Faculty Collaboration Database

Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors. Clin Cancer Res 2007 Jun 15;13(12):3623-9

Date

05/19/2007

Pubmed ID

17510207

DOI

10.1158/1078-0432.CCR-07-0158

Scopus ID

2-s2.0-34250755529 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

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/m(2)/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80-245 mg/m(2)/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/m(2)/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m(2)/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m(2)/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m(2)/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/m(2) over 1 h) and BMS-214662 (160 mg/m(2) over 1 h) administered weekly.

Author List

Bailey HH, Alberti DB, Thomas JP, Mulkerin DL, Binger KA, Gottardis MM, Martell RE, Wilding G

Author

James P. Thomas MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Benzodiazepines
Female
Humans
Imidazoles
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Paclitaxel