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Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

Lookup NU author(s): Dr Ashraf Azzabi, Dr Andrew Hughes, Dr Paula Calvert, Professor Ruth Plummer, Melanie Griffin, Kevin Fishwick, Professor Alan Calvert, Professor Alan Boddy

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Abstract

The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1-5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m-2 day-1 temozolomide and 225 mg m-2 day-1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted. © 2005 Cancer Research UK.


Publication metadata

Author(s): Azzabi AS, Hughes AM, Calvert PM, Plummer ER, Todd R, Griffin MJ, Lind MJ, Maraveyas A, Kelly C, Fishwick KA, Calvert AH, Boddy AV

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2005

Volume: 92

Issue: 6

Pages: 1006-1012

Print publication date: 08/03/2005

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

URL: http://dx.doi.org/10.1038/sj.bjc.6602438

DOI: 10.1038/sj.bjc.6602438

PubMed id: 15756276


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