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Phase I Trial of 40-kd Branched Pegylated Interferon Alfa-2a for Patients With Advanced Renal Cell Carcinoma

From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, and Department of Medical Imaging, Memorial Sloan-Kettering Cancer Center, New York, NY; and Hoffmann-La Roche, Inc, Nutley, NJ, and Welwyn, United Kingdom.

Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.

PURPOSE: Pegylated (40 kd) interferon alfa-2a (IFN2a) (PEGASYS, Hoffman-La Roche, Nutley, NJ; PEG-IFN) is a modified form of recombinant human IFN2a with sustained absorption and prolonged half-life after subcutaneous administration. A phase I study of PEG-IFN with pharmacokinetic and pharmacodynamic evaluations was conducted in previously untreated patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: Twenty-seven patients were enrolled onto cohorts of three or six patients. PEG-IFN was administered on a weekly basis by subcutaneous injection. The dose was escalated from 180 µg/wk to a maximum of 540 µg/wk in 90-µg increments. Serial venous blood samples were drawn to assess concentrations of PEG-IFN and two immunologic surrogates, neopterin and 2'-5' oligoadenylate synthetase (OAS).

RESULTS: The maximum-tolerated dose was determined as 540 µg/wk, because two patients experienced dose-limiting toxicity within 28 days of starting treatment. One developed serum grade 3 ALT elevation, and a second developed grade 3 fatigue. Six patients were treated at 450 µg/wk without dose-limiting toxicity. Over the course of treatment, the side-effect profile was mostly mild to moderate in intensity. Adverse events included fatigue, fever, headache, myalgia, nausea, and decreased appetite. Five patients (19%) achieved a partial response. The mean maximum serum concentration increased from 5.0 to 27 ng/mL, and mean area under the curve increased from 247 to 2,981 ng/h/mL, with dose escalation from 180 µg/wk to 540 µg/wk. Serum concentration of PEG-IFN was sustained at close to peak during the dosing interval, and steady-state was achieved in approximately 5 weeks. The immunologic surrogates, neopterin and OAS, were induced at all doses with a sustained concentration profile similar to PEG-IFN.

CONCLUSION: PEG-IFN is a modified form of IFN2a with distinct pharmacokinetic advantages and immunomodulatory and antitumor activity for patients with advanced RCC. A dose of 450 µg/wk by subcutaneous administration was determined as a suitable dose for further study. PEG-IFN is more convenient to administer than IFN and has potential for increased efficacy, less toxicity, or both. The efficacy and toxicity of PEG-IFN will be further assessed in clinical trials and compared with IFN.

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