Originally published as JCO Early Release 10.1200/JCO.2007.14.5193 on March 17 2008

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Phase I Study of Recombinant Interleukin-21 in Patients With Metastatic Melanoma and Renal Cell Carcinoma

John A. Thompson, Brendan D. Curti, Bruce G. Redman, Shailender Bhatia, Jeffrey S. Weber, Sanjiv S. Agarwala, Eric L. Sievers, Steven D. Hughes, Todd A. DeVries, Diana F. Hausman

From the University of Washington; ZymoGenetics Inc, Seattle, WA; Providence Portland Medical Center, Portland, OR; University of Michigan Health System, Ann Arbor, MI; University of Southern California, Los Angeles, CA; and the University of Pittsburgh Cancer Institute, Pittsburgh, PA

Corresponding author: John A. Thompson, MD, Seattle Cancer Care Alliance, 825 Eastlake Ave East, Mailstop G4-830, Seattle, WA 98109-1023; e-mail: jat{at}u.washington.edu

Purpose A phase I study of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of recombinant human interleukin-21 (rIL-21).

Patients and Methods Patients who had one or fewer prior systemic treatments for metastatic MM or RCC were treated with rIL-21 administered for two 5-day cycles on days 1 through 5 and 15 through 19 of a treatment course; rIL-21 was administered by rapid intravenous infusion in an outpatient setting. Cohorts of patients received doses ranging from 3 to 100 µg/kg/dose, and an expanded cohort was treated at the MTD. Patients with stable disease (SD) or better could receive additional treatment cycles.

Results Forty-three patients were treated (24 MM; 19 RCC), including 28 in the expanded cohort. Dose-limiting toxicities consisted primarily of transient grade 3 laboratory abnormalities. The MTD was estimated to be 30 µg/kg. The most common adverse events included flu-like symptoms, pruritus, and rash. Twelve patients received up to five additional two-cycle courses of treatment without cumulative toxicity, except for one patient with reversible grade 4 hepatotoxicity. Serum concentrations of rIL-21 increased in a dose-proportional manner. Dose-dependent increases in soluble CD25 reflected lymphocyte activation. Antitumor activity was observed in both MM (one complete response and 11 SD) and RCC (four partial responses, 13 SD).

Conclusion Outpatient therapy with rIL-21 at 30 µg/kg was well tolerated, had dose-dependent pharmacokinetics and pharmacodynamics, and was associated with antitumor activity in patients with MM and RCC.

published online ahead of print at www.jco.org on March 17, 2008

Supported by ZymoGenetics Inc, Seattle, WA.

Presented in part at the International Society for Biological Therapy of Cancer Annual Meeting, Alexandria, VA, November 10-13, 2005; the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005; 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006; European Organisation for the Research and Treatment of Cancer, Prague, Czech Republic, November 7-10, 2006.

ClinicalTrials.gov identifier: NCT00095108 [ClinicalTrials.gov] .

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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