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 1study of recombinant human IL-21in 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 Ag/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-21was generally well tolerated and no DLTs were observed at the 1, 3, and 10 Ag/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 Ag/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 Â 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 Ag/kg in the 5+9 regimen.

Purpose: Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8 + T cells, natural killer (NK) cells, and other cell types. We report final clinical and biological results of a phase II study of recombinant human IL-21 (rIL-21) in patients with metastatic melanoma. Experimental Design: Open-label, single-arm, two-stage trial. Eligibility criteria: unresectable metastatic melanoma, measurable disease by Response Evaluation Criteria in Solid Tumors, no prior systemic therapy (adjuvant IFN permitted), adequate major organ function, good performance status, no significant autoimmune disease, and life expectancy at least 4 months. Primary objective: antitumor efficacy (response rate). Secondary objectives: safety, blood biomarkers, and generation of anti-rIL-21 antibodies. rIL-21 (30 Ag/kg/dose) was administered by intravenous bolus injection in 8-week cycles (5 dosing days followed by 9 days of rest for 6 weeks and then 2 weeks off treatment). Results: Stage I of the study comprised 14 patients. One confirmed complete response (CR) was observed, and as per protocol, 10 more patients were accrued to stage II (total n = 24: 10 female and 14 male). Best tumor response included one confirmed CR and one confirmed partial response, both with lung metastases. Treatment was overall well tolerated. Biomarker analyses showed increases in serum soluble CD25, frequencies of CD25 + NK and CD8 + Tcells, and mRNA for IFN-g, perforin, and granzyme B in CD8 + Tand NK cells. Conclusions: rIL-21administered at 30 Ag/kg/d in 5-day cycles every second week is biologically active and well tolerated in patients with metastatic melanoma. Confirmed responses, including one CR, were observed.

Purpose Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers. Here we report the eVects of systemic IL-21 therapy on the immune system in two phase 1 trials with this novel cytokine. Experimental design Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 g/kg using two planned treatment regimens: thrice weekly for 6 weeks (3/week); or once daily for Wve consecutive days followed by nine dose-free days (5 + 9). The following biomarkers were studied in peripheral blood mononuclear cells (PBMC) during treatment: phosphorylation of STAT3, alterations in the composition of leukocyte subsets, ex vivo cytotoxicity, expression of eVector molecules in enriched CD8 + T cells and CD56 + NK cells by quantitative RT-PCR, and gene array proWling of CD8 + T cells. Results EVects of IL-21 were observed at all dose levels. In the 5 + 9 regimen IL-21 induced a dose dependent decrease in circulating NK cells and T cells followed by a return to baseline in resting periods. In both CD8 + T cells and CD56+ NK cells we found up-regulation of perforin and granzyme B mRNA. In addition, full transcriptome analysis of CD8 + T cells displayed changes in several transcripts associated with increased cell cycle progression, cellular motility, and immune activation. Finally, cytotoxicity assays showed that IL-21 enhanced the ability of NK cells to kill sensitive targets ex vivo. Conclusions IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8 + T cell activation.

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D1-dopamine receptor antagonists. Both compounds have been labeled with 11C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D1-dopamine receptors. This striatal uptake was displaced by high doses of the selective D1-antagonist SCH 23390 (2 mg/kg) but not by the 5HT2-antagonist ketanserin (1.5 mg/kg) or the selective D2-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [11C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [11C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24-28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [11C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [11C]NNC 756 the ratio was about 5. This ratio of 5 for [11C]NNC 756 is the highest obtained so far for PET radioligands for the D1-dopamine receptor.

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