Assessment of the biological and pharmacological effects of the ανβ3 and ανβ5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors

Abstract

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.

Integrin αvβ3‐targeted cancer therapy

“…[Jain, 2005]. [Color figure can be viewed in the online version] [Delbaldo et al, 2008;Patel et al, 2001;Posey et al, 2001] Phase II [Beekman et al, 2006;Colevas et al, 2004;Hariharan et al, 2007;MacDonald et al, 2008;Nabors et al, 2007;Raguse et al, 2004] ATN-161 Ac-PHSCN-NH 2 α 5 β 1 , α v β 3 Phase II [Cianfrocca et al, 2006;Donate et al, 2008] …”

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

“…Results from a number of clinical trials reveal consistent pharmacokinetic measures [42,44,[83][84][85].…”

“…Phase I studies of cilengitide monotherapy among adult solid tumor and GBM patients did not identify dose dependent or dose-limiting toxicity despite wide dosing ranges of cilengitide tested (up to 2400 mg/m 2 which approximates 4000 mg twice weekly) [42,44,85]. Furthermore, no consistent toxicities have been observed in additional phase II studies [9,43,83,85,101,102]. Among all adverse events reported, regardless of causality, among patients treated with cilengitide, the most common observed nonhematologic toxicities include fatigue, nausea, dyspnea, headache, peripheral edema, diarrhea, constipation and anorexia.…”

“…Novel endpoints incorporating correlative assessments to determine biological activity were evaluated in a second phase I study in advanced solid tumor patients [83]. In this study cilengitide was again administered twice weekly as a 1-hour infusion beginning at a dose level of 120 mg/m 2 .…”

Acute Depletion of Endothelial β3-Integrin Transiently Inhibits Tumor Growth and Angiogenesis in Mice

“…This is a goal worth pursuing. Unlike current Food and Drug Administrationapproved antiangiogenic drugs, αvβ3-integrin antagonists seem to be well tolerated, 46 likely because of the fact that the vascular expression of αvβ3-integrin is restricted to neoangiogenic vessels. In contrast, the targets of other antiangiogenic drugs are expressed in nearly all adult vascular endothelial cells, 47 and these drugs (especially those with broadspectrum activity) are linked with significant side effects, such as renal toxicity, bleeding, arterial thromboembolic events, wound healing complications, and gastrointestinal perforation, as well as vessel regression in several healthy tissues.…”