Tumor angiogenesis is a complex multistep process involving diverse processes that include inciting triggers associated with tumor proliferation and hypoxic stimuli, growth factor stimulation of receptors, endothelial cell proliferation, and both cell-cell and cell-extracellular matrix interactions. The α integrins are critical proteins that are involved in the regulation, proliferation, survival, and signaling functions of normal and tumor-associated endothelial cells and are distinct from vascular endothelial growth factor signaling pathway. Furthermore, integrins act in concert with vascular endothelial growth factor to regulate, orchestrate, and amplify angiogenesis through signaling events involved in endothelial cell migration, proliferation, invasion, and anoikis resistance (20
). Integrin-mediated signal transduction pathways regulate the endothelial cell cytoskeleton to coordinate the complex process of vascular morphogenesis and organize into multicellular tubes with functional lumens (5
). Fibronectin and its major receptor, α5
integrin, have a central role in this successful vascular development and therefore represent an attractive target for antiangiogenesis therapy in malignancies. Volociximab represents the first mAb in clinical development that specifically binds α5
The starting dose for this phase I study, 0.5 mg/kg, represented a very conservative dose and was based on the absence of homology of the target in humans from the preclinical models used for toxicology. In the current study no evidence of a DLT was observed despite a 30-fold increase in the doses evaluated, confirming the feasibility and safety of the dose range tested. A constellation of mild or modest non-hematologic adverse events were noted, which included fatigue, nausea, anorexia, fever, arthralgias, myalgias, and headache. Albeit α5
integrin is expressed on normal peripheral blood monocytes, there were no clinically apparent infectious complications associated with volociximab (23
Although volociximab is a chimeric antibody, hypersensitivity reactions were rare. Human antichimeric antibodies were detected in three patients, and only one patient experienced a modest hypersensitivity reaction. Based on these findings, routine premedication is unnecessary.
At the dose range examined in this study, volociximab showed nonlinear pharmacokinetic parameters consistent with a target-saturation effect. The estimates of volociximab CL declined with increasing doses. The target, α5
integrin, is expressed on normal peripheral blood monocytes, on the extracellular membrane of some tumor cells, as well as exposed within neovasculature (23
). As such, the process of binding and saturation of target sites seems to account for the increased CL at lower doses (24
). Consistent with these findings, the saturation of free α5
integrin sites on monocytes by volociximab was dose-dependent and was uniformly diminished to a mean value of <2% at the highest dose of 15 mg/kg. These results, taken together, may have important implications. Dose-reductions from the highest dose determined in this study may result in increased CL of volociximab, as well as incomplete saturation of all α5
integrin target sites.
The study was initially designed to estimate the pharmacokinetic parameters of volociximab by fitting individual data with a uniform sampling regimen for all subjects. However, a few subjects missed the last sample collection on days 81 as a result of disease progression or enrollment into the extension study. In addition, two subjects at the lower doses had insufficient samples to support the fitting of the individual data for pharmacokinetic parameter estimation. Therefore, data from all patients were pooled and analyzed using the mixed-effect modeling approach (17
). An attempt to fit the two-compartment pharmacokinetic model with both linear and nonlinear elimination to the data was unsuccessful, and the parameters associated with the nonlinear elimination were poorly estimated. Therefore, the results with a two-compartment linear pharmacokinetic model were reported. The final estimate value of V1
of volociximab closely resembles the plasma volume in humans, as is expected for a high molecular weight protein and consistent with the values reported for other therapeutic chimeric mAb (25
). The mean terminal t1/2
of volociximab was ~30 days for subjects in the 10- and 15-mg/kg dose group and is consistent with the t1/2
of natural IgG4 in humans (18
). The dose-dependent CL values suggest that the nonlinear pharmacokinetic of volociximab is probably due to a saturated receptor-mediated CL mechanism; and also due to a human antichimeric antibody–mediated clearance pathway, because the three patients with high CL values in the lower-dose groups tested positive for human antichimeric antibodies (17
Preliminary but encouraging activity was seen in two patients in the 15-mg/kg group. One patient with renal cell carcinoma refractory to sunitinib had a reduction in the size of pulmonary lesions and remained on study for 7 months, and a patient with visceral metastases from melanoma had durable stable disease for 14 months. The appearance of durable stable disease is intriguing. In contrast to most tumor cells, α5
integrin is expressed on the surface of some melanoma tumor cells (27
). The durable stable disease may be, at least in part, the result of direct action of volociximab on tumor cells, in addition to the intended antiangiogenesis effect.
In conclusion, volociximab can be safely administered to patients with advanced malignancies with doses of up to 15 mg/kg weekly for prolonged periods. To fully evaluate the role of volociximab in anticancer therapy, either as a single agent, in combination with chemotherapy, or with other antiangiogenesis inhibitors, additional disease-directed studies should be undertaken.