This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Plummer, R. Articles by Verrill, M. Search for Related Content PubMed PubMed Citation Articles by Plummer, R. Articles by Verrill, M.

A Phase I and Pharmacokinetic Study of Ixabepilone in Combination with Carboplatin in Patients with Advanced Solid Malignancies

Authors' Affiliations: ¹ Northern Centre for Cancer Treatment; ² Northern Institute for Cancer Research, Newcastle upon Tyne, United Kingdom; ³ Nottingham City Hospital, Nottingham, United Kingdom; ⁴ Bristol-Myers Squibb, Uxbridge, United Kingdom; and ⁵ Bristol-Myers Squibb, Wallingford, Connecticut

Requests for reprints: Ruth Plummer, Northern Centre for Cancer Treatment, Westgate Road, Newcastle upon Tyne NE4 6BE, United Kingdom. Phone: 44-191-2563599; Fax: 44-191-2261170; E-mail: ruth.plummer{at}ncl.ac.uk.

Purpose: To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety.

Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B).

Results: Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m² per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m² over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m² over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m² ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m² ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B).

Conclusions: Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.