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An Open-Label, Two-Arm, Phase I Trial of Recombinant Human Interleukin-21 in Patients with Metastatic Melanoma

Authors' Affiliations: ¹ Austin Health; ² Peter MacCallum Cancer Centre; ³ Cancer Trials Australia, Melbourne, Victoria, Australia; and ⁴ Novo Nordisk A/S, Copenhagen, Denmark

Requests for reprints: Ian D. Davis, Ludwig Institute for Cancer Research, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-3-9496-5726; Fax: 61-3-9457-6698; E-mail: Ian.Davis{at}ludwig.edu.au.

Purpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8⁺ T cells and natural killer cells. We report a phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors.

Experimental Design: Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 µg/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9).

Results: Twenty-nine patients entered the study. IL-21 was generally well tolerated and no DLTs were observed at the 1, 3, and 10 µg/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 µg/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8⁺ cells. One partial tumor response observed after treatment with IL-21 for 2 x 6 weeks (3/wk) became complete 3 months later.

Conclusions: IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 µg/kg in the 5+9 regimen.

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