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Annals of Oncology 2007 18(9):1548-1553; doi:10.1093/annonc/mdm198
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© 2007 European Society for Medical Oncology

Phase I clinical study of the novel epothilone B analogue BMS-310705 given on a weekly schedule

C Sessa1, A Perotti2, A Lladò1, S Cresta2, G Capri2, M Voi3, S Marsoni4, I Corradino4 and L Gianni2,*

1 IOSI, Bellinzona, Switzerland
2 Istituto Nazionale Tumori, Milano
3 Bristol-Myers Squibb, Wallingford CT, USA
4 SENDO, Milano, Italy

* Correspondence to: Dr L. Gianni, MD, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy. Tel: +39-02-2390-2789; Fax: +30-02-2390-2012; E-mail: luca.gianni{at}istitutotumori.mi.it

Background: BMS-310705, a water-soluble semi-synthetic analogue of epothilone B, was selected for clinical development because of its in vivo anti-tumour activity and toxicity profile similar to that of ixabepilone, currently the most extensively evaluated and promising epothilone B analogue. The improved solubility of BMS-310705 allowed a cremophore-free formulation that avoided the need for pre-medication.

Patients and methods: Two schedules were tested, one with drug administrations on days (D) 1, 8 and 15 followed by 1-week's rest, the other with administrations on D1 and 8 (D1&8 schedule) followed by 1-week's rest. Treatment was given as a 15-min infusion without pre-medication against hypersensitivity. The plasma pharmacokinetics of BMS-310705 was studied in 30 patients. An accelerated titration design 2B was applied for dose escalations. Twenty-seven patients were accrued in the D1, 8, 15 and 32 in the D1&8 schedule.

Results: The dose was escalated from 5–30 mg/m2/week with diarrhoea as dose-limiting toxicity; 15 and 20 mg/m2 were the recommended doses in the D1, 8, 15 and D1&8 schedule, respectively. Other frequent non-haematological toxicities were neurotoxicity, mainly paraesthesia, asthenia and myalgia. Preliminary results showed linear pharmacokinetics along the range of doses tested with a short half-life. Five objective responses were reported.

Conclusions: Further clinical development of BMS-310705 might be worthwhile in solid tumours where ixabepilone or other epothilones are not indicated.

Key words: accelerated titration design, epothilone b analogue, phase I, tubulin binder

Received for publication December 29, 2006. Revision received April 5, 2007. Accepted for publication April 11, 2007.


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