A dose-escalation phase I trial of nimotuzumab, an antibody against the epidermal growth factor receptor, in patients with advanced solid malignancies

• Published in: Investigational new drugs 2011-10, Vol.29 (5), p.996-1003
• Main Authors: You, Benoit, Brade, Anthony, Magalhaes, Joao M., Siu, Lillian L., Oza, Amit, Lovell, Sonya, Wang, Lisa, Hedley, David W., Nicacio, Leonardo V., Chen, Eric X.
• Format: Article
• Language: English
• Subjects: Aged; Antibodies; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - metabolism; Biopsy; Cancer therapies; Clinical trials; Disease Progression; Dose-Response Relationship, Drug; Drug dosages; Epidermal growth factor; Female; Glioma; Granulocytes; Growth factors; Health care networks; Hematology; Hospitals; Humans; Kaplan-Meier Estimate; Kinases; Ligands; Male; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Monoclonal antibodies; Neoplasm Staging; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - pathology; Oncology; Patients; Pharmacodynamics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Studies; Time Factors; Toxicity; Treatment Outcome; Tumors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-010-9444-0

Summary Purpose : N imotuzumab is a humanized monoclonal antibody which inhibits the ligand-dependent activation of epidermal growth factor receptor (EGFR). We conducted a phase I trial to assess the pharmacodynamic (PD) effects of escalating doses of nimotuzumab administered alone in patients with advanced solid cancers patients. Experimental design : Patients were treated with escalating doses of weekly intravenous nimotuzumab at doses ranging between 100 and 800 mg. Tumor and skin biopsies were done before start of treatment and repeated 3 weeks after to assess immunohistochemical expression of EGFR and its downstream components. Results : Seventeen patients were enrolled, including 1 patient never treated. Although 1 dose-limiting-toxicity (DLT) was observed at 100 mg (grade 3 fatigue), nimotuzumab dose was escalated to 800 mg with no other DLT. No grade 4 toxicity was observed. Only 3 patients developed a grade 1 acneiform rash (18.7%). One patient achieved a partial response (6.2%) and 8 patients had stable disease (50.0%). The median TTP was 2.4 months. No significant changes in EGFR, AKT, ERK and Ki67 immuno-stainings were observed between pre- and on-treatment tumor or skin biopsies. Conclusion : Nimotuzumab could be safety administered up to 800 mg with manageable toxicity. No relationships were found between pharmacodynamic effects on EGFR downstream signaling pathways and drug efficacy or toxicity.