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Background:Pre-clinical data indicate enhanced anti-tumour activity when combining recombinant human interleukin-21 (rIL-21), a class 1 cytokine, with cetuximab, a monoclonal antibody, targeting the epidermal growth factor receptor. This phase 1 trial assessed the safety and tolerability of escalating doses of rIL-21 in combination with cetuximab in chemo-naïve patients with stage IV colorectal cancer.Patients and methods:Sequential cohorts of PS 0–1, asymptomatic patients, were treated weekly with cetuximab 250 mg m−2 intravenously (i.v.) plus escalating i.v. doses of rIL-21 following an initial loading dose of cetuximab 400 mg m−2. Initial treatment period was 8 weeks, with extension permitted in patients without disease progression.Results:In all, 15 patients were included in this study. Adverse events related to rIL-21 or rIL-21 plus cetuximab included lethargy, nausea/vomiting, stomatitis, lymphopenia and pyrexia and were mainly ⩽ grade 2. One dose limiting toxicity occurred (grade 3 diarrhoea). Maximum tolerated dose was not determined because of the premature study closure. Maximum administered dose was 100 μg kg−1 rIL-21 weekly. In all, 60% of the patients had stable disease. Immune activation was confirmed by various T- and NK-cell activation biomarkers, including dose-dependent increases in serum sCD25.Conclusion:rIL-21 weekly combined with cetuximab is well tolerated at doses up to 100 μg kg−1 and results in activation of immune response biomarkers.

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Ethyl tert-butyl ether (ETBE) might replace methyl tert-butyl ether (MTBE), a widely used additive in unleaded gasoline. The aim of this study was to evaluate uptake and disposition of ETBE, and eight healthy male volunteers were exposed to ETBE vapor (0, 5, 25, and 50 ppm) during 2 h of light physical exercise. ETBE and the proposed metabolites tert-butyl alcohol (TBA) and acetone were analyzed in exhaled air, blood, and urine. Compared to a previous MTBE study (A. Nihlen et al., 1998b, Toxicol. Appl. Pharmacol. 148, 274-280) lower respiratory uptake of ETBE (32-34%) was seen as well as a slightly higher respiratory exhalation (45-50% of absorbed ETBE). The kinetic profile of ETBE could be described by four phases in blood (average half-times of 2 min, 18 min, 1.7 h, and 28 h) and two phases in urine (8 min and 8.6 h). Postexposure half-times of TBA in blood and urine were on average 12 and 8 h, respectively. The 48-h pulmonary excretion of TBA accounted for 1.4-3.8% of the absorbed ETBE, on an equimolar basis. Urinary excretion of ETBE and TBA was low, below 1% of the ETBE uptake, indicating further metabolism of TBA or other routes of metabolism and elimination. The kinetics of ETBE and TBA were linear up to 50 ppm. Based upon blood profile, levels in blood and urine, and kinetic profile we suggest that TBA is a more appropriate biomarker for ETBE than the parent ether itself. The acetone level in blood was higher after ETBE exposures compared to control exposure, and acetone is probably partly formed from ETBE.