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.


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.


CONCLUSIONS
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.
CRUK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. n.steele@nhs.net
N
N
Steele
A
A
Anthony
M
M
Saunders
B
B
Esmarck
E
E
Ehrnrooth
P E G
PE
Kristjansen
A
A
Nihlén
L T
LT
Hansen
J
J
Cassidy
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome; D000098546:Interleukin-21
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007378:Interleukins; D066246:ErbB Receptors; D000098546:Interleukin-21; D000068818:Cetuximab