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Phase I and Pharmacokinetic Study of Weekly Docetaxel, Cisplatin, and Daily Capecitabine in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ Department of Medicine, Roswell Park Cancer Institute; ² Department of Medicine, State University of New York at Buffalo, Buffalo, New York; ³ Molecular Therapeutics/Drug Discovery Program, ⁴ Biostatistics Facility, University of Pittsburgh Cancer Institute; ⁵ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine; and ⁶ Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Marwan Fakih, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8189 or 716-845-3362; Fax: 716-845-8008; E-mail: marwan.fakih{at}roswellpark.org.

Purpose: Docetaxel, cisplatin, and capecitabine are three active chemotherapeutic agents with different mechanisms of action. This phase I study investigated the feasibility and pharmacokinetics of this combination given on a weekly schedule.

Experimental Design: Docetaxel and cisplatin were given i.v. over 30 minutes on days 1 and 8 and capecitabine was given orally bid on days 1 to 14 (every 21 days). Escalation occurred in cohorts of three patients until the maximum tolerated dose was defined. Pharmacokinetics studies of docetaxel and total and ultrafiltrate platinum after cisplatin administration were done on cycle 1 (with capecitabine) and cycle 2 (without capecitabine).

Results: Twenty-five patients were enrolled. Two of six patients at dose level 5 had a dose-limiting infection and diarrhea. One of six evaluable patients at dose level 4 (27 mg/m² docetaxel, 27 mg/m² cisplatin, 825 mg/m² capecitabine) had a dose-limiting hypomagnesemia. Pharmacokinetics of docetaxel were similar on cycles 1 and 2. Area under the plasma concentrations versus time curves of total platinum was significantly greater in cycle 2 compared with cycle 1 (P = 0.001). There was no difference in the disposition of docetaxel on cycles 1 and 2.

Conclusions: The recommended docetaxel, cisplatin, and capecitabine dose for phase II studies is 27/27/825 mg/m². The alteration in total and ultrafiltrate platinum disposition on cycle 2 compared with cycle 1 may be inherent to sequential cisplatin administration; however, prior treatment with capecitabine cannot be ruled out as a factor.