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Phase I Trial of Weekly Paclitaxel and BMS-214662 in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin and ² Oncology Drug Discovery and Oncology Global Clinical Development, Bristol-Myers Squibb, Princeton, New Jersey

Requests for reprints: Howard H. Bailey, University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, K4/650 CSC, 600 Highland Avenue, Madison, WI 53792. Phone: 608-263-8624; Fax: 608-265-8133; E-mail: hhbailey{at}wisc.edu.

Purpose: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor.

Experimental Design: Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m²/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80–245 mg/m²/wk) over 1 h starting 30 min after completion of paclitaxel.

Results: Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m²/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m²/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m²/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m²/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion.

Conclusions: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m² over 1 h) and BMS-214662 (160 mg/m² over 1 h) administered weekly.