A phase I clinical and pharmacokinetic study of Ro 31-7453 given as a 7- or 14-day oral twice daily schedule every 4 weeks in patients with solid tumors

Salazar, R., Bissett, D., Twelves, C., Breimer, L., Demario, M., Campbell, S., Zhi, J., Ritland, S. and Cassidy, J. (2004) A phase I clinical and pharmacokinetic study of Ro 31-7453 given as a 7- or 14-day oral twice daily schedule every 4 weeks in patients with solid tumors. Clinical Cancer Research, 10(13), pp. 4374-4382. (doi: 10.1158/1078-0432.CCR-04-0135)

Abstract

Purpose: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models. Experimental Design: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively. Results: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40-77 years), and median Karnofsky performance status was 80 (range, 60-100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m(2) twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m(2) bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1-7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m(2) bid and 125 mg/m(2) bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t(1/2) of similar to9 h and a t(max) of similar to4 h. One patient with pretreated lung cancer had a partial response. Conclusions: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m(2) bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cassidy, Professor James
• Authors: Salazar, R., Bissett, D., Twelves, C., Breimer, L., Demario, M., Campbell, S., Zhi, J., Ritland, S., and Cassidy, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432