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Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer

From the Department of Medicine, Gustave Roussy Institute, Villejuif, France, and Clinical Research Department, Daiichi Pharmaceuticals UK Ltd, London, United Kingdom.

Address reprint requests to Eric Raymond, MD, Department of Medicine, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France; email raymond{at}igr.fr

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks.

PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m². All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography.

RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h·m². The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m².

CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m² every 3 weeks in patients previously treated with chemotherapy.

V.B. and E.R. contributed equally to this work, and both should be considered as first authors.

Presented in part at the 1999 Annual Meeting of the American Association for Cancer Research, Philadelphia, PA.

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