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A Phase I and Pharmacokinetic Study of Weekly Oxaliplatin Followed by Paclitaxel in Patients with Solid Tumors

Authors' Affiliations: ¹ Division of Hematology and Oncology, Department of Medicine, ² Department of Pharmacology, and ³ Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio; and ⁴ Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Eric H. Kraut, The Ohio State University, A434B Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-3161; Fax: 614-293-7529; E-mail: Eric.Kraut{at}osumc.edu.

Purpose: Oxaliplatin and paclitaxel are widely used in treating solid tumors. We designed a phase I study with the purpose of determining the maximal tolerated dose and pharmacokinetic properties of weekly oxaliplatin followed by paclitaxel based on evidence suggesting that weekly administration of both drugs allows equivalent dose intensity with less neurotoxicity.

Experimental Design: Twenty-three patients with advanced solid tumors were treated. Starting doses were 35 mg/m² oxaliplatin followed by 45 mg/m² paclitaxel weekly for 4 weeks every 6 weeks. Dose was escalated as follows: 45 mg/m² oxaliplatin and 45 mg/m² paclitaxel, 60 mg/m² oxaliplatin and 45 mg/m² paclitaxel, and 60 mg/m² oxaliplatin and 60 mg/m² paclitaxel. Pharmacokinetic studies were evaluated during the first course of therapy for oxaliplatin using population kinetics approach.

Results: A total of 49 courses were administered. The dose-limiting toxicity was peripheral neuropathy with oxaliplatin and paclitaxel both at 60 mg/m². There were three partial responses. There was evidence of pharmacokinetic interaction with a significant amount of total platinum (46.2-49.5%/24 h) eliminated in the urine in this group of patients, consistent with published data from others. The total body clearance values of plasma platinum and ultrafiltrable platinum were higher in this combination compared with corresponding values from our previous study with oxaliplatin only (P < 0.001).

Conclusions: The recommended phase II dose of this combination is 60 mg/m² oxaliplatin followed by 45 mg/m² paclitaxel. Evidence of antitumor activity and acceptable toxicity with this combination and schedule warrants further investigation. We have obtained more definitive pharmacokinetic properties of oxaliplatin and confirmed its drug interaction with paclitaxel in the current sequence.