Articles by Giaccone, G. Search for Related Content PubMed PubMed Citation Articles by Bröker, L. E. Articles by Giaccone, G.

Phase I Trial with BMS-275183, a Novel Oral Taxane with Promising Antitumor Activity

Authors' Affiliations: ¹ VU University Medical Center, Amsterdam, ² University Medical Center Groningen, Groningen, the Netherlands; and ³ Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut

Requests for reprints: Giuseppe Giaccone, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. Phone: 31-20-4444-321; Fax: 31-20-4444-079; E-mail: g.giaccone{at}vumc.nl.

Purpose: BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel. We did a dose-escalating phase I study to investigate its safety, tolerability, pharmacokinetics, and possible antitumor activity.

Experimental Design: A cycle consisted of four weekly doses of BMS-275183. The starting dose was 5 mg, which was increased by 100% increments (i.e., 5, 10, 20 mg/m², etc.) in each new cohort consisting of one patient. Cohorts were expanded when toxicity was encountered, and 20 patients were treated at the maximum tolerated dose (MTD). Plasma pharmacokinetics were done on days 1 and 15.

Results: A total of 48 patients were enrolled in this trial. Dose-limiting toxicities consisted of neuropathy, fatigue, diarrhea, and neutropenia. First cycle severe neuropathy was reported in four patients treated at 320 (n = 1), 240 (n = 2), and 160 mg/m² (n = 1), whereas eight patients treated at dose levels ranging from 160 to 320 mg/m² experienced grade 2 neuropathy in cycle one. The MTD was 200 mg/m², as 3 of 20 patients experienced grade 3 or 4 toxicity in cycle one [fatigue (n = 2), and neutropenia/diarrhea (n = 1)]. BMS-275183 was rapidly absorbed with a mean plasma half-life of 22 hours. We observed a significant correlation between drug-exposure and toxicity. Tumor responses were observed in 9 of 38 evaluable patients with non–small cell lung cancer, prostate carcinoma, and other tumor types.

Conclusions: BMS-275183 is generally well tolerated on a weekly schedule. The main toxicity is peripheral neuropathy, and the MTD is 200 mg/m². Promising activity was observed in several tumor types, and a phase II trial in non–small cell lung cancer has been initiated.

This article has been cited by other articles:

				L. E. Broker, M. Valdivieso, M. J. Pilat, P. DeLuca, X. Zhou, S. Parker, G. Giaccone, and P. M. LoRusso Effect of Food on the Pharmacokinetic Behavior of the Potent Oral Taxane BMS-275183 Clin. Cancer Res., July 1, 2008; 14(13): 4186 - 4191. [Abstract] [Full Text] [PDF]

				L. E. Broker, S. A. Veltkamp, E. I. Heath, B. C. Kuenen, H. Gall, L. Astier, S. Parker, L. Kayitalire, P. M. Lorusso, J. H.M. Schellens, et al. A Phase I Safety and Pharmacologic Study of a Twice Weekly Dosing Regimen of the Oral Taxane BMS-275183 Clin. Cancer Res., July 1, 2007; 13(13): 3906 - 3912. [Abstract] [Full Text] [PDF]