Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a phase I trial.
OBJECTIVE
This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21).


METHODS
Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 μg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks.


RESULTS
Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 μg/kg, although five of seven patients at the 300 μg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-γ, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8(+) T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response.


CONCLUSIONS
Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC.
Schmidt
Henrik
H
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. henrschm@rm.dk
Brown
Janet
J
Mouritzen
Ulrik
U
Selby
Peter
P
Fode
Kirsten
K
Svane
Inge Marie
IM
Cook
Graham P
GP
Mollerup
David Hal
DH
Geertsen
Poul F
PF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007378:Interleukins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000098546:Interleukin-21
D007378:Interleukins; D011994:Recombinant Proteins; D000098546:Interleukin-21