title: Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations.
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.
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Azzabi
authors.forename: A N
authors.initials: AN
authors.lastname: Hughes
authors.forename: P M
authors.initials: PM
authors.lastname: Calvert
authors.forename: E R
authors.initials: ER
authors.lastname: Plummer
authors.forename: R
authors.initials: R
authors.lastname: Todd
authors.forename: M J
authors.initials: MJ
authors.lastname: Griffin
authors.forename: M J
authors.initials: MJ
authors.lastname: Lind
authors.forename: A
authors.initials: A
authors.lastname: Maraveyas
authors.forename: C
authors.initials: C
authors.lastname: Kelly
authors.forename: K
authors.initials: K
authors.lastname: Fishwick
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
authors.forename: A V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077204:Temozolomide
chemical_list: D003606:Dacarbazine; D017239:Paclitaxel; D000077204:Temozolomide