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Title: An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma.
Austin Authors: Davis, Ian D;Skrumsager, Birte K;Cebon, Jonathan S ;Nicholaou, Theo;Barlow, John W;Moller, Niels Peter Hundahl;Skak, Kresten;Lundsgaard, Dorthe;Frederiksen, Klaus Stensgaard;Thygesen, Peter;McArthur, Grant A
Affiliation: Austin Health, Heidelberg, Victoria, Australia
Issue Date: 15-Jun-2007
Publication information: Clinical Cancer Research; 13(12): 3630-6
Abstract: 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.Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 microg/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).Twenty-nine patients entered the study. IL-21 was generally well tolerated and no DLTs were observed at the 1, 3, and 10 microg/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 microg/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.IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 microg/kg in the 5+9 regimen.
Gov't Doc #: 17575227
DOI: 10.1158/1078-0432.CCR-07-0410
Journal: Clinical Cancer Research
Type: Journal Article
Subjects: Adult
Antineoplastic Agents.administration & dosage.adverse effects.pharmacokinetics
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay
Granzymes.drug effects
Interleukin-2 Receptor alpha Subunit.blood.drug effects
Interleukins.administration & dosage.adverse effects.pharmacokinetics
Maximum Tolerated Dose
Melanoma.drug therapy
Middle Aged
Pore Forming Cytotoxic Proteins.drug effects
Recombinant Proteins.administration & dosage.adverse effects.pharmacokinetics
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