Summary
Purpose BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s). Methods This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m2/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days. Results Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m2/day to 18 mg/m2/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m2/day and 18 mg/m2/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m2. Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis. Conclusions BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.
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References
Huizing MT et al (1997) Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre. J Clin Oncol 15(1):317–329
Mastalerz H et al (2003) The discovery of BMS-275183: an orally efficacious novel taxane. Bioorg Med Chem 11(20):4315–4323
Rose WC et al (2001) Preclinical pharmacology of BMS-275183, an orally active taxane. Clin Cancer Res 7(7):2016–2021
Clay R, BMS-275183: One-Month Oral Toxicity Study in Rats.(Study No. 99727). Covance Report, 2000. 1.0
Gill M, BMS-275183: One-Month Oral Toxicity Study in Dogs. (Study No.99728). Covance Report, 2000. 1.0
Broker LE et al (2006) Phase I trial with BMS-275183, a novel oral taxane with promising antitumor activity. Clin Cancer Res 12(6):1760–1767
Broker LE et al (2007) A phase I safety and pharmacologic study of a twice weekly dosing regimen of the oral taxane BMS-275183. Clin Cancer Res 13(13):3906–3912
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Heath, E.I., LoRusso, P., Ramalingam, S.S. et al. A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies. Invest New Drugs 29, 1426–1431 (2011). https://doi.org/10.1007/s10637-010-9498-z
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DOI: https://doi.org/10.1007/s10637-010-9498-z