Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma

Purpose: Pegylated (40 kd) interferon alfa-2 alpha (IFN alpha 2a) (PEGASYS, Hoffman-La Roche, Nutrey, NJ; PEG-IFN) is a modified form of recombinant h uman IFN alpha 2a with sustained absorption and prolonged half-life after s ubcutaneous administration. A phase I study of PEG-IFN with pharmacokinetic and pharmacodynamic evaluations was conducted in previously untreated pati ents with advanced renal cell carcinoma (RCC). Patients and Methods: Twenty-seven patients were enrolled onto cohorts of t hree or six patients. PEG-IFN was administered on a weekly basis by subcuta neous injection. The dose was escalated from 180 mug/wk to a maximum of 540 mug/wk in 90-mug increments. Serial venous blood samples were drawn to ass ess concentrations of PEG-IFN and two immunologic surrogates, neopterin and 2'-5' oligoadenylate synthetase (OAS). Results: The maximum-tolerated dose was determined as 540 mug/wk, because t wo patients experienced dose-limiting toxicity within 28 days of starting t reatment. One developed serum grade 3 ALT elevation, and a second developed grade 3 fatigue. Six patients were treated at 450 mug/wk without dose-limi ting toxicity. Over the course of treatment, the side-effect profile was mo stly mild to moderate in intensity. Adverse events included fatigue, fever, headache, myalgia, nausea, and decreased appetite. Five patients (19%) ach ieved a partial response. The mean maximum serum concentration increased fr om 5.0 to 27 ng/mL, and mean area under the curve increased from 247 to 2,9 81 ng/h/mL, with dose escalation from 180 mug/wk to 540 mug/wk. Serum conce ntration of PEG-IFN was sustained at close to peak during the dosing interv al, and steady-state wets achieved in approximately 5 weeks. The immunologi c 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 IFN alpha 2a with distinct pharma cokinetic advantages and immunomodulatory and antitumor activity for patien ts with advanced RCC. A dose of 450 mug/wk by subcutaneous administration w as determined as a suitable dose for further study. PEG-IFN is more conveni ent to administer than IFN alpha and has potential for increased efficacy, less toxicity, or both. The efficacy and toxicity of PEG-IFN will be furthe r assessed in clinical trials and compared with IFN alpha. J Clin Oncol 19: 1312-1319. (C) 2001 by American Society of Clinical Oncology.