Volociximab, a Chimeric Monoclonal Antibody that Specifically Binds α5β1 Integrin: A Phase I, Pharmacokinetic, and Biological Correlative Study

Abstract

Purpose This study aimed to assess the safety and feasibility of administering volociximab, a chimeric monoclonal antibody that specifically binds to α5β1 integrin, and to determine the pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. Experimental Design Patients with advanced solid malignancies were treated with escalating doses of volociximab i.v. administered over 60 minutes. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human antichimeric antibody formation, and determine the saturation of α5β1 sites on peripheral blood monocytes. Results Twenty-one patients received 223 infusions of volociximab at doses ranging from 0.5 to 15 mg/kg i.v. on days 1, 15, 22, 29, and 36; and weekly thereafter. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. Mild (grade 1 or 2), reversible fatigue was the principal toxicity of volociximab at the highest dose levels of 10 and 15 mg/kg. Nausea, fever, anorexia, headache, vomiting, and myalgias were mild and infrequent, and there was no hematologic toxicity. Volociximab had biexponential distribution; clearance was inversely related to increasing dose, and the half-life at 15 mg/kg was estimated as being 30 days. Three patients tested positive for anti-volociximab antibodies. Saturation of monocyte α5β1 integrin sites was dose-dependent up to 15 mg/kg. There was one minor response (renal, 7 months) and one durable stable disease (melanoma, 14 months). Conclusions Volociximab can be safely administered at 15 mg/kg i.v. per week. The absence of severe toxicities and preliminary activity at the highest dose level warrants further disease-directed studies.

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

“…The a5b1monoclonal antibody volociximab has been in clinical trials but was abandoned in the absence of discernible clinical efficacy in a range of solid tumors, both as single agent and in combination with cytotoxic chemotherapy. [21][22][23][24] Only a few patients with prostate cancer were included in these studies and the data are insufficient to draw conclusions.…”

Integrins as therapeutic targets: lessons and opportunities

“…Volociximab is an anti-α 5 antibody under development for solid tumours [69][70] . Recent evidence suggests that inhibition of both α V β 3 and α 5 β 1 may be required for optimum effects on angiogenesis 71 .…”

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

“…Of note, phase I studies in advanced solid tumor patients with each of these MAbs confirmed their overall safety and lack of "class-associated" toxicities; in fact, a maximal tolerated dose (MTD) could not be identified in any of these dose-escalation trials. In addition, evidence of anti-tumor activity was observed despite the dose escalation study design [76][77][78].…”