title: An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Austin Health, Melbourne, Victoria, Australia. Ian.Davis@ludwig.edu.au
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Birte K
authors.initials: BK
authors.lastname: Skrumsager
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Theo
authors.initials: T
authors.lastname: Nicholaou
authors.forename: John W
authors.initials: JW
authors.lastname: Barlow
authors.forename: Niels Peter Hundahl
authors.initials: NP
authors.lastname: Moller
authors.forename: Kresten
authors.initials: K
authors.lastname: Skak
authors.forename: Dorthe
authors.initials: D
authors.lastname: Lundsgaard
authors.forename: Klaus Stensgaard
authors.initials: KS
authors.lastname: Frederiksen
authors.forename: Peter
authors.initials: P
authors.lastname: Thygesen
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D053804:Granzymes / Q000187:drug effects; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000187:drug effects; D007378:Interleukins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000098546:Interleukin-21
chemical_list: D000970:Antineoplastic Agents; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; D054353:Perforin; D053804:Granzymes; D000098546:Interleukin-21