Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors.
BACKGROUND
Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose.


METHODS
The doses of cilengitide were 600 or 1200 mg/m(2) as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate.


RESULTS
Twenty patients received 50 courses of cilengitide with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and endothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity.


CONCLUSIONS
Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays.
Hariharan
S
S
University of Colorado Cancer Center, Aurora, CO 80045, USA.
Gustafson
D
D
Holden
S
S
McConkey
D
D
Davis
D
D
Morrow
M
M
Basche
M
M
Gore
L
L
Zang
C
C
O'Bryant
C L
CL
Baron
A
A
Gallemann
D
D
Colevas
D
D
Eckhardt
S G
SG
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000097:blood / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D039302:Integrin alphaVbeta3 / Q000627:therapeutic use*; D016023:Integrins / Q000627:therapeutic use*; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D019030:Receptors, Vitronectin / Q000627:therapeutic use*; D012910:Snake Venoms / Q000493:pharmacokinetics / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D015815:Cell Adhesion Molecules; D039302:Integrin alphaVbeta3; D016023:Integrins; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide