An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma.
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.
Davis
Ian D
ID
Austin Health, Melbourne, Victoria, Australia. Ian.Davis@ludwig.edu.au
Skrumsager
Birte K
BK
Cebon
Jonathan
J
Nicholaou
Theo
T
Barlow
John W
JW
Moller
Niels Peter Hundahl
NP
Skak
Kresten
K
Lundsgaard
Dorthe
D
Frederiksen
Klaus Stensgaard
KS
Thygesen
Peter
P
McArthur
Grant A
GA
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
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