Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin Journal Article

Authors: Baselga, J.; Pfister, D.; Cooper, M. R.; Cohen, R.; Burtness, B.; Bos, M.; D'Andrea, G.; Seidman, A.; Norton, L.; Gunnett, K.; Falcey, J.; Anderson, V.; Waksal, H.; Mendelsohn, J.
Article Title: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin
Abstract: Purpose: The epidermal growth factor (EGF) receptor is frequently overexpressed in epithelial tumors. C225 is a human-to-murine chimeric monoclonal antibody that binds to the receptor and inhibits growth of cancer cells expressing the receptor. We evaluated the pharmacokinetics and toxicity of C225 in patients with advanced tumors overexpressing EGF receptors. Patients and Methods: We treated 52 patients in three successive phase I clinical trials of C225 as a single dose (n = 13), weekly multiple dose (n = 17), and weekly multiple dose with cisplatin (n = 22). C225 dose levels were 5, 20, 50, and 100 mg/m2. In the study combining C225 with cisplatin, limited to patients with either head and neck or non-small-cell lung cancer, C225 was further escalated to 200 and 400 mg/m2. Cisplatin was given at a dose of 60 mg/m2 once every 4 weeks, and treatment was continued for up to 12 weeks if no disease progression occurred. Results: C225 displayed nonlinear pharmacokinetics, with antibody doses in the range of 200 to 400 mg/m2 being associated with complete saturation of systemic clearance. C225 clearance did not change with repeated administration or with coadministration of cisplatin. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Patients experiencing disease stabilization were seen in all studies. In the study combining C225 and cisplatin, nine (69%) of 13 patients treated with antibody doses ≥ 50 mg/m2 completed 12 weeks of therapy, and two partial responses were observed. Conclusion: C225 has dose-dependent pharmacokinetics, and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses. (C) 2000 American Society of Clinical Oncology.
Keywords: adult; major clinical study; clinical trial; drug tolerability; carcinoma, squamous cell; cisplatin; drug safety; antineoplastic agents; gastrointestinal symptom; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; drug administration schedule; receptor, epidermal growth factor; dose-response relationship, drug; asthenia; dyspnea; fever; gene expression regulation, neoplastic; antibodies, monoclonal; recombinant fusion proteins; drug distribution; head and neck cancer; head and neck neoplasms; remission induction; drug clearance; area under curve; safety; phase 1 clinical trial; infusions, intravenous; epidermal growth factor receptor antibody; skin allergy; neoplasms, glandular and epithelial; chimeric antibody; humans; human; male; female; priority journal; article; epiglottitis
Journal Title: Journal of Clinical Oncology
Volume: 18
Issue: 4
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2000-02-14
Start Page: 904
End Page: 914
Language: English
PUBMED: 10673534
PROVIDER: scopus
Notes: Export Date: 18 November 2015 -- Source: Scopus