A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer

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.