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

• Published in: Clinical cancer research 2007-06, Vol.13 (12), p.3630-3636
• Main Authors: Davis, Ian D, Skrumsager, Birte K, Cebon, Jonathan, Nicholaou, Theo, Barlow, John W, Moller, Niels Peter Hundahl, Skak, Kresten, Lundsgaard, Dorthe, Frederiksen, Klaus Stensgaard, Thygesen, Peter, McArthur, Grant A
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; clinical trial; cytokines; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Granzymes - drug effects; Humans; IL-21; Interleukin-2 Receptor alpha Subunit - blood; Interleukin-2 Receptor alpha Subunit - drug effects; Interleukins - administration & dosage; Interleukins - adverse effects; Interleukins - pharmacokinetics; Male; Maximum Tolerated Dose; melanoma; Melanoma - drug therapy; Middle Aged; Perforin; Phase 1; Pore Forming Cytotoxic Proteins - drug effects; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0410

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 × 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.