TY - JOUR
T1 - Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer
AU - Shin, Dong M.
AU - Perez-Soler, Roman
AU - Zhang, Peter
AU - Lawhorn, Kristie
AU - Khuri, Fadlo R.
AU - Glisson, Bonnie S.
AU - Hong, Waun Ki
AU - Donato, Nicholas J.
AU - Wu, Ji Y.
AU - Shin, Hyung Ju C.
AU - Myers, Jeffrey
AU - Clayman, Gary
AU - Mendelsohn, John
AU - Pfister, David
AU - Falcey, John
AU - Waksal, Harlan
PY - 2001
Y1 - 2001
N2 - C225, a human-mouse chimerized monoclonal antibody directed against the epidermal growth factor receptor (EGFr), has a synergistic effect with cisplatin in xenograft models. To determine the tumor EGFr saturation dose with C225 and the fate of infused C225, we conducted a Phase Ib study with C225 in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck. Using tumor samples, we assessed tumor EGFr saturation by antibody using immunohistochemistry studies, the EGFr tyrosine kinase assay, and detection of the EGFr/C225 complex formation by immunoblot. Potential candidates were screened for EGFr expression in their tumors, and 12 patients who had high levels of EGFr expression and tumors easily accessible for repeated biopsies (pretherapy, 24 h after first C225 infusion, 24 h before third C225 infusion) were entered at three different dose levels of C225 with a fixed dose of cisplatin. The median value of tumor EGFr saturation increased to 95% at the higher dose levels. EGFr tyrosine kinase activity was significantly reduced after C225 infusion, and EGFr/C225 complexes were also detected at higher doses of C225. The loading dose of C225 at 400 mg/m2 with a maintenance dose at 250 mg/m2 achieved a high percentage of saturation of EGFr in tumor tissue, and these doses were recommended for Phases H or HI clinical trials. Six (67%) of nine evaluable patients achieved major responses, including two (22%) complete responses. Mild to moderate degrees of allergic reaction and folliculitis-like skin reactions were demonstrated. We conclude that infused C225 binds and significantly saturates tumor EGFr, which may render a high degree of antitumor activity, and provides a novel mechanism for targeting cancer therapy for patients who have EGFr expression in their tumors.
AB - C225, a human-mouse chimerized monoclonal antibody directed against the epidermal growth factor receptor (EGFr), has a synergistic effect with cisplatin in xenograft models. To determine the tumor EGFr saturation dose with C225 and the fate of infused C225, we conducted a Phase Ib study with C225 in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck. Using tumor samples, we assessed tumor EGFr saturation by antibody using immunohistochemistry studies, the EGFr tyrosine kinase assay, and detection of the EGFr/C225 complex formation by immunoblot. Potential candidates were screened for EGFr expression in their tumors, and 12 patients who had high levels of EGFr expression and tumors easily accessible for repeated biopsies (pretherapy, 24 h after first C225 infusion, 24 h before third C225 infusion) were entered at three different dose levels of C225 with a fixed dose of cisplatin. The median value of tumor EGFr saturation increased to 95% at the higher dose levels. EGFr tyrosine kinase activity was significantly reduced after C225 infusion, and EGFr/C225 complexes were also detected at higher doses of C225. The loading dose of C225 at 400 mg/m2 with a maintenance dose at 250 mg/m2 achieved a high percentage of saturation of EGFr in tumor tissue, and these doses were recommended for Phases H or HI clinical trials. Six (67%) of nine evaluable patients achieved major responses, including two (22%) complete responses. Mild to moderate degrees of allergic reaction and folliculitis-like skin reactions were demonstrated. We conclude that infused C225 binds and significantly saturates tumor EGFr, which may render a high degree of antitumor activity, and provides a novel mechanism for targeting cancer therapy for patients who have EGFr expression in their tumors.
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M3 - Article
C2 - 11350885
AN - SCOPUS:0034895886
SN - 1078-0432
VL - 7
SP - 1204
EP - 1213
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -