title: Pharmacodynamic (phase 0) study using etaracizumab in advanced melanoma.
abstract: 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.
authors.affiliation: University of Pittsburgh Cancer Institute, PA, USA.
authors.forename: Stergios J
authors.initials: SJ
authors.lastname: Moschos
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Sander
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wang
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Reppert
authors.forename: Laura M
authors.initials: LM
authors.lastname: Drogowski
authors.forename: Drazen M
authors.initials: DM
authors.lastname: Jukic
authors.forename: Uma N M
authors.initials: UN
authors.lastname: Rao
authors.forename: Charalambos
authors.initials: C
authors.lastname: Athanassiou
authors.forename: Manuela
authors.initials: M
authors.lastname: Buzoianu
authors.forename: Maja
authors.initials: M
authors.lastname: Mandic
authors.forename: Laura
authors.initials: L
authors.lastname: Richman
authors.forename: LuAnn
authors.initials: L
authors.lastname: McKinney
authors.forename: Joel
authors.initials: J
authors.lastname: Leininger
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
authors.forename: Luz
authors.initials: L
authors.lastname: Hammershaimb
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000097:blood; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000276:immunology; D019394:Ki-67 Antigen / Q000097:blood; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016019:Survival Analysis; D013610:Tachycardia / Q000139:chemically induced; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D039302:Integrin alphaVbeta3; D019394:Ki-67 Antigen; D042461:Vascular Endothelial Growth Factor A; C112567:etaracizumab