Pharmacodynamic (phase 0) study using etaracizumab in advanced melanoma.
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.
Moschos
Stergios J
SJ
University of Pittsburgh Cancer Institute, PA, USA.
Sander
Cindy A
CA
Wang
Wenjun
W
Reppert
Shelley L
SL
Drogowski
Laura M
LM
Jukic
Drazen M
DM
Rao
Uma N M
UN
Athanassiou
Charalambos
C
Buzoianu
Manuela
M
Mandic
Maja
M
Richman
Laura
L
McKinney
LuAnn
L
Leininger
Joel
J
Tice
David A
DA
Hammershaimb
Luz
L
Kirkwood
John M
JM
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
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