Pharmacodynamic (Phase 0) Study Using Etaracizumab in Advanced Melanoma
| Autor: | Manuela Buzoianu, David A. Tice, Wenjun Wang, Uma N. M. Rao, John M. Kirkwood, Drazen M. Jukic, Stergios J. Moschos, LuAnn McKinney, Laura M Drogowski, Charalambos N. Athanassiou, Laura K. Richman, Shelley L. Reppert, Joel Leininger, Cindy Sander, Maja Mandic, Luz Hammershaimb |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Vascular Endothelial Growth Factor A Cancer Research Pathology medicine.medical_specialty Time Factors Angiogenesis medicine.medical_treatment Immunology Pharmacology Antibodies Monoclonal Humanized Cohort Studies Etaracizumab Tachycardia Biomarkers Tumor medicine Humans Immunology and Allergy Neoplasm Metastasis Melanoma Aged Aged 80 and over Dose-Response Relationship Drug business.industry Antibodies Monoclonal Cancer Immunotherapy Middle Aged Integrin alphaVbeta3 medicine.disease Immunohistochemistry Survival Analysis Vascular endothelial growth factor A Ki-67 Antigen Treatment Outcome Pharmacodynamics Female business Follow-Up Studies medicine.drug |
| Zdroj: | Journal of Immunotherapy. 33:316-325 |
| ISSN: | 1524-9557 |
| Popis: | AlphaVbeta3 (alphavbeta3) is an important molecule for tumor-induced angiogenesis and is upregulated in metastatic melanoma (MM). We proposed to study the mechanism of action of etaracizumab, a monoclonal antibody targeting alphavbeta3, in MM. Patients with MM and biopsiable tumor were treated with etaracizumab in 3 dose cohorts starting from 8 mg/kg. Tumor saturation by etaracizumab using LM609 immunohistochemical staining of tumor sections was the primary endpoint. Subsequent dose cohorts were defined based on the tumor saturation by etaracizumab. Secondary end points were analysis of clinical benefit and changes from baseline of several tumor and peripheral blood biomarkers. Eighteen patients were enrolled at 3 dose levels. Etaracizumab showed better melanoma cell saturation at the 8mg/kg and 1 mg/kg dose compared with the 4 mg/kg dose and better vascular endothelial cell saturation at 8 mg/kg compared with lower dose groups. Etaracizumab demonstrated an acceptable safety profile. The optimal biologic dose out of those selected for investigation was 8 mg/kg. Patients treated at the highest dose may have had better clinical benefit secondary to suppression of the activated immediate downstream effector of alphavbeta3 signaling, FAK, in melanoma cells, but this alone did not ultimately affect melanoma cell proliferation or apoptosis. No apparent antiangiogenic or immunomodulatory effects of etaracizumab were noted. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|